Non-coding RNAs in Cancer: Markers in Disease Progression and Therapy

Topic Information

Dear Colleagues,

Non-coding RNAs like miRNA, lncRNA or circRNA have been shown to be important regulators of gene expression. They are involved in regulation of fundamental physiological processes, and increasing evidence showed the significant role of ncRNAs in various diseases including cancer. However, considering the large number of existing ncRNAs, only a part of these molecules has been studied with regard to their role in cancer. In addition to further identification of their specific interactors, the role of ncRNAs as cancer markers and potential therapy targets is of high importance.

The Special Issue would like to focus on the following topics:

• Effect of specific ncRNAs on progression of different cancer entities: underlying molecular mechanisms
• Role of ncRNAs as cancer markers and therapy targets
• Role of circRNAs in cancer (since this ncRNA type has been least studied due to its late discovery)
• Role of competing endogenous RNAs (ceRNA) affecting miRNA action and mRNA expression in terms of tumor progression, diagnosis, and therapy
• Creating a database of lncRNA/circRNA interaction with specific miRNAs targets, as a tool to facilitate studies on the role of ncRNAs in cancer progression and therapy

Keywords

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biomedicines biomedicines	3.9	5.2	2013	14.6 Days	CHF 2600
Cancers cancers	4.5	8.0	2009	17.4 Days	CHF 2900
Current Oncology curroncol	2.8	3.3	1994	19.8 Days	CHF 2200
Non-Coding RNA ncrna	3.6	6.7	2015	26.8 Days	CHF 1800
Onco onco	-	-	2021	27.8 Days	CHF 1000

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Published Papers (9 papers)

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All Biomedicines Cancers Current Oncology ncRNA Onco

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Open AccessArticle

Organotypic 3D Cell-Architecture Impacts the Expression Pattern of miRNAs–mRNAs Network in Breast Cancer SKBR3 Cells

by María de los Ángeles Gastélum-López, Maribel Aguilar-Medina, Cristina García Mata, Jorge López-Gutiérrez, Geovanni Romero-Quintana, Mercedes Bermúdez, Mariana Avendaño-Felix, César López-Camarillo, Carlos Pérez-Plascencia, Adriana S Beltrán and Rosalío Ramos-Payán

Non-Coding RNA 2023, 9(6), 66; https://doi.org/10.3390/ncrna9060066 - 26 Oct 2023

Cited by 1 | Viewed by 3208

Abstract

Background. Currently, most of the research on breast cancer has been carried out in conventional two-dimensional (2D) cell cultures due to its practical benefits, however, the three-dimensional (3D) cell culture is becoming the model of choice in cancer research because it allows cell–cell [...] Read more.

Background. Currently, most of the research on breast cancer has been carried out in conventional two-dimensional (2D) cell cultures due to its practical benefits, however, the three-dimensional (3D) cell culture is becoming the model of choice in cancer research because it allows cell–cell and cell–extracellular matrix (ECM) interactions, mimicking the native microenvironment of tumors in vivo. Methods. In this work, we evaluated the effect of 3D cell organization on the expression pattern of miRNAs (by Small-RNAseq) and mRNAs (by microarrays) in the breast cancer SKBR3 cell line and analyzed the biological processes and signaling pathways regulated by the differentially expressed protein-coding genes (DE-mRNAs) and miRNAs (DE-microRNAs) found in the organoids. Results. We obtained well-defined cell-aggregated organoids with a grape cluster-like morphology with a size up to 9.2 × 10⁵ μm³. The transcriptomic assays showed that cell growth in organoids significantly affected (all p < 0.01) the gene expression patterns of both miRNAs, and mRNAs, finding 20 upregulated and 19 downregulated DE-microRNAs, as well as 49 upregulated and 123 downregulated DE-mRNAs. In silico analysis showed that a subset of 11 upregulated DE-microRNAs target 70 downregulated DE-mRNAs. These genes are involved in 150 gene ontology (GO) biological processes such as regulation of cell morphogenesis, regulation of cell shape, regulation of canonical Wnt signaling pathway, morphogenesis of epithelium, regulation of cytoskeleton organization, as well as in the MAPK and AGE–RAGE signaling KEGG-pathways. Interestingly, hsa-mir-122-5p (Fold Change (FC) = 15.4), hsa-mir-369-3p (FC = 11.4), and hsa-mir-10b-5p (FC = 20.1) regulated up to 81% of the 70 downregulated DE-mRNAs. Conclusion. The organotypic 3D cell-organization architecture of breast cancer SKBR3 cells impacts the expression pattern of the miRNAs–mRNAs network mainly through overexpression of hsa-mir-122-5p, hsa-mir-369-3p, and hsa-mir-10b-5p. All these findings suggest that the interaction between cell–cell and cell–ECM as well as the change in the culture architecture impacts gene expression, and, therefore, support the pertinence of migrating breast cancer research from conventional cultures to 3D models. Full article

(This article belongs to the Topic Non-coding RNAs in Cancer: Markers in Disease Progression and Therapy)
(This article belongs to the Section Small Non-Coding RNA)

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41 pages, 1523 KiB  

Open AccessReview

The Intergenic Type LncRNA (LINC RNA) Faces in Cancer with In Silico Scope and a Directed Lens to LINC00511: A Step toward ncRNA Precision

by Shorouk Eldash, Eman F. Sanad, Dina Nada and Nadia M. Hamdy

Non-Coding RNA 2023, 9(5), 58; https://doi.org/10.3390/ncrna9050058 - 25 Sep 2023

Cited by 10 | Viewed by 3135

Abstract

Background: Long intergenic non-coding RNA, is one type of lncRNA, exerting various cellular activities, as does ncRNA, including the regulation of gene expression and chromatin remodeling. The abnormal expression of lincRNAs can induce or suppress carcinogenesis. Main body: LincRNAs can regulate cancer progression [...] Read more.

Background: Long intergenic non-coding RNA, is one type of lncRNA, exerting various cellular activities, as does ncRNA, including the regulation of gene expression and chromatin remodeling. The abnormal expression of lincRNAs can induce or suppress carcinogenesis. Main body: LincRNAs can regulate cancer progression through different mechanisms and are considered as potential drug targets. Genetic variations such as single nucleotide polymorphisms (SNPs) in lincRNAs may affect gene expression and messenger ribonucleic acid (mRNA) stability. SNPs in lincRNAs have been found to be associated with different types of cancer, as well. Specifically, LINC00511 has been known to promote the progression of multiple malignancies such as breast cancer, colorectal cancer, lung cancer, hepatocellular carcinoma, and others, making it a promising cancer prognostic molecular marker. Conclusion: LincRNAs have been proved to be associated with different cancer types through various pathways. Herein, we performed a comprehensive literature and in silico databases search listing lncRNAs, lincRNAs including LINC00511, lncRNAs’ SNPs, as well as LINC00511 SNPs in different cancer types, focusing on their role in various cancer types and mechanism(s) of action. Full article

(This article belongs to the Topic Non-coding RNAs in Cancer: Markers in Disease Progression and Therapy)
(This article belongs to the Section Long Non-Coding RNA)

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18 pages, 1974 KiB  

Open AccessReview

Pseudogenes in Cancer: State of the Art

by Arturo Kenzuke Nakamura-García and Jesús Espinal-Enríquez

Cancers 2023, 15(16), 4024; https://doi.org/10.3390/cancers15164024 - 8 Aug 2023

Cited by 10 | Viewed by 3446

Abstract

Pseudogenes are duplicates of protein-coding genes that have accumulated multiple detrimental alterations, rendering them unable to produce the protein they encode. Initially disregarded as “junk DNA” due to their perceived lack of functionality, research on their biological roles has been hindered by this [...] Read more.

Pseudogenes are duplicates of protein-coding genes that have accumulated multiple detrimental alterations, rendering them unable to produce the protein they encode. Initially disregarded as “junk DNA” due to their perceived lack of functionality, research on their biological roles has been hindered by this assumption. Nevertheless, recent focus has shifted towards these molecules due to their abnormal expression in cancer phenotypes. In this review, our objective is to provide a thorough overview of the current understanding of pseudogene formation, the mechanisms governing their expression, and the roles they may play in promoting tumorigenesis. Full article

(This article belongs to the Topic Non-coding RNAs in Cancer: Markers in Disease Progression and Therapy)

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17 pages, 3108 KiB  

Open AccessArticle

Telomere Transcription in MLL-Rearranged Leukemia Cell Lines: Increased Levels of TERRA Associate with Lymphoid Lineage and Are Independent of Telomere Length and Ploidy

by Corrado Caslini and Amparo Serna

Biomedicines 2023, 11(3), 925; https://doi.org/10.3390/biomedicines11030925 - 16 Mar 2023

Viewed by 2002

Abstract

Telomere transcription into telomeric repeat-containing RNA (TERRA) is an integral component of all aspects of chromosome end protection consisting of telomerase- or recombination-dependent telomere elongation, telomere capping, and the preservation of the (sub)telomeric heterochromatin structure. The chromatin modifier and transcriptional regulator MLL binds [...] Read more.

Telomere transcription into telomeric repeat-containing RNA (TERRA) is an integral component of all aspects of chromosome end protection consisting of telomerase- or recombination-dependent telomere elongation, telomere capping, and the preservation of the (sub)telomeric heterochromatin structure. The chromatin modifier and transcriptional regulator MLL binds to telomeres and regulates TERRA transcription in telomere length homeostasis and response to telomere dysfunction. MLL fusion proteins (MLL-FPs), the product of MLL rearrangements in leukemia, also bind to telomeric chromatin. However, an effect on telomere transcription in MLL-rearranged (MLL-r) leukemia has not yet been evaluated. Here, we show increased UUAGGG repeat-containing RNA levels in MLL-r acute lymphoblastic leukemia (ALL) when compared to non-MLL-r ALL and myeloid leukemia. MLL rearrangements do not affect telomere length and UUAGGG repeat-containing RNA levels correlate with mean telomere length and reflect increased levels of TERRA. Furthermore, high levels of TERRA in MLL-r ALL occur in the presence of telomerase activity and are independent of ploidy, an underestimated source of variation on the overall transcriptome size in a cell. This MLL rearrangement-dependent and lymphoid lineage-associated increase in levels of TERRA supports a sustained telomere transcription by MLL-FPs that correlates with marked genomic stability previously reported in pediatric MLL-r ALL. Full article

(This article belongs to the Topic Non-coding RNAs in Cancer: Markers in Disease Progression and Therapy)

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19 pages, 2426 KiB  

Open AccessArticle

tRNA-Derived RNA Fragments Are Novel Biomarkers for Diagnosis, Prognosis, and Tumor Subtypes in Prostate Cancer

by Weigang Liu, Mengqian Yu, Sheng Cheng, Xiaoxu Zhou, Jia Li, Yan Lu, Pengyuan Liu and Shiping Ding

Curr. Oncol. 2023, 30(1), 981-999; https://doi.org/10.3390/curroncol30010075 - 10 Jan 2023

Cited by 6 | Viewed by 3181

Abstract

Background: tRNA-derived RNA fragments (tRFs) are a novel class of small ncRNA that are derived from precursor or mature tRNAs. Recently, the general relevance of their roles and clinical values in tumorigenesis, metastasis, and recurrence have been increasingly highlighted. However, there has been [...] Read more.

Background: tRNA-derived RNA fragments (tRFs) are a novel class of small ncRNA that are derived from precursor or mature tRNAs. Recently, the general relevance of their roles and clinical values in tumorigenesis, metastasis, and recurrence have been increasingly highlighted. However, there has been no specific systematic study to elucidate any potential clinical significance for these tRFs in prostate adenocarcinoma (PRAD), one of the most common and malignant cancers that threatens male health worldwide. Here, we investigate the clinical value of 5′-tRFs in PRAD. Methods: Small RNA sequencing data were analyzed to discover new 5′-tRFs biomarkers for PRAD. Machine learning algorithms were used to identify 5′-tRF classifiers to distinguish PRAD tumors from normal tissues. LASSO and Cox regression analyses were used to construct 5′-tRF prognostic predictive models. NMF and consensus clustering analyses were performed on 5′-tRF profiles to identify molecular subtypes of PRAD. Results: The overall levels of 5′-tRFs were significantly upregulated in the PRAD tumor samples compared to their adjacent normal samples. tRF classifiers composed of 13 5′-tRFs achieved AUC values as high as 0.963, showing high sensitivity and specificity in distinguishing PRAD tumors from normal samples. Multiple 5′-tRFs were identified as being associated with the PRAD prognosis. The tRF score, defined by a set of eight 5′-tRFs, was highly predictive of survival in PRAD patients. The combination of tRF and Gleason scores showed a significantly better performance than the Gleason score alone, suggesting that 5′-tRFs can offer PRAD patients additional and improved prognostic information. Four molecular subtypes of the PRAD tumor were identified based on their 5′-tRF expression profiles. Genetically, these 5′-tRFs PRAD tumor subtypes exhibited distinct genomic landscapes in tumor cells. Clinically, they showed marked differences in survival and clinicopathological features. Conclusions: 5′-tRFs are potential clinical biomarkers for the diagnosis, prognosis, and classification of tumor subtypes on a molecular level. These can help clinicians formulate personalized treatment plans for PRAD patients and may have similar potential applications for other disease types. Full article

(This article belongs to the Topic Non-coding RNAs in Cancer: Markers in Disease Progression and Therapy)

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16 pages, 3271 KiB  

Open AccessArticle

Long Non-Coding RNAs Associated with Mitogen-Activated Protein Kinase in Human Pancreatic Cancer

by Tomohiko Ishikawa, Shinichi Fukushige, Yuriko Saiki, Katsuya Hirose, Takako Hiyoshi, Takenori Ogawa, Yukio Katori and Toru Furukawa

Cancers 2023, 15(1), 303; https://doi.org/10.3390/cancers15010303 - 2 Jan 2023

Cited by 4 | Viewed by 2702

Abstract

Long non-coding RNAs (lncRNAs) have emerged as a significant player in various cancers, including pancreatic cancer. However, how lncRNAs are aberrantly expressed in cancers is largely unknown. We hypothesized that lncRNAs would be regulated by signaling pathways and contribute to malignant phenotypes of [...] Read more.

Long non-coding RNAs (lncRNAs) have emerged as a significant player in various cancers, including pancreatic cancer. However, how lncRNAs are aberrantly expressed in cancers is largely unknown. We hypothesized that lncRNAs would be regulated by signaling pathways and contribute to malignant phenotypes of cancer. In this study, to understand the significance of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), which is a major aberrant signaling pathway in pancreatic cancer, for the expression of lncRNAs, we performed comparative transcriptome analyses between pancreatic cancer cell lines with or without activation of MAPK. We identified 45 lncRNAs presumably associated with MAPK in pancreatic cancer cells; among these, LINC00941 was consistently upregulated by MAPK. The immediate genomic upstream region flanking LINC00941 was identified as a promoter region, the activity of which was found to be preferentially associated with MAPK activity via ETS-1 binding site. LINC00941 promoted cell proliferation in vitro. Moreover, TCGA data analysis indicated that high expression of LINC00941 was associated with poor prognosis of patients with pancreatic cancer. Transcriptomes comparing transcriptions between cells with and without LINC00941 knockdown revealed 3229 differentially expressed genes involved in 44 biological processes, including the glycoprotein biosynthetic process, beta-catenin-TCF complex assembly, and histone modification. These results indicate that MAPK mediates the aberrant expression of lncRNAs. LINC00941 is the lncRNA by MAPK most consistently promoted, and is implicated in the dismal prognosis of pancreatic cancer. MAPK-associated lncRNAs may play pivotal roles in malignant phenotypes of pancreatic cancer, and as such might represent both potentially valid therapeutic targets and diagnostic biomarkers. Full article

(This article belongs to the Topic Non-coding RNAs in Cancer: Markers in Disease Progression and Therapy)

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5 pages, 1325 KiB  

Open AccessBrief Report

Is Evolutionary Conservation a Useful Predictor for Cancer Long Noncoding RNAs? Insights from the Cancer LncRNA Census 3

by Adrienne Vancura, Alejandro H. Gutierrez, Thorben Hennig, Carlos Pulido-Quetglas, Frank J. Slack, Rory Johnson and Simon Haefliger

Non-Coding RNA 2022, 8(6), 82; https://doi.org/10.3390/ncrna8060082 - 7 Dec 2022

Cited by 3 | Viewed by 2970

Abstract

Evolutionary conservation is a measure of gene functionality that is widely used to prioritise long noncoding RNAs (lncRNA) in cancer research. Intriguingly, while updating our Cancer LncRNA Census (CLC), we observed an inverse relationship between year of discovery and evolutionary conservation. This observation [...] Read more.

Evolutionary conservation is a measure of gene functionality that is widely used to prioritise long noncoding RNAs (lncRNA) in cancer research. Intriguingly, while updating our Cancer LncRNA Census (CLC), we observed an inverse relationship between year of discovery and evolutionary conservation. This observation is specific to cancer over other diseases, implying a sampling bias in the selection of lncRNA candidates and casting doubt on the value of evolutionary metrics for the prioritisation of cancer-related lncRNAs. Full article

(This article belongs to the Topic Non-coding RNAs in Cancer: Markers in Disease Progression and Therapy)
(This article belongs to the Section Long Non-Coding RNA)

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21 pages, 1399 KiB  

Open AccessArticle

Systematic Investigation of the Diagnostic and Prognostic Impact of LINC01087 in Human Cancers

by Fatima Domenica Elisa De Palma, Vincent Carbonnier, Francesco Salvatore, Guido Kroemer, Jonathan G. Pol and Maria Chiara Maiuri

Cancers 2022, 14(23), 5980; https://doi.org/10.3390/cancers14235980 - 3 Dec 2022

Cited by 5 | Viewed by 3270

Abstract

(1) Background: Long non-coding RNAs may constitute epigenetic biomarkers for the diagnosis, prognosis, and therapeutic response of a variety of tumors. In this context, we aimed at assessing the diagnostic and prognostic value of the recently described long intergenic non-coding RNA 01087 (LINC01087) [...] Read more.

(1) Background: Long non-coding RNAs may constitute epigenetic biomarkers for the diagnosis, prognosis, and therapeutic response of a variety of tumors. In this context, we aimed at assessing the diagnostic and prognostic value of the recently described long intergenic non-coding RNA 01087 (LINC01087) in human cancers. (2) Methods: We studied the expression of LINC01087 across 30 oncological indications by interrogating public resources. Data extracted from the TCGA and GTEx databases were exploited to plot receiver operating characteristic curves (ROC) and determine the diagnostic performance of LINC01087. Survival data from TCGA and KM-Plotter directories allowed us to graph Kaplan–Meier curves and evaluate the prognostic value of LINC01087. To investigate the function of LINC01087, gene ontology (GO) annotation and Kyoto Encyclopedia of Gene and Genomes (KEGG) enrichment analyses were performed. Furthermore, interactions between LINC01087 and both miRNA and mRNA were studied by means of bioinformatics tools. (3) Results: LINC01087 was significantly deregulated in 7 out of 30 cancers, showing a predominant upregulation. Notably, it was overexpressed in breast (BC), esophageal (ESCA), and ovarian (OV) cancers, as well as lung squamous cell carcinoma (LUSC), stomach adenocarcinoma (STAD), and uterine carcinosarcoma (UCS). By contrast, LINC01087 displayed downregulation in testicular germ cell tumors (TGCT). ROC curve analyses identified LINC01087 as a potential diagnostic indicator in BC, ESCA, OV, STAD, and TGCT. Moreover, high and low expression of LINC01087 predicted a favorable prognosis in BC and papillary cell carcinoma, respectively. In silico analyses indicated that deregulation of LINC01087 in cancer was associated with a modulation of genes related to ion channel, transporter, and peptide receptor activity. (4) Conclusions: the quantification of an altered abundance of LINC01087 in tissue specimens might be clinically useful for the diagnosis and prognosis of some hormone-related tumors, including BC, OV, and TGCT, as well as other cancer types such as ESCA and STAD. Moreover, our study revealed the potential of LINC01087 (and perhaps other lncRNAs) to regulate neuroactive molecules in cancer. Full article

(This article belongs to the Topic Non-coding RNAs in Cancer: Markers in Disease Progression and Therapy)

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17 pages, 3653 KiB  

Open AccessArticle

The Androgen Regulated lncRNA NAALADL2-AS2 Promotes Tumor Cell Survival in Prostate Cancer

by Levi Groen, Viktor Yurevych, Harshitha Ramu, Johnny Chen, Lianne Steenge, Sabrina Boer, Renske Kuiper, Frank P. Smit, Gerald W. Verhaegh, Niven Mehra and Jack A. Schalken

Non-Coding RNA 2022, 8(6), 81; https://doi.org/10.3390/ncrna8060081 - 1 Dec 2022

Cited by 4 | Viewed by 3111

Abstract

Castration resistance is the leading cause of death in men with prostate cancer. Recent studies indicate long noncoding RNAs (lncRNAs) to be important drivers of therapy resistance. The aim of this study was to identify differentially expressed lncRNAs in castration-resistant prostate cancer (CRPC) [...] Read more.

Castration resistance is the leading cause of death in men with prostate cancer. Recent studies indicate long noncoding RNAs (lncRNAs) to be important drivers of therapy resistance. The aim of this study was to identify differentially expressed lncRNAs in castration-resistant prostate cancer (CRPC) and to functionally characterize them in vitro. Tumor-derived RNA-sequencing data were used to quantify and compare the expression of 11,469 lncRNAs in benign, primary prostate cancer, and CRPC samples. CRPC-associated lncRNAs were selected for semi-quantitative PCR validation on 68 surgical tumor specimens. In vitro functional studies were performed by antisense-oligonucleotide-mediated lncRNA knockdown in hormone-sensitive prostate cancer (HSPC) and CRPC cell line models. Subsequently, cell proliferation, apoptosis, cell cycle, transcriptome and pathway analyses were performed using the appropriate assays. Transcriptome analysis of a prostate cancer tumor specimens unveiled NAALADL2-AS2 as a novel CRPC-upregulated lncRNA. The expression of NAALADL2-AS2 was found to be particularly high in HSPC in vitro models and to increase under androgen deprived conditions. NAALADL2-AS2 knockdown decreased cell viability and increased caspase activity and apoptotic cells. Cellular fractionization and RNA fluorescent in situ hybridization identified NAALADL2-AS2 as a nuclear transcript. Transcriptome and pathway analyses revealed that NAALADL2-AS2 modulates the expression of genes involved with cell cycle control and glycogen metabolism. We hypothesize that the nuclear lncRNA, NAALADL2-AS2, functions as a pro-survival signal in prostate cancer cells under pressure of targeted hormone therapy. Full article

(This article belongs to the Topic Non-coding RNAs in Cancer: Markers in Disease Progression and Therapy)
(This article belongs to the Section Long Non-Coding RNA)

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