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Noncoding RNAs as New Instruments in the Orchestration of Cell Death and Cancer Therapy Resistance

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (15 May 2021) | Viewed by 25860

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Prof. Dr. Silvia Zappavigna

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Department of Precision Medicine, University of Campania “L. Vanvitelli” via L. De Crecchio 7, 80138 Naples, Italy
Interests: target therapy; cell death mechanisms; microRNAs; long non-coding RNAs; biomarkers; nanotechnology; drug delivery; signal transduction; cancer; circulating tumor cells; glioblastoma; prostate cancer; hepatocellular cancer
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Dr. Amalia Luce

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Department of Precision Medicine, University of Campania “L. Vanvitelli” via L. De Crecchio 7, 80138 Naples, Italy
Interests: microRNAs; long non-coding RNAs; extracellular vesicles; regulation of gene expression; cell death mechanisms; cell signaling; cancer therapy; drug delivery systems; target therapy; immunotherapy; prostate cancer; colorectal cancer; glioblastoma
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

Noncoding RNAs (ncRNAs) are emerging as key orchestrators of tumorigenesis. Recent advances in biotechnologies, such as high-throughput sequencing, genome editing, and mouse modeling, have allowed for functional studies of ncRNAs to provide new perspectives in the fight against cancer. In addition to miRNAs and lncRNAs, that play a key role in the regulation of gene expression, other novel ncRNAs, such as transfer RNA (tRNA) fragments, snoRNA-related lncRNAs (sno-lncRNAs), and circRNAs have also appeared on the radar of cancer researchers. Increasing evidence shows that ncRNAs function either as tumor suppressors or oncogenes by regulating one or several cancer hallmarks, including evading cell death, metastasis, and drug resistance. Cancer therapy resistance is a major challenge in clinics and scientific research, resulting in tumor recurrence and metastasis. The mechanisms of therapy resistance are complex and result from multiple factors. Among them, ncRNAs have been shown to regulate drug resistance by targeting drug resistance-related genes or influencing genes related to cell proliferation and cell death. Indeed, ncRNAs target and inhibit the expression of several cellular regulators, including those controlling programmed cell death via the intrinsic and extrinsic, p53-, and endoplasmic reticulum (ER) stress-induced apoptotic pathways, as well as pathways of necroptosis, mitophagy, and autophagy.

This Special issue will focus on the recent advances in “Noncoding RNAs as New Instruments in the Orchestration of Cell Death and Cancer Therapy Resistance”, including new findings concerning ncRNAs that modulate apoptosis, autophagy, and other programmed cell death and cancer resistance pathways, as well as emerging data on miRNA–lncRNA interactions that affect cell death regulation and mechanisms of resistance to therapy. Current research progress on ncRNAs for clinical and/or potential translational applications, including the identification of novel therapeutic approaches for ncRNA targeting and delivery strategies, will be also appreciated.

Prof. Silvia Zappavigna
Prof. Amalia Luce
Guest Editors

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Keywords

regulatory ncRNAs
cell death mechanisms
cancer therapy
cancer resistance
ncRNA based-therapy
ncRNA deregulation
delivery strategies
miRNA/lncRNA interactions

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Published Papers (7 papers)

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Research

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13 pages, 1861 KiB

Open AccessArticle

Pharmacological Inhibition of miR-130 Family Suppresses Bladder Tumor Growth by Targeting Various Oncogenic Pathways via PTPN1

by Yuya Monoe, Kentaro Jingushi, Akitaka Kawase, Takayuki Hirono, Ryo Hirose, Yoshino Nakatsuji, Kaori Kitae, Yuko Ueda, Hiroaki Hase, Yuichi Abe, Jun Adachi, Takeshi Tomonaga and Kazutake Tsujikawa

Int. J. Mol. Sci. 2021, 22(9), 4751; https://doi.org/10.3390/ijms22094751 - 29 Apr 2021

Cited by 9 | Viewed by 2974

Abstract

Previously, we have revealed that the miR-130 family (miR-130b, miR-301a, and miR-301b) functions as an oncomiR in bladder cancer. The pharmacological inhibition of the miR-130 family molecules by the seed-targeting strategy with an 8-mer tiny locked nucleic acid (LNA) inhibits the growth, migration, and invasion of bladder cancer cells by repressing stress fiber formation. Here, we searched for a functionally advanced target sequence with LNA for the miR-130 family with low cytotoxicity and found LNA #9 (A(L)^i^i^A(L)^T(L)^T(L)^G(L)^5(L)^A(L)^5(L)^T(L)^G) as a candidate LNA. LNA #9 inhibited cell growth in vitro and in an in vivo orthotopic bladder cancer model. Proteome-wide tyrosine phosphorylation analysis suggested that the miR-130 family upregulates a wide range of receptor tyrosine kinases (RTKs) signaling via the expression of phosphorylated Src (pSrc^Tyr416). SILAC-based proteome analysis and a luciferase assay identified protein tyrosine phosphatase non-receptor type 1 (PTPN1), which is implicated as a negative regulator of multiple signaling pathways downstream of RTKs as a target gene of the miR-130 family. The miR-130-targeted LNA increased and decreased PTPN1 and pSrc^Tyr416 expressions, respectively. PTPN1 knockdown led to increased tumor properties (cell growth, invasion, and migration) and increased pSrc^Tyr416 expression in bladder cancer cells, suggesting that the miR-130 family upregulates multiple RTK signaling by targeting PTPN1 and subsequent Src activation in bladder cancer. Thus, our newly designed miR-130 family targeting LNA could be a promising nucleic acid therapeutic agent for bladder cancer. Full article

(This article belongs to the Special Issue Noncoding RNAs as New Instruments in the Orchestration of Cell Death and Cancer Therapy Resistance)

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19 pages, 2304 KiB

Open AccessArticle

S-Adenosylmethionine Inhibits Cell Growth and Migration of Triple Negative Breast Cancer Cells through Upregulating MiRNA-34c and MiRNA-449a

by Alessandra Coppola, Concetta Paola Ilisso, Antonietta Stellavato, Chiara Schiraldi, Michele Caraglia, Laura Mosca, Giovanna Cacciapuoti and Marina Porcelli

Int. J. Mol. Sci. 2021, 22(1), 286; https://doi.org/10.3390/ijms22010286 - 30 Dec 2020

Cited by 13 | Viewed by 3166

Abstract

Triple-negative breast cancer (TNBC) is one of the most common malignancies worldwide and shows maximum invasiveness and a high risk of metastasis. Recently, many natural compounds have been highlighted as a valuable source of new and less toxic drugs to enhance breast cancer therapy. Among them, S-adenosyl-L-methionine (AdoMet) has emerged as a promising anti-cancer agent. MicroRNA (miRNA or miR)-based gene therapy provides an interesting antitumor approach to integrated cancer therapy. In this study, we evaluated AdoMet-induced modulation of miRNA-34c and miRNA-449a expression in MDA-MB-231 and MDA-MB-468 TNBC cells. We demonstrated that AdoMet upregulates miR-34c and miR-449a expression in both cell lines. We found that the combination of AdoMet with miR-34c or miR-449a mimic strongly potentiated the pro-apoptotic effect of the sulfonium compound by a caspase-dependent mechanism. For the first time, by video time-lapse microscopy, we showed that AdoMet inhibited the in vitro migration of MDA-MB-231 and MDA-MB-468 cells and that the combination with miR-34c or miR-449a mimic strengthened the effect of the sulfonium compound through the modulation of β-catenin and Small Mother Against Decapentaplegic (SMAD) signaling pathways. Our results furnished the first evidence that AdoMet exerts its antitumor effects in TNBC cells through upregulating the expression of miR-34c and miR-449a. Full article

(This article belongs to the Special Issue Noncoding RNAs as New Instruments in the Orchestration of Cell Death and Cancer Therapy Resistance)

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13 pages, 1738 KiB

Open AccessArticle

Identification of Recurrent Mutations in the microRNA-Binding Sites of B-Cell Lymphoma-Associated Genes in Follicular Lymphoma

by Erika Larrea, Marta Fernandez-Mercado, José Afonso Guerra-Assunção, Jun Wang, Ibai Goicoechea, Ayman Gaafar, Izaskun Ceberio, Carmen Lobo, Jessica Okosun, Anton J. Enright, Jude Fitzgibbon and Charles H. Lawrie

Int. J. Mol. Sci. 2020, 21(22), 8795; https://doi.org/10.3390/ijms21228795 - 20 Nov 2020

Cited by 2 | Viewed by 2652

Abstract

Follicular lymphoma (FL) is a common indolent B-cell lymphoma that can transform into the more aggressive transformed FL (tFL). However, the molecular process driving this transformation is uncertain. In this work, we aimed to identify microRNA (miRNA)-binding sites recurrently mutated in follicular lymphoma patients, as well as in transformed FL patients. Using whole-genome sequencing data from FL tumors, we discovered 544 mutations located in bioinformatically predicted microRNA-binding sites. We then studied these specific regions using targeted sequencing in a cohort of 55 FL patients, found 16 recurrent mutations, and identified a further 69 variants. After filtering for QC, we identified 21 genes with mutated miRNA-binding sites that were also enriched for B-cell-associated genes by Gene Ontology. Over 40% of mutations identified in these genes were present exclusively in tFL patients. We validated the predicted miRNA-binding sites of five of the genes by luciferase assay and demonstrated that the identified mutations in BCL2 and EZH2 genes impaired the binding efficiency of miR-5008 and miR-144 and regulated the endogenous levels of messenger RNA (mRNA). Full article

(This article belongs to the Special Issue Noncoding RNAs as New Instruments in the Orchestration of Cell Death and Cancer Therapy Resistance)

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18 pages, 5861 KiB

Open AccessArticle

Tumor Suppressor Role of hsa-miR-193a-3p and -5p in Cutaneous Melanoma

by Beatrice Polini, Sara Carpi, Stefano Doccini, Valentina Citi, Alma Martelli, Sara Feola, Filippo Maria Santorelli, Vincenzo Cerullo, Antonella Romanini and Paola Nieri

Int. J. Mol. Sci. 2020, 21(17), 6183; https://doi.org/10.3390/ijms21176183 - 27 Aug 2020

Cited by 18 | Viewed by 3254

Abstract

Background: Remarkable deregulation of several microRNAs (miRNAs) is demonstrated in cutaneous melanoma. hsa-miR-193a-3p is reported to be under-expressed in tissues and in plasma of melanoma patients, but the role of both miR-193a arms in melanoma is not known yet. Methods: After observing the reduced levels of miR-193a arms in plasma exosomes of melanoma patients, the effects of hsa-miR-193a-3p and –5p transfection in cutaneous melanoma cell lines are investigated. Results: In melanoma cell lines A375, 501Mel, and MeWo, the ectopic over-expression of miR-193a arms significantly reduced cell viability as well as the expression of genes involved in proliferation (ERBB2, KRAS, PIK3R3, and MTOR) and apoptosis (MCL1 and NUSAP1). These functional features were accompanied by a significant downregulation of Akt and Erk pathways and a strong increase in the apoptotic process. Since in silico databases revealed TROY, an orphan member of the tumor necrosis receptor family, as a potential direct target of miR-193a-5p, this possibility was investigated using the luciferase assay and excluded by our results. Conclusions: Our results underline a relevant role of miR-193a, both -3p and -5p, as tumor suppressors clarifying the intracellular mechanisms involved and suggesting that their ectopic over-expression could represent a novel treatment for cutaneous melanoma patients. Full article

(This article belongs to the Special Issue Noncoding RNAs as New Instruments in the Orchestration of Cell Death and Cancer Therapy Resistance)

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Review

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15 pages, 1054 KiB

Open AccessReview

The Role of microRNAs in Development of Colitis-Associated Colorectal Cancer

by Marco Bocchetti, Maria Grazia Ferraro, Filippo Ricciardiello, Alessandro Ottaiano, Amalia Luce, Alessia Maria Cossu, Marianna Scrima, Wing-Yan Leung, Marianna Abate, Paola Stiuso, Michele Caraglia, Silvia Zappavigna and Tung On Yau

Int. J. Mol. Sci. 2021, 22(8), 3967; https://doi.org/10.3390/ijms22083967 - 12 Apr 2021

Cited by 29 | Viewed by 4593

Abstract

Colorectal cancer (CRC) is the third most deadly cancer worldwide, and inflammatory bowel disease (IBD) is one of the critical factors in CRC carcinogenesis. IBD is responsible for an unphysiological and sustained chronic inflammation environment favoring the transformation. MicroRNAs (miRNAs) belong to a class of highly conserved short single-stranded segments (18–25 nucleotides) non-coding RNA and have been extensively discussed in both CRC and IBD. However, the role of miRNAs in the development of colitis-associated CRC (CAC) is less clear. The aim of this review is to summarize the major upregulated (miR-18a, miR-19a, miR-21, miR-31, miR-155 and miR-214) and downregulated (miR-124, miR-193a-3p and miR-139-5p) miRNAs in CAC, and their roles in genes’ expression modulation in chronic colonic-inflammation-induced carcinogenesis, including programmed cell-death pathways. These miRNAs dysregulation could be applied for early CAC diagnosis, to predict therapy efficacy and for precision treatment. Full article

(This article belongs to the Special Issue Noncoding RNAs as New Instruments in the Orchestration of Cell Death and Cancer Therapy Resistance)

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16 pages, 319 KiB

Open AccessReview

Comprehensive Review on the Clinical Relevance of Long Non-Coding RNAs in Cutaneous Melanoma

by Vincenzo De Falco, Stefania Napolitano, Daniela Esposito, Luigi Pio Guerrera, Davide Ciardiello, Luigi Formisano and Teresa Troiani

Int. J. Mol. Sci. 2021, 22(3), 1166; https://doi.org/10.3390/ijms22031166 - 25 Jan 2021

Cited by 8 | Viewed by 2423

Abstract

Cutaneous melanoma is considered a rare tumor, although it is one of the most common cancers in young adults and its incidence has risen in the last decades. Targeted therapy, with BRAF and MEK inhibitors, and immunotherapy revolutionized the treatment of metastatic melanoma but there is still a considerable percentage of patients with primary or acquired resistance to these therapies. Recently, oncology researchers directed their attention at the role of long non-coding RNAs (lncRNAs) in different types of cancers, including melanoma. lncRNAs are RNA transcripts, initially considered “junk sequences”, that have been proven to have a crucial role in the fine regulation of physiological and pathological processes of different tissues. Furthermore, they are more expressed in tumors than protein-coding genes, constituting perfect candidates either as biomarkers (diagnostic, prognostic, predictive) or as therapeutic targets. In this work, we reviewed all the literature available for lncRNA in melanoma, elucidating all the potential roles in this tumor. Full article

(This article belongs to the Special Issue Noncoding RNAs as New Instruments in the Orchestration of Cell Death and Cancer Therapy Resistance)

20 pages, 686 KiB

Open AccessReview

The Functions and Unique Features of LncRNAs in Cancer Development and Tumorigenesis

by Kenzui Taniue and Nobuyoshi Akimitsu

Int. J. Mol. Sci. 2021, 22(2), 632; https://doi.org/10.3390/ijms22020632 - 10 Jan 2021

Cited by 133 | Viewed by 5637

Abstract

Over the past decades, research on cancer biology has focused on the involvement of protein-coding genes in cancer development. Long noncoding RNAs (lncRNAs), which are transcripts longer than 200 nucleotides that lack protein-coding potential, are an important class of RNA molecules that are involved in a variety of biological functions. Although the functions of a majority of lncRNAs have yet to be clarified, some lncRNAs have been shown to be associated with human diseases such as cancer. LncRNAs have been shown to contribute to many important cancer phenotypes through their interactions with other cellular macromolecules including DNA, protein and RNA. Here we describe the literature regarding the biogenesis and features of lncRNAs. We also present an overview of the current knowledge regarding the roles of lncRNAs in cancer from the view of various aspects of cellular homeostasis, including proliferation, survival, migration and genomic stability. Furthermore, we discuss the methodologies used to identify the function of lncRNAs in cancer development and tumorigenesis. Better understanding of the molecular mechanisms involving lncRNA functions in cancer is critical for the development of diagnostic and therapeutic strategies against tumorigenesis. Full article

(This article belongs to the Special Issue Noncoding RNAs as New Instruments in the Orchestration of Cell Death and Cancer Therapy Resistance)

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Noncoding RNAs as New Instruments in the Orchestration of Cell Death and Cancer Therapy Resistance

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