Cancers

2024

Jump to: 2021, 2020, 2019

12 pages, 1812 KiB

Open AccessArticle

Colocalised Genetic Associations Reveal Alternative Splicing Variants as Candidate Causal Links for Breast Cancer Risk in 10 Loci

by André Besouro-Duarte, Beatriz Carrasqueiro, Sofia Sousa, Joana M. Xavier and Ana-Teresa Maia

Cancers 2024, 16(17), 3020; https://doi.org/10.3390/cancers16173020 - 29 Aug 2024

Viewed by 760

Abstract

Genome-wide association studies (GWASs) have revealed numerous loci associated with breast cancer risk, yet the precise causal variants, their impact on molecular mechanisms, and the affected genes often remain elusive. We hypothesised that specific variants exert their influence by affecting cis-regulatory alternative splice [...] Read more.

Genome-wide association studies (GWASs) have revealed numerous loci associated with breast cancer risk, yet the precise causal variants, their impact on molecular mechanisms, and the affected genes often remain elusive. We hypothesised that specific variants exert their influence by affecting cis-regulatory alternative splice elements. An analysis of splicing quantitative trait loci (sQTL) in healthy breast tissue from female individuals identified multiple variants linked to alterations in splicing ratios. Through colocalisation analysis, we pinpointed 43 variants within twelve genes that serve as candidate causal links between sQTL and GWAS findings. In silico splice analysis highlighted a potential mechanism for three genes—FDPS, SGCE, and MRPL11—where variants in proximity to or on the splice site modulate usage, resulting in alternative splice transcripts. Further in vitro/vivo studies are imperative to fully understand how these identified changes contribute to breast oncogenesis. Moreover, investigating their potential as biomarkers for breast cancer risk could enhance screening strategies and early detection methods for breast cancer. Full article

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2021

Jump to: 2024, 2020, 2019

16 pages, 2250 KiB

Open AccessArticle

Expression of Endogenous Retroviral RNA in Prostate Tumors has Prognostic Value and Shows Differences among Americans of African Versus European/Middle Eastern Ancestry

by Vinay Kumar, Michael McClelland, James Nguyen, Gabriela De Robles, Michael Ittmann, Patricia Castro, Dan Mercola, Zhenyu Jia and Farah Rahmatpanah

Cancers 2021, 13(24), 6347; https://doi.org/10.3390/cancers13246347 - 17 Dec 2021

Cited by 4 | Viewed by 3758

Abstract

Endogenous retroviruses (ERVs) are abundant, repetitive elements dispersed across the human genome and are implicated in various diseases. We investigated two potential roles for ERVs in prostate cancer (PCa). First, the PCa of Black Americans (BA) is diagnosed at an earlier median age [...] Read more.

Endogenous retroviruses (ERVs) are abundant, repetitive elements dispersed across the human genome and are implicated in various diseases. We investigated two potential roles for ERVs in prostate cancer (PCa). First, the PCa of Black Americans (BA) is diagnosed at an earlier median age and at a more advanced stage than the PCa of White Americans (WA). We used publicly available RNA-seq data from tumor-enriched samples of 27 BA and 65 WA PCa patients in order to identify 12 differentially expressed ERVs (p_adj < 0.1) and used a tissue microarray of the PCa cores from an independent set of BA and WA patients to validate the differential protein expression of one of these ERVs, ERV3-1 (p = 2.829 × 10⁻⁷). Second, we used 57 PCa tumors from patients of all ancestries from one hospital as a training set to identify the ERVs associated with time to biochemical relapse. A 29-ERV prognostic panel was then tested and validated on 35 separate PCa tumors from patients obtained in two different hospitals with a dramatic increase in prognostic power relative to clinical parameters alone (p = 7.4 × 10⁻¹¹). In summary, ERV RNA expression differences in the prostate tumors of patients of different ancestries may be associated with dissimilarities in the mechanism of cancer progression. In addition, the correlation of expression of certain ERVs in prostate tumors with the risk of biochemical relapse indicates a possible role for ERV expression in cancer progression. Full article

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22 pages, 2392 KiB

Open AccessReview

Long Non-Coding RNA (lncRNA) in Oral Squamous Cell Carcinoma: Biological Function and Clinical Application

by Jianfei Tang, Xiaodan Fang, Juan Chen, Haixia Zhang and Zhangui Tang

Cancers 2021, 13(23), 5944; https://doi.org/10.3390/cancers13235944 - 26 Nov 2021

Cited by 28 | Viewed by 3959

Abstract

Oral squamous cell carcinoma (OSCC) is a type of malignancy with high mortality, leading to poor prognosis worldwide. However, the molecular mechanisms underlying OSCC carcinogenesis have not been fully understood. Recently, the discovery and characterization of long non-coding RNAs (lncRNAs) have revealed their [...] Read more.

Oral squamous cell carcinoma (OSCC) is a type of malignancy with high mortality, leading to poor prognosis worldwide. However, the molecular mechanisms underlying OSCC carcinogenesis have not been fully understood. Recently, the discovery and characterization of long non-coding RNAs (lncRNAs) have revealed their regulatory importance in OSCC. Abnormal expression of lncRNAs has been broadly implicated in the initiation and progress of tumors. In this review, we summarize the functions and molecular mechanisms regarding these lncRNAs in OSCC. In addition, we highlight the crosstalk between lncRNA and tumor microenvironment (TME), and discuss the potential applications of lncRNAs as diagnostic and prognostic tools and therapeutic targets in OSCC. Notably, we also discuss lncRNA-targeted therapeutic techniques including CRISPR-Cas9 as well as immune checkpoint therapies to target lncRNA and the PD-1/PD-L1 axis. Therefore, this review presents the future perspectives of lncRNAs in OSCC therapy, but more research is needed to allow the applications of these findings to the clinic. Full article

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17 pages, 1829 KiB

Open AccessReview

The lncRNAs in HBV-Related HCCs: Targeting Chromatin Dynamics and Beyond

by Vincenzo Alfano, Mirjam B. Zeisel, Massimo Levrero and Francesca Guerrieri

Cancers 2021, 13(13), 3115; https://doi.org/10.3390/cancers13133115 - 22 Jun 2021

Cited by 8 | Viewed by 3276

Abstract

Hepatocellular carcinoma (HCC) represents the fourth leading and fastest rising cause of cancer death (841,000 new cases and 782,000 deaths annually), and hepatitis B (HBV), with 250 million people chronically infected at risk of developing HCC, accounts for >50% of the cases worldwide. [...] Read more.

Hepatocellular carcinoma (HCC) represents the fourth leading and fastest rising cause of cancer death (841,000 new cases and 782,000 deaths annually), and hepatitis B (HBV), with 250 million people chronically infected at risk of developing HCC, accounts for >50% of the cases worldwide. Long non-coding RNAs (lncRNAs), untranslated transcripts longer than 200 nucleotides, are implicated in gene regulation at the transcriptional and post-transcriptional levels, exerting their activities both in the nuclear and cytoplasmic compartments. Thanks to high-throughput sequencing techniques, several lncRNAs have been shown to favor the establishment of chronic HBV infection, to change the host transcriptome to establish a pro-carcinogenic environment, and to directly participate in HCC development and progression. In this review, we summarize current knowledge on the role of lncRNAs in HBV infection and HBV-related liver carcinogenesis and discuss the potential of lncRNAs as predictive or diagnostic biomarkers. Full article

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23 pages, 1509 KiB

Open AccessReview

Long Intergenic Non-Coding RNAs in HNSCC: From “Junk DNA” to Important Prognostic Factor

by Joanna Kozłowska, Tomasz Kolenda, Paulina Poter, Joanna Sobocińska, Kacper Guglas, Maciej Stasiak, Renata Bliźniak, Anna Teresiak and Katarzyna Lamperska

Cancers 2021, 13(12), 2949; https://doi.org/10.3390/cancers13122949 - 12 Jun 2021

Cited by 23 | Viewed by 4656

Abstract

Head and neck squamous cell carcinoma is one of the most common and fatal cancers worldwide. Even a multimodal approach consisting of standard chemo- and radiotherapy along with surgical resection is only effective in approximately 50% of the cases. The rest of the [...] Read more.

Head and neck squamous cell carcinoma is one of the most common and fatal cancers worldwide. Even a multimodal approach consisting of standard chemo- and radiotherapy along with surgical resection is only effective in approximately 50% of the cases. The rest of the patients develop a relapse of the disease and acquire resistance to treatment. Especially this group of individuals needs novel, personalized, targeted therapy. The first step to discovering such solutions is to investigate the tumor microenvironment, thus understanding the role and mechanism of the function of coding and non-coding sequences of the human genome. In recent years, RNA molecules gained great interest when the complex character of their impact on our biology allowed them to come out of the shadows of the “junk DNA” label. Furthermore, long non-coding RNAs (lncRNA), specifically the intergenic subgroup (lincRNA), are one of the most aberrantly expressed in several malignancies, which makes them particularly promising future diagnostic biomarkers and therapeutic targets. This review contains characteristics of known and validated lincRNAs in HNSCC, such as XIST, MALAT, HOTAIR, HOTTIP, lincRNA-p21, LINC02487, LINC02195, LINC00668, LINC00519, LINC00511, LINC00460, LINC00312, and LINC00052, with a description of their prognostic abilities. Even though much work remains to be done, lincRNAs are important factors in cancer biology that will become valuable biomarkers of tumor stage, outcome prognosis, and contribution to personalized medicine. Full article

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22 pages, 3576 KiB

Open AccessArticle

MicroRNAs Deregulated in Intraductal Papillary Mucinous Neoplasm Converge on Actin Cytoskeleton-Related Pathways That Are Maintained in Pancreatic Ductal Adenocarcinoma

by Elena Fernandez-Castañer, Maria Vila-Casadesus, Elena Vila-Navarro, Carolina Parra, Juan Jose Lozano, Antoni Castells and Meritxell Gironella

Cancers 2021, 13(10), 2369; https://doi.org/10.3390/cancers13102369 - 14 May 2021

Viewed by 2985

Abstract

Intraductal papillary mucinous neoplasms (IPMN) are pancreatic cystic lesions that can develop into pancreatic ductal adenocarcinoma (PDAC). Although there is an increasing incidence of IPMN diagnosis, the mechanisms of formation and progression into invasive cancer remain unclear. MicroRNAs (miRNAs) are small non-coding RNAs, [...] Read more.

Intraductal papillary mucinous neoplasms (IPMN) are pancreatic cystic lesions that can develop into pancreatic ductal adenocarcinoma (PDAC). Although there is an increasing incidence of IPMN diagnosis, the mechanisms of formation and progression into invasive cancer remain unclear. MicroRNAs (miRNAs) are small non-coding RNAs, repressors of mRNA translation, and promising diagnostic biomarkers for IPMN and PDAC. Functional information on the role of early-altered miRNAs in this setting would offer novel strategies for tracking the IPMN-to-PDAC progression. In order to detect mRNAs that are likely to be under miRNA regulation in IPMNs, whole transcriptome and miRNome data from normal pancreatic tissue (n = 3) and IPMN lesions (n = 4) were combined and filtered according to negative correlation and miRNA-target prediction databases by using miRComb R package. Further comparison analysis with PDAC data allowed us to obtain a subset of miRNA-mRNA pairs shared in IPMN and PDAC. Functional enrichment analysis unravelled processes that are mainly related with cell structure, actin cytoskeleton, and metabolism. MiR-181a appeared as a master regulator of these processes. The expression of selected miRNA-mRNA pairs was validated by qRT-PCR in an independent cohort of patients (n = 40), and then analysed in different pancreatic cell lines. Finally, we generated a cellular model of HPDE cells stably overexpressing miR-181a, which showed a significant alteration of actin cytoskeleton structures accompanied by a significant downregulation of EPB41L4B and SEL1L expression. In situ hybridization of miR-181a and immunohistochemistry of EPB41L4B and SEL1L in pancreatic tissues (n = 4 Healthy; n = 3 IPMN; n = 4 PDAC) were also carried out. In this study, we offer insights on the potential implication of miRNA alteration in the regulation of structural and metabolic changes that pancreatic cells experience during IPMN establishment and that are maintained in PDAC. Full article

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45 pages, 1465 KiB

Open AccessReview

Epigenetic Regulation of MicroRNA Clusters and Families during Tumor Development

by Jana Gregorova, Petra Vychytilova-Faltejskova and Sabina Sevcikova

Cancers 2021, 13(6), 1333; https://doi.org/10.3390/cancers13061333 - 16 Mar 2021

Cited by 29 | Viewed by 5131

Abstract

MicroRNAs are small non-coding single-stranded RNA molecules regulating gene expression on a post-transcriptional level based on the seed sequence similarity. They are frequently clustered; thus, they are either simultaneously transcribed into a single polycistronic transcript or they may be transcribed independently. Importantly, microRNA [...] Read more.

MicroRNAs are small non-coding single-stranded RNA molecules regulating gene expression on a post-transcriptional level based on the seed sequence similarity. They are frequently clustered; thus, they are either simultaneously transcribed into a single polycistronic transcript or they may be transcribed independently. Importantly, microRNA families that contain the same seed region and thus target related signaling proteins, may be localized in one or more clusters, which are in a close relationship. MicroRNAs are involved in basic physiological processes, and their deregulation is associated with the origin of various pathologies, including solid tumors or hematologic malignancies. Recently, the interplay between the expression of microRNA clusters and families and epigenetic machinery was described, indicating aberrant DNA methylation or histone modifications as major mechanisms responsible for microRNA deregulation during cancerogenesis. In this review, the most studied microRNA clusters and families affected by hyper- or hypomethylation as well as by histone modifications are presented with the focus on particular mechanisms. Finally, the diagnostic and prognostic potential of microRNA clusters and families is discussed together with technologies currently used for epigenetic-based cancer therapies. Full article

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34 pages, 1520 KiB

Open AccessSystematic Review

MicroRNA as Epigenetic Modifiers in Endometrial Cancer: A Systematic Review

by Amélia Favier, Grégoire Rocher, Annette K. Larsen, Romain Delangle, Catherine Uzan, Michèle Sabbah, Mathieu Castela, Alex Duval, Céline Mehats and Geoffroy Canlorbe

Cancers 2021, 13(5), 1137; https://doi.org/10.3390/cancers13051137 - 6 Mar 2021

Cited by 19 | Viewed by 4882

Abstract

The objective of this systematic review is to summarize our current knowledge on the influence of miRNAs in the epigenetic deregulation of tumor-related genes in endometrial cancer (EC). We conducted a literature search on the role of miRNAs in the epigenetic regulation of [...] Read more.

The objective of this systematic review is to summarize our current knowledge on the influence of miRNAs in the epigenetic deregulation of tumor-related genes in endometrial cancer (EC). We conducted a literature search on the role of miRNAs in the epigenetic regulation of EC applying the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The following terms were used: microRNA, miRNA, miR, endometrial cancer, endometrium, epigenetic, epimutation, hypermethylation, lynch, deacetylase, DICER, novel biomarker, histone, chromatin. The miRNAs were classified and are presented according to their function (tumor suppressor or onco-miRNA), their targets (when known), their expression levels in EC tissue vs the normal surrounding tissue, and the degree of DNA methylation in miRNA loci and CpG sites. Data were collected from 201 articles, including 190 original articles, published between November 1, 2008 and September 30, 2020 identifying 313 different miRNAs implicated in epigenetic regulation of EC. Overall, we identified a total of 148 miRNAs with decreased expression in EC, 140 miRNAs with increased expression in EC, and 22 miRNAs with discordant expression levels. The literature implicated different epigenetic phenomena including altered miRNA expression levels (miR-182, -230), changes in the methylation of miRNA loci (miR-34b, -129-2, -130a/b, -152, -200b, -625) and increased/decreased methylation of target genes (miR-30d,-191). This work provides an overview of all miRNAs reported to be involved in epigenetic regulation in EC including DNA methylation and RNA-associated silencing. These findings may contribute to novel strategies in diagnosis, risk assessment, and treatments aimed at miRNAs, their target genes or DNA methylation. Full article

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24 pages, 17392 KiB

Open AccessArticle

Integrative Transcriptomic Network Analysis of Butyrate Treated Colorectal Cancer Cells

by Saira R. Ali, Ayla Orang, Shashikanth Marri, Ross A. McKinnon, Robyn Meech and Michael Z. Michael

Cancers 2021, 13(4), 636; https://doi.org/10.3390/cancers13040636 - 5 Feb 2021

Cited by 13 | Viewed by 2687

Abstract

Diet-derived histone deacetylase inhibitor (HDACi), butyrate, alters global acetylation and consequently global gene expression in colorectal cancer (CRC) cells to exert its anticancer effects. Aberrant microRNA (miRNA) expression contributes to CRC development and progression. Butyrate-mediated modulation of microRNA (miRNA) expression remains under-investigated. This [...] Read more.

Diet-derived histone deacetylase inhibitor (HDACi), butyrate, alters global acetylation and consequently global gene expression in colorectal cancer (CRC) cells to exert its anticancer effects. Aberrant microRNA (miRNA) expression contributes to CRC development and progression. Butyrate-mediated modulation of microRNA (miRNA) expression remains under-investigated. This study employed a systems biology approach to gain a comprehensive understanding of the complex miRNA-mRNA interactions contributing to the butyrate response in CRC cells. Next-generation sequencing, gene ontology (GO) and pathway enrichment analyses were utilized to reveal the extent of butyrate-mediated gene regulation in CRC cells. Changes in cell proliferation, apoptosis, the cell cycle and gene expression induced by miRNAs and target gene knockdown in CRC cells were assessed. Butyrate induced differential expression of 113 miRNAs and 2447 protein-coding genes in HCT116 cells. Butyrate also altered transcript splicing of 1589 protein-coding genes. GO, and pathway enrichment analyses revealed the cell cycle to be a central target of the butyrate response. Two butyrate-induced miRNAs, miR-139 and miR-542, acted cooperatively with butyrate to induce apoptosis and reduce CRC cell proliferation by regulating target genes, including cell cycle-related EIF4G2 and BIRC5. EIF4G2 RNA interference mimicked the miR-139-mediated reduction in cell proliferation. The cell cycle is a critical pathway involved in the butyrate response of CRC cells. These findings reveal novel roles for miRNAs in the cell cycle-related, anticancer effects of butyrate in CRC cells. Full article

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29 pages, 1354 KiB

Open AccessReview

MicroRNAs in the Pathogenesis of Hepatocellular Carcinoma: A Review

by Asahiro Morishita, Kyoko Oura, Tomoko Tadokoro, Koji Fujita, Joji Tani and Tsutomu Masaki

Cancers 2021, 13(3), 514; https://doi.org/10.3390/cancers13030514 - 29 Jan 2021

Cited by 72 | Viewed by 5290

Abstract

Hepatocellular carcinoma (HCC) is the seventh most frequent cancer and the fourth leading cause of cancer mortality worldwide. Despite substantial advances in therapeutic strategies, the prognosis of late-stage HCC remains dismal because of the high recurrence rate. A better understanding of the etiology [...] Read more.

Hepatocellular carcinoma (HCC) is the seventh most frequent cancer and the fourth leading cause of cancer mortality worldwide. Despite substantial advances in therapeutic strategies, the prognosis of late-stage HCC remains dismal because of the high recurrence rate. A better understanding of the etiology of HCC is therefore necessary to improve outcomes. MicroRNAs (miRNAs) are small, endogenous, noncoding, single-stranded RNAs that modulate the expression of their target genes at the posttranscriptional and translational levels. Aberrant expression of miRNAs has frequently been detected in cancer-associated genomic regions or fragile sites in various human cancers and has been observed in both HCC cells and tissues. The precise patterns of aberrant miRNA expression differ depending on disease etiology, including various causes of hepatocarcinogenesis, such as viral hepatitis, alcoholic liver disease, or nonalcoholic steatohepatitis. However, little is known about the underlying mechanisms and the association of miRNAs with the pathogenesis of HCC of various etiologies. In the present review, we summarize the key mechanisms of miRNAs in the pathogenesis of HCC and emphasize their potential utility as valuable diagnostic and prognostic biomarkers, as well as innovative therapeutic targets, in HCC diagnosis and treatment. Full article

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2020

Jump to: 2024, 2021, 2019

32 pages, 840 KiB

Open AccessFeature PaperReview

Non-Coding RNAs as Mediators of Epigenetic Changes in Malignancies

by Subhasree Kumar, Edward A. Gonzalez, Pranela Rameshwar and Jean-Pierre Etchegaray

Cancers 2020, 12(12), 3657; https://doi.org/10.3390/cancers12123657 - 5 Dec 2020

Cited by 74 | Viewed by 7357

Abstract

Non-coding RNAs (ncRNAs) are untranslated RNA molecules that regulate gene expressions. NcRNAs include small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), circular RNAs (cRNAs) and piwi-interacting RNAs (piRNAs). This review focuses on two types of ncRNAs: microRNAs [...] Read more.

Non-coding RNAs (ncRNAs) are untranslated RNA molecules that regulate gene expressions. NcRNAs include small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), circular RNAs (cRNAs) and piwi-interacting RNAs (piRNAs). This review focuses on two types of ncRNAs: microRNAs (miRNAs) or short interfering RNAs (siRNAs) and long non-coding RNAs (lncRNAs). We highlight the mechanisms by which miRNAs and lncRNAs impact the epigenome in the context of cancer. Both miRNAs and lncRNAs have the ability to interact with numerous epigenetic modifiers and transcription factors to influence gene expression. The aberrant expression of these ncRNAs is associated with the development and progression of tumors. The primary reason for their deregulated expression can be attributed to epigenetic alterations. Epigenetic alterations can cause the misregulation of ncRNAs. The experimental evidence indicated that most abnormally expressed ncRNAs impact cellular proliferation and apoptotic pathways, and such changes are cancer-dependent. In vitro and in vivo experiments show that, depending on the cancer type, either the upregulation or downregulation of ncRNAs can prevent the proliferation and progression of cancer. Therefore, a better understanding on how ncRNAs impact tumorigenesis could serve to develop new therapeutic treatments. Here, we review the involvement of ncRNAs in cancer epigenetics and highlight their use in clinical therapy. Full article

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29 pages, 1503 KiB

Open AccessReview

Modulatory Role of microRNAs in Triple Negative Breast Cancer with Basal-Like Phenotype

by Andrea Angius, Paolo Cossu-Rocca, Caterina Arru, Maria Rosaria Muroni, Vincenzo Rallo, Ciriaco Carru, Paolo Uva, Giovanna Pira, Sandra Orrù and Maria Rosaria De Miglio

Cancers 2020, 12(11), 3298; https://doi.org/10.3390/cancers12113298 - 7 Nov 2020

Cited by 22 | Viewed by 4621

Abstract

Development of new research, classification, and therapeutic options are urgently required due to the fact that TNBC is a heterogeneous malignancy. The expression of high molecular weight cytokeratins identifies a biologically and clinically distinct subgroup of TNBCs with a basal-like phenotype, representing about [...] Read more.

Development of new research, classification, and therapeutic options are urgently required due to the fact that TNBC is a heterogeneous malignancy. The expression of high molecular weight cytokeratins identifies a biologically and clinically distinct subgroup of TNBCs with a basal-like phenotype, representing about 75% of TNBCs, while the remaining 25% includes all other intrinsic subtypes. The triple negative phenotype in basal-like breast cancer (BLBC) makes it unresponsive to endocrine therapy, i.e., tamoxifen, aromatase inhibitors, and/or anti-HER2-targeted therapies; for this reason, only chemotherapy can be considered an approach available for systemic treatment even if it shows poor prognosis. Therefore, treatment for these subgroups of patients is a strong challenge for oncologists due to disease heterogeneity and the absence of unambiguous molecular targets. Dysregulation of the cellular miRNAome has been related to huge cellular process deregulations underlying human malignancy. Consequently, epigenetics is a field of great promise in cancer research. Increasing evidence suggests that specific miRNA clusters/signatures might be of clinical utility in TNBCs with basal-like phenotype. The epigenetic mechanisms behind tumorigenesis enable progress in the treatment, diagnosis, and prevention of cancer. This review intends to summarize the epigenetic findings related to miRNAome in TNBCs with basal-like phenotype. Full article

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32 pages, 1669 KiB

Open AccessReview

LncRNAs in Cancer: From garbage to Junk

by Marianna Aprile, Vicky Katopodi, Eleonora Leucci and Valerio Costa

Cancers 2020, 12(11), 3220; https://doi.org/10.3390/cancers12113220 - 31 Oct 2020

Cited by 44 | Viewed by 4955

Abstract

Sequencing-based transcriptomics has significantly redefined the concept of genome complexity, leading to the identification of thousands of lncRNA genes identification of thousands of lncRNA genes whose products possess transcriptional and/or post-transcriptional regulatory functions that help to shape cell functionality and fate. Indeed, it [...] Read more.

Sequencing-based transcriptomics has significantly redefined the concept of genome complexity, leading to the identification of thousands of lncRNA genes identification of thousands of lncRNA genes whose products possess transcriptional and/or post-transcriptional regulatory functions that help to shape cell functionality and fate. Indeed, it is well-established now that lncRNAs play a key role in the regulation of gene expression through epigenetic and posttranscriptional mechanims. The rapid increase of studies reporting lncRNAs alteration in cancers has also highlighted their relevance for tumorigenesis. Herein we describe the most prominent examples of well-established lncRNAs having oncogenic and/or tumor suppressive activity. We also discuss how technical advances have provided new therapeutic strategies based on their targeting, and also report the challenges towards their use in the clinical settings. Full article

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19 pages, 1092 KiB

Open AccessReview

Roles of Non-Coding RNAs on Anaplastic Thyroid Carcinomas

by Plabon Kumar Das, Saharia Yeasmin Asha, Ichiro Abe, Farhadul Islam and Alfred K. Lam

Cancers 2020, 12(11), 3159; https://doi.org/10.3390/cancers12113159 - 28 Oct 2020

Cited by 18 | Viewed by 3260

Abstract

Anaplastic thyroid cancer (ATC) remains as one of the most aggressive human carcinomas with poor survival rates in patients with the cancer despite therapeutic interventions. Novel targeted and personalized therapies could solve the puzzle of poor survival rates of patients with ATC. In [...] Read more.

Anaplastic thyroid cancer (ATC) remains as one of the most aggressive human carcinomas with poor survival rates in patients with the cancer despite therapeutic interventions. Novel targeted and personalized therapies could solve the puzzle of poor survival rates of patients with ATC. In this review, we discuss the role of non-coding RNAs in the regulation of gene expression in ATC as well as how the changes in their expression could potentially reshape the characteristics of ATCs. A broad range of miRNA, such as miR-205, miR-19a, miR-17-3p and miR-17-5p, miR-618, miR-20a, miR-155, etc., have abnormal expressions in ATC tissues and cells when compared to those of non-neoplastic thyroid tissues and cells. Moreover, lncRNAs, such as H19, Human leukocyte antigen (HLA) complex P5 (HCP5), Urothelial carcinoma-associated 1 (UCA1), Nuclear paraspeckle assembly transcript 1 (NEAT1), etc., participate in transcription and post-transcriptional regulation of gene expression in ATC cells. Dysregulations of these non-coding RNAs were associated with development and progression of ATC by modulating the functions of oncogenes during tumour progression. Thus, restoration of the abnormal expression of these miRNAs and lncRNAs may serve as promising ways to treat the patients with ATC. In addition, siRNA mediated inhibition of several oncogenes may act as a potential option against ATC. Thus, non-coding RNAs can be useful as prognostic biomarkers and potential therapeutic targets for the better management of patients with ATC. Full article

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14 pages, 3102 KiB

Open AccessArticle

Prognostic Stratification of Bladder Cancer Patients with a MicroRNA-Based Approach

by Ilaria Cavallari, Angela Grassi, Paola Del Bianco, Alberto Aceti, Carlotta Zaborra, Evgeniya Sharova, Irene Bertazzolo, Donna M. D’Agostino, Massimo Iafrate and Vincenzo Ciminale

Cancers 2020, 12(11), 3133; https://doi.org/10.3390/cancers12113133 - 26 Oct 2020

Cited by 9 | Viewed by 2744

Abstract

Robust non-invasive tests for prognostic stratification of bladder cancer (BCa) patients are in high demand. Following a comprehensive analysis of studies on BCa, we selected a panel of 29 microRNAs (miRNAs) and analyzed their levels in urine and plasma samples in a prospective [...] Read more.

Robust non-invasive tests for prognostic stratification of bladder cancer (BCa) patients are in high demand. Following a comprehensive analysis of studies on BCa, we selected a panel of 29 microRNAs (miRNAs) and analyzed their levels in urine and plasma samples in a prospective cohort of 63 BCa patients (32 at high risk of recurrence and 31 low-risk cases) and 37 healthy controls using RT-qPCR. To design an assay suitable for large-scale testing, we applied a hierarchical pipeline to select the miRNAs that were not affected by confounding factors such as haematuria and urine specific gravity, and exceeded stringent cut-off criteria (fold change > 2.5 and p-value < 0.005). Using a two-step decision tree based on the urine levels of miR-34a-5p, miR-200a-3p and miR-193a-5p, normalized against miR-125b-5p, patients could be classified as high- or low-risk with a sensitivity of 0.844, specificity of 0.806 and accuracy of 0.825. Furthermore, univariate Cox proportional hazards regression analyses indicated that increased urine levels of miR-29a-3p, miR-34a-5p, miR-193a-5p, miR-200c-3p, miR-205-5p and miR-532-5p were associated with a shorter event-free survival (hazard ratios > 3.1, p-value < 0.05). Taken together, our findings suggest that measuring the urine levels of these miRNAs could provide a novel cost-effective, noninvasive test for risk assessment of BCa patients. Full article

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13 pages, 3308 KiB

Open AccessArticle

De Novo A-to-I RNA Editing Discovery in lncRNA

by Domenico Alessandro Silvestris, Chiara Scopa, Sara Hanchi, Franco Locatelli and Angela Gallo

Cancers 2020, 12(10), 2959; https://doi.org/10.3390/cancers12102959 - 13 Oct 2020

Cited by 17 | Viewed by 2808

Abstract

Background: Adenosine to inosine (A-to-I) RNA editing is the most frequent editing event in humans. It converts adenosine to inosine in double-stranded RNA regions (in coding and non-coding RNAs) through the action of the adenosine deaminase acting on RNA (ADAR) enzymes. Long non-coding [...] Read more.

Background: Adenosine to inosine (A-to-I) RNA editing is the most frequent editing event in humans. It converts adenosine to inosine in double-stranded RNA regions (in coding and non-coding RNAs) through the action of the adenosine deaminase acting on RNA (ADAR) enzymes. Long non-coding RNAs, particularly abundant in the brain, account for a large fraction of the human transcriptome, and their important regulatory role is becoming progressively evident in both normal and transformed cells. Results: Herein, we present a bioinformatic analysis to generate a comprehensive inosinome picture in long non-coding RNAs (lncRNAs), using an ad hoc index and searching for de novo editing events in the normal brain cortex as well as in glioblastoma, a highly aggressive human brain cancer. We discovered >10,000 new sites and 335 novel lncRNAs that undergo editing, never reported before. We found a generalized downregulation of editing at multiple lncRNA sites in glioblastoma samples when compared to the normal brain cortex. Conclusion: Overall, our study discloses a novel layer of complexity that controls lncRNAs in the brain and brain cancer. Full article

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21 pages, 2063 KiB

Open AccessReview

Epigenetic Mechanisms of LncRNAs Binding to Protein in Carcinogenesis

by Tae-Jin Shin, Kang-Hoon Lee and Je-Yoel Cho

Cancers 2020, 12(10), 2925; https://doi.org/10.3390/cancers12102925 - 11 Oct 2020

Cited by 23 | Viewed by 3512

Abstract

Epigenetic dysregulation is an important feature for cancer initiation and progression. Long non-coding RNAs (lncRNAs) are transcripts that stably present as RNA forms with no translated protein and have lengths larger than 200 nucleotides. LncRNA can epigenetically regulate either oncogenes or tumor suppressor [...] Read more.

Epigenetic dysregulation is an important feature for cancer initiation and progression. Long non-coding RNAs (lncRNAs) are transcripts that stably present as RNA forms with no translated protein and have lengths larger than 200 nucleotides. LncRNA can epigenetically regulate either oncogenes or tumor suppressor genes. Nowadays, the combined research of lncRNA plus protein analysis is gaining more attention. LncRNA controls gene expression directly by binding to transcription factors of target genes and indirectly by complexing with other proteins to bind to target proteins and cause protein degradation, reduced protein stability, or interference with the binding of other proteins. Various studies have indicated that lncRNA contributes to cancer development by modulating genes epigenetically and studies have been done to determine which proteins are combined with lncRNA and contribute to cancer development. In this review, we look in depth at the epigenetic regulatory function of lncRNAs that are capable of complexing with other proteins in cancer development. Full article

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25 pages, 2201 KiB

Open AccessReview

Regulatory Mechanisms of Epigenetic miRNA Relationships in Human Cancer and Potential as Therapeutic Targets

by K. M. Taufiqul Arif, Esther K. Elliott, Larisa M. Haupt and Lyn R. Griffiths

Cancers 2020, 12(10), 2922; https://doi.org/10.3390/cancers12102922 - 11 Oct 2020

Cited by 92 | Viewed by 6980

Abstract

Initiation and progression of cancer are under both genetic and epigenetic regulation. Epigenetic modifications including alterations in DNA methylation, RNA and histone modifications can lead to microRNA (miRNA) gene dysregulation and malignant cellular transformation and are hereditary and reversible. miRNAs are small non-coding [...] Read more.

Initiation and progression of cancer are under both genetic and epigenetic regulation. Epigenetic modifications including alterations in DNA methylation, RNA and histone modifications can lead to microRNA (miRNA) gene dysregulation and malignant cellular transformation and are hereditary and reversible. miRNAs are small non-coding RNAs which regulate the expression of specific target genes through degradation or inhibition of translation of the target mRNA. miRNAs can target epigenetic modifier enzymes involved in epigenetic modulation, establishing a trilateral regulatory “epi–miR–epi” feedback circuit. The intricate association between miRNAs and the epigenetic architecture is an important feature through which to monitor gene expression profiles in cancer. This review summarises the involvement of epigenetically regulated miRNAs and miRNA-mediated epigenetic modulations in various cancers. In addition, the application of bioinformatics tools to study these networks and the use of therapeutic miRNAs for the treatment of cancer are also reviewed. A comprehensive interpretation of these mechanisms and the interwoven bond between miRNAs and epigenetics is crucial for understanding how the human epigenome is maintained, how aberrant miRNA expression can contribute to tumorigenesis and how knowledge of these factors can be translated into diagnostic and therapeutic tool development. Full article

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26 pages, 1731 KiB

Open AccessReview

Non-Coding and Regulatory RNAs as Epigenetic Remodelers of Fatty Acid Homeostasis in Cancer

by Silvia Cruz-Gil, Lara P. Fernández, Ruth Sánchez-Martínez, Marta Gómez de Cedrón and Ana Ramírez de Molina

Cancers 2020, 12(10), 2890; https://doi.org/10.3390/cancers12102890 - 9 Oct 2020

Cited by 6 | Viewed by 3190

Abstract

Cancer cells commonly display metabolic fluctuations. Together with the Warburg effect and the increased glutaminolysis, alterations in lipid metabolism homeostasis have been recognized as a hallmark of cancer. Highly proliferative cancer cells upregulate de novo synthesis of fatty acids (FAs) which are required [...] Read more.

Cancer cells commonly display metabolic fluctuations. Together with the Warburg effect and the increased glutaminolysis, alterations in lipid metabolism homeostasis have been recognized as a hallmark of cancer. Highly proliferative cancer cells upregulate de novo synthesis of fatty acids (FAs) which are required to support tumor progression by exerting multiple roles including structural cell membrane composition, regulators of the intracellular redox homeostasis, ATP synthesis, intracellular cell signaling molecules, and extracellular mediators of the tumor microenvironment. Epigenetic modifications have been shown to play a crucial role in human development, but also in the initiation and progression of complex diseases. The study of epigenetic processes could help to design new integral strategies for the prevention and treatment of metabolic disorders including cancer. Herein, we first describe the main altered intracellular fatty acid processes to support cancer initiation and progression. Next, we focus on the most important regulatory and non-coding RNAs (small noncoding RNA—sncRNAs—long non-coding RNAs—lncRNAs—and other regulatory RNAs) which may target the altered fatty acids pathway in cancer. Full article

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17 pages, 1706 KiB

Open AccessReview

tRNA-Derived Small RNAs: Novel Epigenetic Regulators

by Joonhyeong Park, Se Hee Ahn, Myung Geun Shin, Hak Kyun Kim and Suhwan Chang

Cancers 2020, 12(10), 2773; https://doi.org/10.3390/cancers12102773 - 27 Sep 2020

Cited by 42 | Viewed by 7135

Abstract

An epigenetic change is a heritable genetic alteration that does not involve any nucleotide changes. While the methylation of specific DNA regions such as CpG islands or histone modifications, including acetylation or methylation, have been investigated in detail, the role of small RNAs [...] Read more.

An epigenetic change is a heritable genetic alteration that does not involve any nucleotide changes. While the methylation of specific DNA regions such as CpG islands or histone modifications, including acetylation or methylation, have been investigated in detail, the role of small RNAs in epigenetic regulation is largely unknown. Among the many types of small RNAs, tRNA-derived small RNAs (tsRNAs) represent a class of noncoding small RNAs with multiple roles in diverse physiological processes, including neovascularization, sperm maturation, immune modulation, and stress response. Regarding these roles, several pioneering studies have revealed that dysregulated tsRNAs are associated with human diseases, such as systemic lupus, neurological disorder, metabolic disorder, and cancer. Moreover, recent findings suggest that tsRNAs regulate the expression of critical genes linked with these diseases by a variety of mechanisms, including epigenetic regulation. In this review, we will describe different classes of tsRNAs based on their biogenesis and will focus on their role in epigenetic regulation. Full article

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21 pages, 2318 KiB

Open AccessReview

Competing Endogenous RNA Networks in the Epithelial to Mesenchymal Transition in Diffuse-Type of Gastric Cancer

by Natalia Landeros, Pablo M. Santoro, Gonzalo Carrasco-Avino and Alejandro H. Corvalan

Cancers 2020, 12(10), 2741; https://doi.org/10.3390/cancers12102741 - 24 Sep 2020

Cited by 32 | Viewed by 4310

Abstract

The diffuse-type of gastric cancer (DGC), molecularly associated with epithelial to mesenchymal transition (EMT), is increasing in incidence. Loss of E-cadherin expression is the hallmark of the EMT process and is largely due to the upregulation of the EMT-inducing transcription factors ZEB1/2, Snail, [...] Read more.

The diffuse-type of gastric cancer (DGC), molecularly associated with epithelial to mesenchymal transition (EMT), is increasing in incidence. Loss of E-cadherin expression is the hallmark of the EMT process and is largely due to the upregulation of the EMT-inducing transcription factors ZEB1/2, Snail, Slug, and Twist1/2. However, ncRNA, such as miRNA and lncRNAs, can also participate in the EMT process through the direct targeting of E-cadherin and other EMT-inducing transcription factors. Additionally, lncRNA can sponge the miRNA pool that targets these transcripts through competing endogenous RNA (ceRNA) networks. In this review, we focus on the role of ncRNA in the direct deregulation of E-cadherin, as well as EMT-inducing transcription factors. Based on the relevance of the ceRNA network hypothesis, and the lack of said networks in EMT, we performed a prediction analysis for all miRNAs and lncRNAs that target E-cadherin, as well as EMT-inducing transcription factors. This analysis resulted in novel predicted ceRNA networks for E-cadherin and EMT-inducing transcription factors (EMT-TFs), as well as the expansion of the molecular basis of the DGC. Full article

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21 pages, 1008 KiB

Open AccessReview

The Interplay between Long Noncoding RNAs and Proteins of the Epigenetic Machinery in Ovarian Cancer

by Naiade Calanca, Cecilie Abildgaard, Cláudia Aparecida Rainho and Silvia Regina Rogatto

Cancers 2020, 12(9), 2701; https://doi.org/10.3390/cancers12092701 - 21 Sep 2020

Cited by 7 | Viewed by 3487

Abstract

Comprehensive large-scale sequencing and bioinformatics analyses have uncovered a myriad of cancer-associated long noncoding RNAs (lncRNAs). Aberrant expression of lncRNAs is associated with epigenetic reprogramming during tumor development and progression, mainly due to their ability to interact with DNA, RNA, or proteins to [...] Read more.

Comprehensive large-scale sequencing and bioinformatics analyses have uncovered a myriad of cancer-associated long noncoding RNAs (lncRNAs). Aberrant expression of lncRNAs is associated with epigenetic reprogramming during tumor development and progression, mainly due to their ability to interact with DNA, RNA, or proteins to regulate gene expression. LncRNAs participate in the control of gene expression patterns during development and cell differentiation and can be cell and cancer type specific. In this review, we described the potential of lncRNAs for clinical applications in ovarian cancer (OC). OC is a complex and heterogeneous disease characterized by relapse, chemoresistance, and high mortality rates. Despite advances in diagnosis and treatment, no significant improvements in long-term survival were observed in OC patients. A set of lncRNAs was associated with survival and response to therapy in this malignancy. We manually curated databases and used bioinformatics tools to identify lncRNAs implicated in the epigenetic regulation, along with examples of direct interactions between the lncRNAs and proteins of the epigenetic machinery in OC. The resources and mechanisms presented herein can improve the understanding of OC biology and provide the basis for further investigations regarding the selection of novel biomarkers and therapeutic targets. Full article

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17 pages, 1338 KiB

Open AccessReview

Epigenetic Associations between lncRNA/circRNA and miRNA in Hepatocellular Carcinoma

by Tae-Su Han, Keun Hur, Hyun-Soo Cho and Hyun Seung Ban

Cancers 2020, 12(9), 2622; https://doi.org/10.3390/cancers12092622 - 14 Sep 2020

Cited by 124 | Viewed by 7739

Abstract

The three major members of non-coding RNAs (ncRNAs), named microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play an important role in hepatocellular carcinoma (HCC) development. Recently, the competing endogenous RNA (ceRNA) regulation model described lncRNA/circRNA as a sponge for miRNAs [...] Read more.

The three major members of non-coding RNAs (ncRNAs), named microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play an important role in hepatocellular carcinoma (HCC) development. Recently, the competing endogenous RNA (ceRNA) regulation model described lncRNA/circRNA as a sponge for miRNAs to indirectly regulate miRNA downstream target genes. Accumulating evidence has indicated that ceRNA regulatory networks are associated with biological processes in HCC, including cancer cell growth, epithelial to mesenchymal transition (EMT), metastasis, and chemoresistance. In this review, we summarize recent discoveries, which are specific ceRNA regulatory networks (lncRNA/circRNA-miRNA-mRNA) in HCC and discuss their clinical significance. Full article

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27 pages, 9316 KiB

Open AccessArticle

Identification of Modulated MicroRNAs Associated with Breast Cancer, Diet, and Physical Activity

by Luca Falzone, Maria Grimaldi, Egidio Celentano, Livia S. A. Augustin and Massimo Libra

Cancers 2020, 12(9), 2555; https://doi.org/10.3390/cancers12092555 - 8 Sep 2020

Cited by 53 | Viewed by 5127

Abstract

Background: Several studies have shown that healthy lifestyles prevent the risk of breast cancer (BC) and are associated with better prognosis. It was hypothesized that lifestyle strategies induce microRNA (miRNA) modulation that, in turn, may lead to important epigenetic modifications. The identification of [...] Read more.

Background: Several studies have shown that healthy lifestyles prevent the risk of breast cancer (BC) and are associated with better prognosis. It was hypothesized that lifestyle strategies induce microRNA (miRNA) modulation that, in turn, may lead to important epigenetic modifications. The identification of miRNAs associated with BC, diet, and physical activity may give further insights into the role played by lifestyle interventions and their efficacy for BC patients. To predict which miRNAs may be modulated by diet and physical activity in BC patients, the analyses of different miRNA expression datasets were performed. Methods: The GEO DataSets database was used to select miRNA expression datasets related to BC patients, dietary interventions, and physical exercise. Further bioinformatic approaches were used to establish the value of selected miRNAs in BC development and prognosis. Results: The analysis of datasets allowed the selection of modulated miRNAs associated with BC development, diet, and physical exercise. Seven miRNAs were also associated with the overall survival of BC patients. Conclusions: The identified miRNAs may play a role in the development of BC and may have a prognostic value in patients treated with integrative interventions including diet and physical activity. Validation of such modulated miRNAs on BC patients undergoing lifestyle strategies will be mandatory. Full article

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22 pages, 1388 KiB

Open AccessReview

Circular RNAs: A New Piece in the Colorectal Cancer Puzzle

by Pinelopi I. Artemaki, Andreas Scorilas and Christos K. Kontos

Cancers 2020, 12(9), 2464; https://doi.org/10.3390/cancers12092464 - 31 Aug 2020

Cited by 44 | Viewed by 3830

Abstract

Colorectal cancer (CRC) is the third most fatal type of malignancy, worldwide. Despite the advances accomplished in the elucidation of its molecular base and the existing CRC biomarkers introduced in the clinical practice, additional research is required. Circular RNAs (circRNAs) constitute a new [...] Read more.

Colorectal cancer (CRC) is the third most fatal type of malignancy, worldwide. Despite the advances accomplished in the elucidation of its molecular base and the existing CRC biomarkers introduced in the clinical practice, additional research is required. Circular RNAs (circRNAs) constitute a new RNA type, formed by back-splicing of primary transcripts. They have been discovered during the 1970s but were characterized as by-products of aberrant splicing. However, the modern high-throughput approaches uncovered their widespread expression; therefore, several questions were raised regarding their potential biological roles. During the last years, great progress has been achieved in the elucidation of their functions: circRNAs can act as microRNA sponges, transcription regulators, and interfere with splicing, as well. Furthermore, they are heavily involved in various human pathological states, including cancer, and could serve as diagnostic and prognostic biomarkers in several diseases. Particularly in CRC, aberrant expression of circRNAs has been observed. More specifically, these molecules either inhibit or promote colorectal carcinogenesis by regulating different molecules and signaling pathways. The present review discusses the characteristics and functions of circRNA, prior to analyzing the multifaceted role of these molecules in CRC and their potential value as biomarkers and therapeutic targets. Full article

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18 pages, 2808 KiB

Open AccessFeature PaperReview

Emerging Cancer Epigenetic Mechanisms Regulated by All-Trans Retinoic Acid

by Stefano Rossetti and Nicoletta Sacchi

Cancers 2020, 12(8), 2275; https://doi.org/10.3390/cancers12082275 - 14 Aug 2020

Cited by 10 | Viewed by 3581

Abstract

All-trans retinoic acid (RA), which is the dietary bioactive derivative obtained from animal (retinol) and plant sources (beta-carotene), is a physiological lipid signal of both embryonic and postembryonic development. During pregnancy, either RA deficiency or an excessive RA intake is teratogenic. Too low [...] Read more.

All-trans retinoic acid (RA), which is the dietary bioactive derivative obtained from animal (retinol) and plant sources (beta-carotene), is a physiological lipid signal of both embryonic and postembryonic development. During pregnancy, either RA deficiency or an excessive RA intake is teratogenic. Too low or too high RA affects not only prenatal, but also postnatal, developmental processes such as myelopoiesis and mammary gland morphogenesis. In this review, we mostly focus on emerging RA-regulated epigenetic mechanisms involving RA receptor alpha (RARA) and Annexin A8 (ANXA8), which is a member of the Annexin family, as well as ANXA8 regulatory microRNAs (miRNAs). The first cancer showing ANXA8 upregulation was reported in acute promyelocytic leukemia (APL), which induces the differentiation arrest of promyelocytes due to defective RA signaling caused by RARA fusion genes as the PML-RARA gene. Over the years, ANXA8 has also been found to be upregulated in other cancers, even in the absence of RARA fusion genes. Mechanistic studies on human mammary cells and mammary glands of mice showed that ANXA8 upregulation is caused by genetic mutations affecting RARA functions. Although not all of the underlying mechanisms of ANXA8 upregulation have been elucidated, the interdependence of RA-RARA and ANXA8 seems to play a relevant role in some normal and tumorigenic settings. Full article

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10 pages, 2012 KiB

Open AccessArticle

LncRNA DLG2-AS1 as a Novel Biomarker in Lung Adenocarcinoma

by Alberto M. Arenas, Marta Cuadros, Alvaro Andrades, Daniel J. García, Isabel F. Coira, María Isabel Rodríguez, Carlos Baliñas-Gavira, Paola Peinado, Juan Carlos Álvarez-Pérez and Pedro P. Medina

Cancers 2020, 12(8), 2080; https://doi.org/10.3390/cancers12082080 - 28 Jul 2020

Cited by 7 | Viewed by 3695

Abstract

Long non-coding RNAs (lncRNAs) are a heterogeneous class of non-coding RNAs whose biological roles are still poorly understood. LncRNAs serve as gene expression regulators, frequently interacting with epigenetic factors to shape the outcomes of crucial biological processes, and playing roles in different pathologies [...] Read more.

Long non-coding RNAs (lncRNAs) are a heterogeneous class of non-coding RNAs whose biological roles are still poorly understood. LncRNAs serve as gene expression regulators, frequently interacting with epigenetic factors to shape the outcomes of crucial biological processes, and playing roles in different pathologies including cancer. Over the last years, growing scientific evidence supports the key role of some lncRNAs in tumor development and proposes them as valuable biomarkers for the clinic. In this study, we aimed to characterize lncRNAs whose expression is altered in tumor samples from patients with lung adenocarcinoma (LUAD) compared to adjacent normal tissue samples. On an RT-qPCR survey of 90 cancer-related lncRNAs, we found one lncRNA, DLG2-AS1, which was consistently downregulated in 70 LUAD patients. To gain insight into its biological function, DLG2-AS1 was cloned and successfully re-expressed in LUAD cancer cell lines. We determined that DLG2-AS1 is not a cis-regulatory element of its overlapping gene DLG2, as their transcription levels were not correlated, nor did DLG2-AS1 restoration modify the expression of DLG2 protein. Furthermore, after generating a receiver operating curve (ROC) and calculating the area under curve (AUC), we found that DLG2-AS1 expression showed high sensitivity and specificity (AUC = 0.726) for the classification of LUAD and normal samples, determining its value as a potential lung cancer biomarker. Full article

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15 pages, 1088 KiB

Open AccessReview

Emerging Contribution of PancRNAs in Cancer

by Neri Mercatelli, Ramona Palombo and Maria Paola Paronetto

Cancers 2020, 12(8), 2035; https://doi.org/10.3390/cancers12082035 - 24 Jul 2020

Cited by 4 | Viewed by 2522

Abstract

“Cancer” includes a heterogeneous group of diseases characterized by abnormal growth beyond natural boundaries. Neoplastic transformation of cells is orchestrated by multiple molecular players, including oncogenic transcription factors, epigenetic modifiers, RNA binding proteins, and coding and noncoding transcripts. The use of computational methods [...] Read more.

“Cancer” includes a heterogeneous group of diseases characterized by abnormal growth beyond natural boundaries. Neoplastic transformation of cells is orchestrated by multiple molecular players, including oncogenic transcription factors, epigenetic modifiers, RNA binding proteins, and coding and noncoding transcripts. The use of computational methods for global and quantitative analysis of RNA processing regulation provides new insights into the genomic and epigenomic features of the cancer transcriptome. In particular, noncoding RNAs are emerging as key molecular players in oncogenesis. Among them, the promoter-associated noncoding RNAs (pancRNAs) are noncoding transcripts acting in cis to regulate their host genes, including tumor suppressors and oncogenes. In this review, we will illustrate the role played by pancRNAs in cancer biology and will discuss the latest findings that connect pancRNAs with cancer risk and progression. The molecular mechanisms involved in the function of pancRNAs may open the path to novel therapeutic opportunities, thus expanding the repertoire of targets to be tested as anticancer agents in the near future. Full article

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15 pages, 1745 KiB

Open AccessArticle

NCL Inhibition Exerts Antineoplastic Effects against Prostate Cancer Cells by Modulating Oncogenic MicroRNAs

by Tyler Sheetz, Joseph Mills, Anna Tessari, Megan Pawlikowski, Ashley E. Braddom, Tasha Posid, Debra L. Zynger, Cindy James, Valerio Embrione, Kareesma Parbhoo, Claudia Foray, Vincenzo Coppola, Carlo M. Croce and Dario Palmieri

Cancers 2020, 12(7), 1861; https://doi.org/10.3390/cancers12071861 - 10 Jul 2020

Cited by 9 | Viewed by 4427

Abstract

Prostate cancer (PCa) is the most frequently diagnosed cancer in men and second most common cause of cancer-related deaths in the United States. Androgen deprivation therapy (ADT) is only temporarily effective for advanced-stage PCa, as the disease inevitably progresses to castration-resistant prostate cancer [...] Read more.

Prostate cancer (PCa) is the most frequently diagnosed cancer in men and second most common cause of cancer-related deaths in the United States. Androgen deprivation therapy (ADT) is only temporarily effective for advanced-stage PCa, as the disease inevitably progresses to castration-resistant prostate cancer (CRPC). The protein nucleolin (NCL) is overexpressed in several types of human tumors where it is also mislocalized to the cell surface. We previously reported the identification of a single-chain fragment variable (scFv) immuno-agent that is able to bind NCL on the surface of breast cancer cells and inhibit proliferation both in vitro and in vivo. In the present study, we evaluated whether NCL could be a valid therapeutic target for PCa, utilizing DU145, PC3 (CRPC), and LNCaP (androgen-sensitive) cell lines. First, we interrogated the publicly available databases and noted that higher NCL mRNA levels are associated with higher Gleason Scores as well as with recurrent and metastatic tumors. Then, using our anti-NCL scFv, we demonstrated that NCL is expressed on the surface of all three tested cell lines and that NCL inhibition results in reduced proliferation and migration. We also measured the inhibitory effect of NCL targeting on the biogenesis of oncogenic microRNAs such as miR-21, -221 and -222, which was cell context dependent. Taken together, our data provide evidence that NCL targeting inhibits the key hallmarks of malignancy in PCa cells and may provide a novel therapeutic option for patients with advanced-stage PCa. Full article

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27 pages, 1680 KiB

Open AccessArticle

Machine Learning-Based Ensemble Recursive Feature Selection of Circulating miRNAs for Cancer Tumor Classification

by Alejandro Lopez-Rincon, Lucero Mendoza-Maldonado, Marlet Martinez-Archundia, Alexander Schönhuth, Aletta D. Kraneveld, Johan Garssen and Alberto Tonda

Cancers 2020, 12(7), 1785; https://doi.org/10.3390/cancers12071785 - 3 Jul 2020

Cited by 39 | Viewed by 5485

Abstract

Circulating microRNAs (miRNA) are small noncoding RNA molecules that can be detected in bodily fluids without the need for major invasive procedures on patients. miRNAs have shown great promise as biomarkers for tumors to both assess their presence and to predict their type [...] Read more.

Circulating microRNAs (miRNA) are small noncoding RNA molecules that can be detected in bodily fluids without the need for major invasive procedures on patients. miRNAs have shown great promise as biomarkers for tumors to both assess their presence and to predict their type and subtype. Recently, thanks to the availability of miRNAs datasets, machine learning techniques have been successfully applied to tumor classification. The results, however, are difficult to assess and interpret by medical experts because the algorithms exploit information from thousands of miRNAs. In this work, we propose a novel technique that aims at reducing the necessary information to the smallest possible set of circulating miRNAs. The dimensionality reduction achieved reflects a very important first step in a potential, clinically actionable, circulating miRNA-based precision medicine pipeline. While it is currently under discussion whether this first step can be taken, we demonstrate here that it is possible to perform classification tasks by exploiting a recursive feature elimination procedure that integrates a heterogeneous ensemble of high-quality, state-of-the-art classifiers on circulating miRNAs. Heterogeneous ensembles can compensate inherent biases of classifiers by using different classification algorithms. Selecting features then further eliminates biases emerging from using data from different studies or batches, yielding more robust and reliable outcomes. The proposed approach is first tested on a tumor classification problem in order to separate 10 different types of cancer, with samples collected over 10 different clinical trials, and later is assessed on a cancer subtype classification task, with the aim to distinguish triple negative breast cancer from other subtypes of breast cancer. Overall, the presented methodology proves to be effective and compares favorably to other state-of-the-art feature selection methods. Full article

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19 pages, 2719 KiB

Open AccessArticle

Tumor-Suppressive miR-192-5p Has Prognostic Value in Pancreatic Ductal Adenocarcinoma

by Isabelle Flammang, Moritz Reese, Anda J. Ströse, Zixuan Yang, Johannes A. Eble and Sameer A. Dhayat

Cancers 2020, 12(6), 1693; https://doi.org/10.3390/cancers12061693 - 25 Jun 2020

Cited by 26 | Viewed by 3541 | Correction

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by fast tumor progression and diagnosis at advanced, inoperable stages. Previous studies could demonstrate an involvement of miR-192-5p in epigenetic regulation of visceral carcinomas. Due to contradictory results, however, the clinical utility of miR-192-5p in PDAC has [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by fast tumor progression and diagnosis at advanced, inoperable stages. Previous studies could demonstrate an involvement of miR-192-5p in epigenetic regulation of visceral carcinomas. Due to contradictory results, however, the clinical utility of miR-192-5p in PDAC has yet to be determined. MiR-192-5p expression was analyzed by RT-qRT-PCR in human PDAC and benign tissue (n = 78), blood serum (n = 81) and serum exosomes (n = 74), as well as in PDAC cell lines (n = 5), chemoresistant cell clones (n = 2), and pancreatic duct cell line H6c7. Analysis of EMT-associated (epithelial-to-mesenchymal transition) proteins was performed by immunohistochemistry and Western blot. MiR-192-5p was deregulated in PDAC as compared to healthy controls (HCs), with downregulation in macrodissected tissue (p < 0.001) and upregulation in blood serum of PDAC UICC (Union for International Cancer Control) stage IV (p = 0.016) and serum exosomes of PDAC UICC stages II to IV (p < 0.001). MiR-192-5p expression in tumor tissue was significantly lower as compared to corresponding peritumoral tissue (PDAC UICC stage II: p < 0.001; PDAC UICC stage III: p = 0.024), while EMT markers ZEB1 and ZEB2 were more frequently expressed in tumor tissue as compared to peritumoral tissue, HCs, and chronic pancreatitis. Tissue-derived (AUC of 0.86; p < 0.0001) and exosomal (AUC of 0.83; p = 0.0004) miR-192-5p could differentiate between PDAC and HCs with good accuracy. Furthermore, high expression of miR-192-5p in PDAC tissue of curatively resected PDAC patients correlated with prolonged overall and recurrence-free survival in multivariate analysis. In vitro, miR-192-5p was downregulated in gemcitabine-resistant cell clones of AsPC-1 (p = 0.029). Transient transfection of MIA PaCa-2 cells with miR-192-5p mimic resulted in downregulation of ZEB2. MiR-192-5p seems to possess a tumor-suppressive role and high potential as a diagnostic and prognostic marker in PDAC. Full article

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25 pages, 1503 KiB

Open AccessReview

Predicting Response to Neoadjuvant Therapy in Colorectal Cancer Patients the Role of Messenger-and Micro-RNA Profiling

by Alberto Izzotti, Chiara Ceccaroli, Marta Geretto, Filippo Grillo Ruggieri, Sara Schenone and Emilio Di Maria

Cancers 2020, 12(6), 1652; https://doi.org/10.3390/cancers12061652 - 22 Jun 2020

Cited by 14 | Viewed by 3428

Abstract

Colorectal cancer patients’ responses to neoadjuvant therapy undergo broad inter-individual variations. The aim of this systematic review is to identify a molecular signature that is predictive of colon cancer downstaging and/or downgrading after neoadjuvant therapy. Among the hundreds analysed in the available studies, [...] Read more.

Colorectal cancer patients’ responses to neoadjuvant therapy undergo broad inter-individual variations. The aim of this systematic review is to identify a molecular signature that is predictive of colon cancer downstaging and/or downgrading after neoadjuvant therapy. Among the hundreds analysed in the available studies, only 19 messenger-RNAs (mRNAs) and six micro-RNAs (miRNAs) were differentially expressed in responders versus non-responders in two or more independent studies. Therefore, a mRNA/miRNA signature can be designed accordingly, with limitations caused by the retrospective nature of these studies, the heterogeneity in study designs and the downgrading/downstaging assessment criteria. This signature can be proposed to tailor neoadjuvant therapy regimens on an individual basis. Full article

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14 pages, 1167 KiB

Open AccessReview

The Emerging Role of MicroRNAs and Other Non-Coding RNAs in Cancer Cachexia

by Joana M. O. Santos, Sara Peixoto da Silva, Rui M. Gil da Costa and Rui Medeiros

Cancers 2020, 12(4), 1004; https://doi.org/10.3390/cancers12041004 - 19 Apr 2020

Cited by 32 | Viewed by 4871

Abstract

Cancer cachexia or wasting is a paraneoplastic syndrome characterized by systemic inflammation and an involuntary loss of body mass that cannot be reversed by normal nutritional support. This syndrome affects 50%–80% of cancer patients, depending on the tumor type and patient characteristics, and [...] Read more.

Cancer cachexia or wasting is a paraneoplastic syndrome characterized by systemic inflammation and an involuntary loss of body mass that cannot be reversed by normal nutritional support. This syndrome affects 50%–80% of cancer patients, depending on the tumor type and patient characteristics, and it is responsible for up to 20% of cancer deaths. MicroRNAs are a class of non-coding RNAs (ncRNAs) with 19 to 24 nucleotides in length of which the function is to regulate gene expression. In the last years, microRNAs and other ncRNAs have been demonstrated to have a crucial role in the pathogenesis of several diseases and clinical potential. Recently, ncRNAs have begun to be associated with cancer cachexia by modulating essential functions like the turnover of skeletal muscle and adipose tissue. Additionally, circulating microRNAs have been suggested as potential biomarkers for patients at risk of developing cancer cachexia. In this review article, we present recent data concerning the role of microRNAs and other ncRNAs in cancer cachexia pathogenesis and their possible clinical relevance. Full article

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14 pages, 1417 KiB

Open AccessReview

Interactions between the MicroRNAs and Microbiota in Cancer Development: Roles and Therapeutic Opportunities

by Alessandro Allegra, Caterina Musolino, Alessandro Tonacci, Giovanni Pioggia and Sebastiano Gangemi

Cancers 2020, 12(4), 805; https://doi.org/10.3390/cancers12040805 - 27 Mar 2020

Cited by 45 | Viewed by 6196

Abstract

The human microbiota is made up of the fungi, bacteria, protozoa and viruses cohabiting within the human body. An altered microbiota can provoke diseases such as cancer. The mechanisms by which a modified microbiota can intervene in the onset and progression of neoplastic [...] Read more.

The human microbiota is made up of the fungi, bacteria, protozoa and viruses cohabiting within the human body. An altered microbiota can provoke diseases such as cancer. The mechanisms by which a modified microbiota can intervene in the onset and progression of neoplastic diseases are manifold. For instance, these include the effects on the immune system and the onset of obesity. A different mechanism seems to be constituted by the continuous and bidirectional relationships existing between microbiota and miRNAs. MiRNAs emerged as a novel group of small endogenous non-coding RNAs from that control gene expression. Several works seem to confirm the presence of a close connection between microbiota and miRNAs. Although the main literature data concern the correlations between microbiota, miRNAs and colon cancer, several researches have revealed the presence of connections with other types of tumour, including the ovarian tumour, cervical carcinoma, hepatic carcinoma, neoplastic pathologies of the central nervous system and the possible implication of the microbiota-miRNAs system on the response to the treatment of neoplastic pathologies. In this review, we summarise the physiological and pathological functions of the microbiota on cancer onset by governing miRNA production. A better knowledge of the bidirectional relationships existing between microbiota and miRNAs could provide new markers for the diagnosis, staging and monitoring of cancer and seems to be a promising approach for antagomir-guided approaches as therapeutic agents. Full article

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2019

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25 pages, 1386 KiB

Open AccessReview

MicroRNA Regulation of Epigenetic Modifiers in Breast Cancer

by Brock Humphries, Zhishan Wang and Chengfeng Yang

Cancers 2019, 11(7), 897; https://doi.org/10.3390/cancers11070897 - 27 Jun 2019

Cited by 51 | Viewed by 6352

Abstract

Epigenetics refers to the heritable changes in gene expression without a change in the DNA sequence itself. Two of these major changes include aberrant DNA methylation as well as changes to histone modification patterns. Alterations to the epigenome can drive expression of oncogenes [...] Read more.

Epigenetics refers to the heritable changes in gene expression without a change in the DNA sequence itself. Two of these major changes include aberrant DNA methylation as well as changes to histone modification patterns. Alterations to the epigenome can drive expression of oncogenes and suppression of tumor suppressors, resulting in tumorigenesis and cancer progression. In addition to modifications of the epigenome, microRNA (miRNA) dysregulation is also a hallmark for cancer initiation and metastasis. Advances in our understanding of cancer biology demonstrate that alterations in the epigenome are not only a major cause of miRNA dysregulation in cancer, but that miRNAs themselves also indirectly drive these DNA and histone modifications. More explicitly, recent work has shown that miRNAs can regulate chromatin structure and gene expression by directly targeting key enzymes involved in these processes. This review aims to summarize these research findings specifically in the context of breast cancer. This review also discusses miRNAs as epigenetic biomarkers and as therapeutics, and presents a comprehensive summary of currently validated epigenetic targets in breast cancer. Full article

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