Cancers

2023

Jump to: 2022, 2021

43 pages, 1011 KiB

Open AccessReview

Non-Coding RNAs in Oral Cancer: Emerging Roles and Clinical Applications

by Saurabh Dey, Bini Biswas, Angela Manoj Appadan, Jaladhi Shah, Jayanta K. Pal, Soumya Basu and Subhayan Sur

Cancers 2023, 15(15), 3752; https://doi.org/10.3390/cancers15153752 - 25 Jul 2023

Cited by 6 | Viewed by 3005

Abstract

Oral cancer (OC) is among the most prevalent cancers in the world. Certain geographical areas are disproportionately affected by OC cases due to the regional differences in dietary habits, tobacco and alcohol consumption. However, conventional therapeutic methods do not yield satisfying treatment outcomes. [...] Read more.

Oral cancer (OC) is among the most prevalent cancers in the world. Certain geographical areas are disproportionately affected by OC cases due to the regional differences in dietary habits, tobacco and alcohol consumption. However, conventional therapeutic methods do not yield satisfying treatment outcomes. Thus, there is an urgent need to understand the disease process and to develop diagnostic and therapeutic strategies for OC. In this review, we discuss the role of various types of ncRNAs in OC, and their promising clinical implications as prognostic or diagnostic markers and therapeutic targets. MicroRNA (miRNA), long ncRNA (lncRNA), circular RNA (circRNA), PIWI-interacting RNA (piRNA), and small nucleolar RNA (snoRNA) are the major ncRNA types whose involvement in OC are emerging. Dysregulated expression of ncRNAs, particularly miRNAs, lncRNAs, and circRNAs, are linked with the initiation, progression, as well as therapy resistance of OC via modulation in a series of cellular pathways through epigenetic, transcriptional, post-transcriptional, and translational modifications. Differential expressions of miRNAs and lncRNAs in blood, saliva or extracellular vesicles have indicated potential diagnostic and prognostic importance. In this review, we have summarized all the promising aspects of ncRNAs in the management of OC. Full article

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2022

Jump to: 2023, 2021

19 pages, 2179 KiB

Open AccessArticle

Integration of p16/HPV DNA Status with a 24-miRNA-Defined Molecular Phenotype Improves Clinically Relevant Stratification of Head and Neck Cancer Patients

by Julia Hess, Kristian Unger, Cornelius Maihoefer, Lars Schüttrumpf, Peter Weber, Sebastian Marschner, Ludmila Wintergerst, Ulrike Pflugradt, Philipp Baumeister, Axel Walch, Christine Woischke, Thomas Kirchner, Martin Werner, Kristin Sörensen, Michael Baumann, Ingeborg Tinhofer, Stephanie E. Combs, Jürgen Debus, Henning Schäfer, Mechthild Krause, Annett Linge, Jens von der Grün, Martin Stuschke, Daniel Zips, Martin Canis, Kirsten Lauber, Ute Ganswindt, Michael Henke, Horst Zitzelsberger and Claus Belka Show full author list Hide full author list

Cancers 2022, 14(15), 3745; https://doi.org/10.3390/cancers14153745 - 31 Jul 2022

Cited by 3 | Viewed by 3227

Abstract

Human papillomavirus (HPV)-driven head and neck squamous cell carcinomas (HNSCC) generally have a more favourable prognosis. We hypothesized that HPV-associated HNSCC may be identified by an miRNA-signature according to their specific molecular pathogenesis, and be characterized by a unique transcriptome compared to HPV-negative [...] Read more.

Human papillomavirus (HPV)-driven head and neck squamous cell carcinomas (HNSCC) generally have a more favourable prognosis. We hypothesized that HPV-associated HNSCC may be identified by an miRNA-signature according to their specific molecular pathogenesis, and be characterized by a unique transcriptome compared to HPV-negative HNSCC. We performed miRNA expression profiling of two p16/HPV DNA characterized HNSCC cohorts of patients treated by adjuvant radio(chemo)therapy (multicentre DKTK-ROG n = 128, single-centre LMU-KKG n = 101). A linear model predicting HPV status built in DKTK-ROG using lasso-regression was tested in LMU-KKG. LMU-KKG tumours (n = 30) were transcriptome profiled for differential gene expression and miRNA-integration. A 24-miRNA signature predicted HPV-status with 94.53% accuracy (AUC: 0.99) in DKTK-ROG, and 86.14% (AUC: 0.86) in LMU-KKG. The prognostic values of 24-miRNA- and p16/HPV DNA status were comparable. Combining p16/HPV DNA and 24-miRNA status allowed patient sub-stratification and identification of an HPV-associated patient subgroup with impaired overall survival. HPV-positive tumours showed downregulated MAPK, Estrogen, EGFR, TGFbeta, WNT signaling activity. miRNA-mRNA integration revealed HPV-specific signaling pathway regulation, including PD−L1 expression/PD−1 checkpoint pathway in cancer in HPV-associated HNSCC. Integration of clinically established p16/HPV DNA with 24-miRNA signature status improved clinically relevant risk stratification, which might be considered for future clinical decision-making with respect to treatment de-escalation in HPV-associated HNSCC. Full article

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19 pages, 5665 KiB

Open AccessReview

Small but Powerful: The Human Vault RNAs as Multifaceted Modulators of Pro-Survival Characteristics and Tumorigenesis

by Stefano Gallo, EunBin Kong, Iolanda Ferro and Norbert Polacek

Cancers 2022, 14(11), 2787; https://doi.org/10.3390/cancers14112787 - 3 Jun 2022

Cited by 13 | Viewed by 4407

Abstract

The importance of non-coding RNAs for regulating gene expression has been uncovered in model systems spanning all three domains of life. More recently, their involvement in modulating signal transduction, cell proliferation, tumorigenesis and cancer progression has also made them promising tools and targets [...] Read more.

The importance of non-coding RNAs for regulating gene expression has been uncovered in model systems spanning all three domains of life. More recently, their involvement in modulating signal transduction, cell proliferation, tumorigenesis and cancer progression has also made them promising tools and targets for oncotherapy. Recent studies revealed a class of highly conserved small ncRNAs, namely vault RNAs, as regulators of several cellular homeostasis mechanisms. The human genome encodes four vault RNA paralogs that share significant sequence and structural similarities, yet they seem to possess distinct roles in mammalian cells. The alteration of vault RNA expression levels has frequently been observed in cancer tissues, thus hinting at a putative role in orchestrating pro-survival characteristics. Over the last decade, significant advances have been achieved in clarifying the relationship between vault RNA and cellular mechanisms involved in cancer development. It became increasingly clear that vault RNAs are involved in controlling apoptosis, lysosome biogenesis and function, as well as autophagy in several malignant cell lines, most likely by modulating signaling pathways (e.g., the pro-survival MAPK cascade). In this review, we discuss the identified and known functions of the human vault RNAs in the context of cell proliferation, tumorigenesis and chemotherapy resistance. Full article

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15 pages, 3077 KiB

Open AccessArticle

Identification of Circulating lncRNAs Associated with Gallbladder Cancer Risk by Tissue-Based Preselection, Cis-eQTL Validation, and Analysis of Association with Genotype-Based Expression

by Alice Blandino, Dominique Scherer, Trine B. Rounge, Sinan U. Umu, Felix Boekstegers, Carol Barahona Ponce, Katherine Marcelain, Valentina Gárate-Calderón, Melanie Waldenberger, Erik Morales, Armando Rojas, César Munoz, Javier Retamales, Gonzalo de Toro, Olga Barajas, María Teresa Rivera, Analía Cortés, Denisse Loader, Javiera Saavedra, Lorena Gutiérrez, Alejandro Ortega, Maria Enriqueta Bertrán, Fernando Gabler, Mónica Campos, Juan Alvarado, Fabrizio Moisán, Loreto Spencer, Bruno Nervi, Daniel E. Carvajal-Hausdorf, Héctor Losada, Mauricio Almau, Plinio Fernández, Ivan Gallegos, Jordi Olloquequi, Macarena Fuentes-Guajardo, Rolando Gonzalez-Jose, Maria Cátira Bortolini, Carla Gallo, Andres Ruiz Linares, Francisco Rothhammer and Justo Lorenzo Bermejo Show full author list Hide full author list

Cancers 2022, 14(3), 634; https://doi.org/10.3390/cancers14030634 - 27 Jan 2022

Cited by 3 | Viewed by 8340

Abstract

Long noncoding RNAs (lncRNAs) play key roles in cell processes and are good candidates for cancer risk prediction. Few studies have investigated the association between individual genotypes and lncRNA expression. Here we integrate three separate datasets with information on lncRNA expression only, both [...] Read more.

Long noncoding RNAs (lncRNAs) play key roles in cell processes and are good candidates for cancer risk prediction. Few studies have investigated the association between individual genotypes and lncRNA expression. Here we integrate three separate datasets with information on lncRNA expression only, both lncRNA expression and genotype, and genotype information only to identify circulating lncRNAs associated with the risk of gallbladder cancer (GBC) using robust linear and logistic regression techniques. In the first dataset, we preselect lncRNAs based on expression changes along the sequence “gallstones → dysplasia → GBC”. In the second dataset, we validate associations between genetic variants and serum expression levels of the preselected lncRNAs (cis-lncRNA-eQTLs) and build lncRNA expression prediction models. In the third dataset, we predict serum lncRNA expression based on individual genotypes and assess the association between genotype-based expression and GBC risk. AC084082.3 and LINC00662 showed increasing expression levels (p-value = 0.009), while C22orf34 expression decreased in the sequence from gallstones to GBC (p-value = 0.04). We identified and validated two cis-LINC00662-eQTLs (r² = 0.26) and three cis-C22orf34-eQTLs (r² = 0.24). Only LINC00662 showed a genotyped-based serum expression associated with GBC risk (OR = 1.25 per log2 expression unit, 95% CI 1.04–1.52, p-value = 0.02). Our results suggest that preselection of lncRNAs based on tissue samples and exploitation of cis-lncRNA-eQTLs may facilitate the identification of circulating noncoding RNAs linked to cancer risk. Full article

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2021

Jump to: 2023, 2022

27 pages, 904 KiB

Open AccessReview

The Emerging Role of PIWI-Interacting RNAs (piRNAs) in Gastrointestinal Cancers: An Updated Perspective

by Ismael Riquelme, Pablo Pérez-Moreno, Pablo Letelier, Priscilla Brebi and Juan Carlos Roa

Cancers 2022, 14(1), 202; https://doi.org/10.3390/cancers14010202 - 31 Dec 2021

Cited by 21 | Viewed by 3377

Abstract

Gastrointestinal (GI) cancers produce ~3.4 million related deaths worldwide, comprising 35% of all cancer-related deaths. The high mortality among GI cancers is due to late diagnosis, the presence of metastasis and drug resistance development. Additionally, current clinical markers do not adequately guide patient [...] Read more.

Gastrointestinal (GI) cancers produce ~3.4 million related deaths worldwide, comprising 35% of all cancer-related deaths. The high mortality among GI cancers is due to late diagnosis, the presence of metastasis and drug resistance development. Additionally, current clinical markers do not adequately guide patient management, thereby new and more reliable biomarkers and therapeutic targets are still needed for these diseases. RNA-seq technology has allowed the discovery of new types of RNA transcripts including PIWI-interacting RNAs (piRNAs), which have particular characteristics that enable these molecules to act via diverse molecular mechanisms for regulating gene expression. Cumulative evidence has described the potential role of piRNAs in the development of several tumor types as a likely explanation for certain genomic abnormalities and signaling pathways’ deregulations observed in cancer. In addition, these piRNAs might be also proposed as promising diagnostic or prognostic biomarkers or as potential therapeutic targets in malignancies. This review describes important topics about piRNAs including their molecular characteristics, biosynthesis processes, gene expression silencing mechanisms, and the manner in which these transcripts have been studied in samples and cell lines of GI cancers to elucidate their implications in these diseases. Moreover, this article discusses the potential clinical usefulness of piRNAs as biomarkers and therapeutic targets in GI cancers. Full article

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22 pages, 4768 KiB

Open AccessArticle

Loss of microRNA-135b Enhances Bone Metastasis in Prostate Cancer and Predicts Aggressiveness in Human Prostate Samples

by Mireia Olivan, Marta Garcia, Leticia Suárez, Marc Guiu, Laura Gros, Olga Méndez, Marina Rigau, Jaume Reventós, Miguel F. Segura, Inés de Torres, Jacques Planas, Xavier de la Cruz, Roger R. Gomis, Juan Morote, Ruth Rodríguez-Barrueco and Anna Santamaria

Cancers 2021, 13(24), 6202; https://doi.org/10.3390/cancers13246202 - 9 Dec 2021

Cited by 9 | Viewed by 4274

Abstract

About 70% of advanced-stage prostate cancer (PCa) patients will experience bone metastasis, which severely affects patients’ quality of life and progresses to lethal PCa in most cases. Hence, understanding the molecular heterogeneity of PCa cell populations and the signaling pathways associated with bone [...] Read more.

About 70% of advanced-stage prostate cancer (PCa) patients will experience bone metastasis, which severely affects patients’ quality of life and progresses to lethal PCa in most cases. Hence, understanding the molecular heterogeneity of PCa cell populations and the signaling pathways associated with bone tropism is crucial. For this purpose, we generated an animal model with high penetrance to metastasize to bone using an intracardiac percutaneous injection of PC3 cells to identify PCa metastasis-promoting factors. Using genomic high-throughput analysis we identified a miRNA signature involved in bone metastasis that also presents potential as a biomarker of PCa progression in human samples. In particular, the downregulation of miR-135b favored the incidence of bone metastases by significantly increasing PCa cells’ migratory capacity. Moreover, the PLAG1, JAKMIP2, PDGFA, and VTI1b target genes were identified as potential mediators of miR-135b’s role in the dissemination to bone. In this study, we provide a genomic signature involved in PCa bone growth, contributing to a better understanding of the mechanisms responsible for this process. In the future, our results could ultimately translate into promising new therapeutic targets for the treatment of lethal PCa. Full article

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34 pages, 4255 KiB

Open AccessReview

The Role of Long Non-Coding RNAs (lncRNAs) in Female Oriented Cancers

by Faiza Naz, Imran Tariq, Sajid Ali, Ahmed Somaida, Eduard Preis and Udo Bakowsky

Cancers 2021, 13(23), 6102; https://doi.org/10.3390/cancers13236102 - 3 Dec 2021

Cited by 17 | Viewed by 4788

Abstract

Recent advances in molecular biology have discovered the mysterious role of long non-coding RNAs (lncRNAs) as potential biomarkers for cancer diagnosis and targets for advanced cancer therapy. Studies have shown that lncRNAs take part in the incidence and development of cancers in humans. [...] Read more.

Recent advances in molecular biology have discovered the mysterious role of long non-coding RNAs (lncRNAs) as potential biomarkers for cancer diagnosis and targets for advanced cancer therapy. Studies have shown that lncRNAs take part in the incidence and development of cancers in humans. However, previously they were considered as mere RNA noise or transcription byproducts lacking any biological function. In this article, we present a summary of the progress on ascertaining the biological functions of five lncRNAs (HOTAIR, NEAT1, H19, MALAT1, and MEG3) in female-oriented cancers, including breast and gynecological cancers, with the perspective of carcinogenesis, cancer proliferation, and metastasis. We provide the current state of knowledge from the past five years of the literature to discuss the clinical importance of such lncRNAs as therapeutic targets or early diagnostic biomarkers. We reviewed the consequences, either oncogenic or tumor-suppressing features, of their aberrant expression in female-oriented cancers. We tried to explain the established mechanism by which they regulate cancer proliferation and metastasis by competing with miRNAs and other mechanisms involved via regulating genes and signaling pathways. In addition, we revealed the association between stated lncRNAs and chemo-resistance or radio-resistance and their potential clinical applications and future perspectives. Full article

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14 pages, 1095 KiB

Open AccessFeature PaperReview

Regulation of Adaptive Tumor Immunity by Non-Coding RNAs

by Eleftheria Papaioannou, María del Pilar González-Molina, Ana M. Prieto-Muñoz, Laura Gámez-Reche and Alicia González-Martín

Cancers 2021, 13(22), 5651; https://doi.org/10.3390/cancers13225651 - 12 Nov 2021

Cited by 5 | Viewed by 3029

Abstract

Cancer immunology research has mainly focused on the role of protein-coding genes in regulating immune responses to tumors. However, despite more than 70% of the human genome is transcribed, less than 2% encodes proteins. Many non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long [...] Read more.

Cancer immunology research has mainly focused on the role of protein-coding genes in regulating immune responses to tumors. However, despite more than 70% of the human genome is transcribed, less than 2% encodes proteins. Many non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have been identified as critical regulators of immune cell development and function, suggesting that they might play important roles in orchestrating immune responses against tumors. In this review, we summarize the scientific advances on the role of ncRNAs in regulating adaptive tumor immunity, and discuss their potential therapeutic value in the context of cancer immunotherapy. Full article

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29 pages, 1306 KiB

Open AccessReview

Extracellular Vesicles in Lung Cancer Metastasis and Their Clinical Applications

by Michela Saviana, Giulia Romano, Patricia Le, Mario Acunzo and Patrick Nana-Sinkam

Cancers 2021, 13(22), 5633; https://doi.org/10.3390/cancers13225633 - 11 Nov 2021

Cited by 13 | Viewed by 4062

Abstract

Extracellular vesicles (EVs) are heterogenous membrane-encapsulated vesicles secreted by every cell into the extracellular environment. EVs carry bioactive molecules, including proteins, lipids, DNA, and different RNA forms, which can be internalized by recipient cells, thus altering their biological characteristics. Given that EVs are [...] Read more.

Extracellular vesicles (EVs) are heterogenous membrane-encapsulated vesicles secreted by every cell into the extracellular environment. EVs carry bioactive molecules, including proteins, lipids, DNA, and different RNA forms, which can be internalized by recipient cells, thus altering their biological characteristics. Given that EVs are commonly found in most body fluids, they have been widely described as mediators of communication in several physiological and pathological processes, including cancer. Moreover, their easy detection in biofluids makes them potentially useful candidates as tumor biomarkers. In this manuscript, we review the current knowledge regarding EVs and non-coding RNAs and their role as drivers of the metastatic process in lung cancer. Furthermore, we present the most recent applications for EVs and non-coding RNAs as cancer therapeutics and their relevance as clinical biomarkers. Full article

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44 pages, 2258 KiB

Open AccessReview

A Focus on Regulatory Networks Linking MicroRNAs, Transcription Factors and Target Genes in Neuroblastoma

by Patrizia Perri, Mirco Ponzoni, Maria Valeria Corrias, Isabella Ceccherini, Simona Candiani and Tiziana Bachetti

Cancers 2021, 13(21), 5528; https://doi.org/10.3390/cancers13215528 - 3 Nov 2021

Cited by 19 | Viewed by 4764

Abstract

Neuroblastoma (NB) is a tumor of the peripheral sympathetic nervous system that substantially contributes to childhood cancer mortality. NB originates from neural crest cells (NCCs) undergoing a defective sympathetic neuronal differentiation and although the starting events leading to the development of NB remain [...] Read more.

Neuroblastoma (NB) is a tumor of the peripheral sympathetic nervous system that substantially contributes to childhood cancer mortality. NB originates from neural crest cells (NCCs) undergoing a defective sympathetic neuronal differentiation and although the starting events leading to the development of NB remain to be fully elucidated, the master role of genetic alterations in key oncogenes has been ascertained: (1) amplification and/or over-expression of MYCN, which is strongly associated with tumor progression and invasion; (2) activating mutations, amplification and/or over-expression of ALK, which is involved in tumor initiation, angiogenesis and invasion; (3) amplification and/or over-expression of LIN28B, promoting proliferation and suppression of neuroblast differentiation; (4) mutations and/or over-expression of PHOX2B, which is involved in the regulation of NB differentiation, stemness maintenance, migration and metastasis. Moreover, altered microRNA (miRNA) expression takes part in generating pathogenetic networks, in which the regulatory loops among transcription factors, miRNAs and target genes lead to complex and aberrant oncogene expression that underlies the development of a tumor. In this review, we have focused on the circuitry linking the oncogenic transcription factors MYCN and PHOX2B with their transcriptional targets ALK and LIN28B and the tumor suppressor microRNAs let-7, miR-34 and miR-204, which should act as down-regulators of their expression. We have also looked at the physiologic role of these genetic and epigenetic determinants in NC development, as well as in terminal differentiation, with their pathogenic dysregulation leading to NB oncogenesis. Full article

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16 pages, 5412 KiB

Open AccessArticle

Molecular Classification of Breast Cancer Utilizing Long Non-Coding RNA (lncRNA) Transcriptomes Identifies Novel Diagnostic lncRNA Panel for Triple-Negative Breast Cancer

by Hibah Shaath, Ramesh Elango and Nehad M. Alajez

Cancers 2021, 13(21), 5350; https://doi.org/10.3390/cancers13215350 - 26 Oct 2021

Cited by 24 | Viewed by 4235

Abstract

Breast cancer remains the world’s most prevalent cancer, responsible for around 685,000 deaths globally despite international research efforts and advances in clinical management. While estrogen receptor positive (ER+), progesterone receptor positive (PR+), and human epidermal growth factor receptor positive (HER2+) subtypes are easily [...] Read more.

Breast cancer remains the world’s most prevalent cancer, responsible for around 685,000 deaths globally despite international research efforts and advances in clinical management. While estrogen receptor positive (ER+), progesterone receptor positive (PR+), and human epidermal growth factor receptor positive (HER2+) subtypes are easily classified and can be targeted, there remains no direct diagnostic test for triple-negative breast cancer (TNBC), except for the lack of receptors expression. The identification of long non-coding RNAs (lncRNAs) and the roles they play in cancer progression has recently proven to be beneficial. In the current study, we utilize RNA sequencing data to identify lncRNA-based biomarkers associated with TNBC, ER+ subtypes, and normal breast tissue. The Marker Finder algorithm identified the lncRNA transcript panel most associated with each molecular subtype and the receiver operating characteristic (ROC) analysis was used to validate the diagnostic potential (area under the curve (AUC) of ≥8.0 and p value < 0.0001). Focusing on TNBC, findings from the discovery cohort were validated in an additional two cohorts, identifying 13 common lncRNA transcripts enriched in TNBC. Binary regression analysis identified a four lncRNA transcript signature (ENST00000425820.1, ENST00000448208.5, ENST00000521666.1, and ENST00000650510.1) with the highest diagnostic power for TNBC. The ENST00000671612.1 lncRNA transcript correlated with worse refractory free survival (RFS). Our data provides a step towards finding a novel diagnostic lncRNA-based panel for TNBC with potential therapeutic implications. Full article

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36 pages, 1098 KiB

Open AccessReview

(In)Distinctive Role of Long Non-Coding RNAs in Common and Rare Ovarian Cancers

by Maja Sabol, Jean Calleja-Agius, Riccardo Di Fiore, Sherif Suleiman, Sureyya Ozcan, Mark P. Ward and Petar Ozretić

Cancers 2021, 13(20), 5040; https://doi.org/10.3390/cancers13205040 - 9 Oct 2021

Cited by 5 | Viewed by 4276

Abstract

Rare ovarian cancers (ROCs) are OCs with an annual incidence of fewer than 6 cases per 100,000 women. They affect women of all ages, but due to their low incidence and the potential clinical inexperience in management, there can be a delay in [...] Read more.

Rare ovarian cancers (ROCs) are OCs with an annual incidence of fewer than 6 cases per 100,000 women. They affect women of all ages, but due to their low incidence and the potential clinical inexperience in management, there can be a delay in diagnosis, leading to a poor prognosis. The underlying causes for these tumors are varied, but generally, the tumors arise due to alterations in gene/protein expression in cellular processes that regulate normal proliferation and its checkpoints. Dysregulation of the cellular processes that lead to cancer includes gene mutations, epimutations, non-coding RNA (ncRNA) regulation, posttranscriptional and posttranslational modifications. Long non-coding RNA (lncRNA) are defined as transcribed RNA molecules, more than 200 nucleotides in length which are not translated into proteins. They regulate gene expression through several mechanisms and therefore add another level of complexity to the regulatory mechanisms affecting tumor development. Since few studies have been performed on ROCs, in this review we summarize the mechanisms of action of lncRNA in OC, with an emphasis on ROCs. Full article

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30 pages, 1262 KiB

Open AccessReview

The Functional Role of Long Non-Coding RNAs in Melanoma

by Michal Wozniak and Malgorzata Czyz

Cancers 2021, 13(19), 4848; https://doi.org/10.3390/cancers13194848 - 28 Sep 2021

Cited by 14 | Viewed by 4385

Abstract

Melanoma is the most lethal skin cancer, with increasing incidence worldwide. The molecular events that drive melanoma development and progression have been extensively studied, resulting in significant improvements in diagnostics and therapeutic approaches. However, a high drug resistance to targeted therapies and adverse [...] Read more.

Melanoma is the most lethal skin cancer, with increasing incidence worldwide. The molecular events that drive melanoma development and progression have been extensively studied, resulting in significant improvements in diagnostics and therapeutic approaches. However, a high drug resistance to targeted therapies and adverse effects of immunotherapies are still a major challenge in melanoma treatment. Therefore, the elucidation of molecular mechanisms of melanomagenesis and cancer response to treatment is of great importance. Recently, many studies have revealed the close association of long noncoding RNAs (lncRNAs) with the development of many cancers, including melanoma. These RNA molecules are able to regulate a plethora of crucial cellular processes including proliferation, differentiation, migration, invasion and apoptosis through diverse mechanisms, and even slight dysregulation of their expression may lead to tumorigenesis. lncRNAs are able to bind to protein complexes, DNA and RNAs, affecting their stability, activity, and localization. They can also regulate gene expression in the nucleus. Several functions of lncRNAs are context-dependent. This review summarizes current knowledge regarding the involvement of lncRNAs in melanoma. Their possible role as prognostic markers of melanoma response to treatment and in resistance to therapy is also discussed Full article

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15 pages, 2258 KiB

Open AccessArticle

High miR-30 Expression Associates with Improved Breast Cancer Patient Survival and Treatment Outcome

by Maral Jamshidi, Rainer Fagerholm, Taru A. Muranen, Sippy Kaur, Swapnil Potdar, Sofia Khan, Eliisa Netti, John-Patrick Mpindi, Bhagwan Yadav, Johanna I. Kiiski, Kristiina Aittomäki, Päivi Heikkilä, Jani Saarela, Ralf Bützow, Carl Blomqvist and Heli Nevanlinna

Cancers 2021, 13(12), 2907; https://doi.org/10.3390/cancers13122907 - 10 Jun 2021

Cited by 5 | Viewed by 3184

Abstract

Deregulated miRNA expression has been suggested in several stages of breast cancer pathogenesis. We have studied the miR-30 family, in particular miR-30d, in relation to breast cancer patient survival and treatment outcomes. With tumor specimens from 1238 breast cancer patients, we analyzed the [...] Read more.

Deregulated miRNA expression has been suggested in several stages of breast cancer pathogenesis. We have studied the miR-30 family, in particular miR-30d, in relation to breast cancer patient survival and treatment outcomes. With tumor specimens from 1238 breast cancer patients, we analyzed the association of miR-30d expression with tumor characteristics with the 5-year occurrence of breast cancer-specific death or distant metastasis (BDDM), and with 10-year breast cancer survival (BCS). We conducted a two-stage drug-screen to investigate the impact of miR-30 family members (miR-30a-30e) on sensitivity to doxorubicin and lapatinib in six breast cancer cell lines HCC1937, HCC1954, MDA-MB-361, MCF7, MDA-MB-436 and CAL-120, using drug sensitivity scores (DSS) to compare the miR-30 family mimics to their specific inhibitors. The study was complemented with Ingenuity Pathway Analysis (IPA) with the METABRIC data. We found that while high miR-30d expression is typical for aggressive tumors, it predicts better metastasis-free (p_BDDM = 0.035, HR = 0.63, 95% CI = 0.4–0.9) and breast cancer-specific survival (p_BCS = 0.018, HR = 0.61, 95% CI = 0.4–0.9), especially in HER2-positive (p_BDDM = 0.0009), ER-negative (p_BDDM = 0.003), p53-positive (p_BDDM = 0.011), and highly proliferating (p_BDDM = 0.0004) subgroups, and after adjuvant chemotherapy (p_BDDM = 0.035). MiR-30d predicted survival independently of standard prognostic markers (p_BDDM = 0.0004). In the drug-screening test, the miR-30 family sensitized the HER2-positive HCC1954 cell line to lapatinib (p < 10⁻²) and HCC1937, MDA-MB-361, MDA-MB-436 and CAL120 to doxorubicin (p < 10⁻⁴) with an opposite impact on MCF7. According to the pathway analysis, the miR-30 family has a suppressive effect on cell motility and metastasis in breast cancer. Our results suggest prognostic and predictive potential for the miR-30 family, which warrants further investigation. Full article

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25 pages, 9210 KiB

Open AccessArticle

LncRNA PART1 Promotes Proliferation and Migration, Is Associated with Cancer Stem Cells, and Alters the miRNA Landscape in Triple-Negative Breast Cancer

by Brianne M. Cruickshank, Marie-Claire D. Wasson, Justin M. Brown, Wasundara Fernando, Jaganathan Venkatesh, Olivia L. Walker, Fiorella Morales-Quintanilla, Margaret L. Dahn, Dejan Vidovic, Cheryl A. Dean, Carter VanIderstine, Graham Dellaire and Paola Marcato

Cancers 2021, 13(11), 2644; https://doi.org/10.3390/cancers13112644 - 27 May 2021

Cited by 17 | Viewed by 5855

Abstract

Triple-negative breast cancers (TNBCs) are aggressive, lack targeted therapies and are enriched in cancer stem cells (CSCs). Novel therapies which target CSCs within these tumors would likely lead to improved outcomes for TNBC patients. Long non-coding RNAs (lncRNAs) are potential therapeutic targets for [...] Read more.

Triple-negative breast cancers (TNBCs) are aggressive, lack targeted therapies and are enriched in cancer stem cells (CSCs). Novel therapies which target CSCs within these tumors would likely lead to improved outcomes for TNBC patients. Long non-coding RNAs (lncRNAs) are potential therapeutic targets for TNBC and CSCs. We demonstrate that lncRNA prostate androgen regulated transcript 1 (PART1) is enriched in TNBCs and in Aldefluor^high CSCs, and is associated with worse outcomes among basal-like breast cancer patients. Although PART1 is androgen inducible in breast cancer cells, analysis of patient tumors indicates its androgen regulation has minimal clinical impact. Knockdown of PART1 in TNBC cell lines and a patient-derived xenograft decreased cell proliferation, migration, tumor growth, and mammosphere formation potential. Transcriptome analyses revealed that the lncRNA affects expression of hundreds of genes (e.g., myosin-Va, MYO5A; zinc fingers and homeoboxes protein 2, ZHX2). MiRNA 4.0 GeneChip and TaqMan assays identified multiple miRNAs that are regulated by cytoplasmic PART1, including miR-190a-3p, miR-937-5p, miR-22-5p, miR-30b-3p, and miR-6870-5p. We confirmed the novel interaction between PART1 and miR-937-5p. In general, miRNAs altered by PART1 were less abundant than PART1, potentially leading to cell line-specific effects in terms miRNA-PART1 interactions and gene regulation. Together, the altered miRNA landscape induced by PART1 explains most of the protein-coding gene regulation changes (e.g., MYO5A) induced by PART1 in TNBC. Full article

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35 pages, 3290 KiB

Open AccessFeature PaperReview

Regulation of Long Non-Coding RNAs by Plant Secondary Metabolites: A Novel Anticancer Therapeutic Approach

by Mohammad Reza Kalhori, Hamid Khodayari, Saeed Khodayari, Miko Vesovic, Gloria Jackson, Mohammad Hosein Farzaei and Anupam Bishayee

Cancers 2021, 13(6), 1274; https://doi.org/10.3390/cancers13061274 - 13 Mar 2021

Cited by 26 | Viewed by 4965

Abstract

Long non-coding RNAs (lncRNAs) are a class of non-coding RNAs that play an essential role in various cellular activities, such as differentiation, proliferation, and apoptosis. Dysregulation of lncRNAs serves a fundamental role in the progression and initiation of various diseases, including cancer. Precision [...] Read more.

Long non-coding RNAs (lncRNAs) are a class of non-coding RNAs that play an essential role in various cellular activities, such as differentiation, proliferation, and apoptosis. Dysregulation of lncRNAs serves a fundamental role in the progression and initiation of various diseases, including cancer. Precision medicine is a suitable and optimal treatment method for cancer so that based on each patient’s genetic content, a specific treatment or drug is prescribed. The rapid advancement of science and technology in recent years has led to many successes in this particular treatment. Phytochemicals are a group of natural compounds extracted from fruits, vegetables, and plants. Through the downregulation of oncogenic lncRNAs or upregulation of tumor suppressor lncRNAs, these bioactive compounds can inhibit metastasis, proliferation, invasion, migration, and cancer cells. These natural products can be a novel and alternative strategy for cancer treatment and improve tumor cells’ sensitivity to standard adjuvant therapies. This review will discuss the antineoplastic effects of bioactive plant secondary metabolites (phytochemicals) via regulation of expression of lncRNAs in various human cancers and their potential for the treatment and prevention of human cancers. Full article

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21 pages, 1005 KiB

Open AccessReview

Involvement of Long Non-Coding RNAs in Glucose Metabolism in Cancer

by Amar Balihodzic, Dominik A. Barth, Felix Prinz and Martin Pichler

Cancers 2021, 13(5), 977; https://doi.org/10.3390/cancers13050977 - 26 Feb 2021

Cited by 22 | Viewed by 4666

Abstract

The rapid and uncontrolled proliferation of cancer cells is supported by metabolic reprogramming. Altered glucose metabolism supports cancer growth and progression. Compared with normal cells, cancer cells show increased glucose uptake, aerobic glycolysis and lactate production. Byproducts of adjusted glucose metabolism provide additional [...] Read more.

The rapid and uncontrolled proliferation of cancer cells is supported by metabolic reprogramming. Altered glucose metabolism supports cancer growth and progression. Compared with normal cells, cancer cells show increased glucose uptake, aerobic glycolysis and lactate production. Byproducts of adjusted glucose metabolism provide additional benefits supporting hallmark capabilities of cancer cells. Long non-coding RNAs (lncRNAs) are a heterogeneous group of transcripts of more than 200 nucleotides in length. They regulate numerous cellular processes, primarily through physical interaction with other molecules. Dysregulated lncRNAs are involved in all hallmarks of cancer including metabolic alterations. They may upregulate metabolic enzymes, modulate the expression of oncogenic or tumor-suppressive genes and disturb metabolic signaling pathways favoring cancer progression. Thus, lncRNAs are not only potential clinical biomarkers for cancer diagnostics and prediction but also possible therapeutic targets. This review summarizes the lncRNAs involved in cancer glucose metabolism and highlights their underlying molecular mechanisms. Full article

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18 pages, 2193 KiB

Open AccessReview

Argonaute Proteins Take Center Stage in Cancers

by Iwona Nowak and Aishe A. Sarshad

Cancers 2021, 13(4), 788; https://doi.org/10.3390/cancers13040788 - 13 Feb 2021

Cited by 17 | Viewed by 4689

Abstract

Argonaute proteins (AGOs) play crucial roles in RNA-induced silencing complex (RISC) formation and activity. AGOs loaded with small RNA molecules (miRNA or siRNA) either catalyze endoribonucleolytic cleavage of target RNAs or recruit factors responsible for translational silencing and target destabilization. miRNAs are well [...] Read more.

Argonaute proteins (AGOs) play crucial roles in RNA-induced silencing complex (RISC) formation and activity. AGOs loaded with small RNA molecules (miRNA or siRNA) either catalyze endoribonucleolytic cleavage of target RNAs or recruit factors responsible for translational silencing and target destabilization. miRNAs are well characterized and broadly studied in tumorigenesis; nevertheless, the functions of the AGOs in cancers have lagged behind. Here, we discuss the current state of knowledge on the role of AGOs in tumorigenesis, highlighting canonical and non-canonical functions of AGOs in cancer cells, as well as the biomarker potential of AGO expression in different of tumor types. Furthermore, we point to the possible application of the AGOs in development of novel therapeutic approaches. Full article

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22 pages, 792 KiB

Open AccessReview

Functional Interaction among lncRNA HOTAIR and MicroRNAs in Cancer and Other Human Diseases

by Monica Cantile, Maurizio Di Bonito, Maura Tracey De Bellis and Gerardo Botti

Cancers 2021, 13(3), 570; https://doi.org/10.3390/cancers13030570 - 2 Feb 2021

Cited by 65 | Viewed by 5948

Abstract

LncRNAs are a class of non-coding RNAs mostly involved in regulation of cancer initiation, metastatic progression, and drug resistance, through participation in post-transcription regulatory processes by interacting with different miRNAs. LncRNAs are able to compete with endogenous RNAs by binding and sequestering miRNAs [...] Read more.

LncRNAs are a class of non-coding RNAs mostly involved in regulation of cancer initiation, metastatic progression, and drug resistance, through participation in post-transcription regulatory processes by interacting with different miRNAs. LncRNAs are able to compete with endogenous RNAs by binding and sequestering miRNAs and thereby regulating the expression of their target genes, often represented by oncogenes. The lncRNA HOX transcript antisense RNA (HOTAIR) represents a diagnostic, prognostic, and predictive biomarker in many human cancers, and its functional interaction with miRNAs has been described as crucial in the modulation of different cellular processes during cancer development. The aim of this review is to highlight the relation between lncRNA HOTAIR and different microRNAs in human diseases, discussing the contribution of these functional interactions, especially in cancer development and progression. Full article

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