The Inescapable Influence of Noncoding RNAs in Cancer

Adams, Brian D.; Anastasiadou, Eleni; Esteller, Manel; He, Lin; Slack, Frank J.

doi:10.1158/0008-5472.can-15-1989

Cited by 45 publications

(34 citation statements)

References 41 publications

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“…The role of lncRNAs in resistance to endocrine therapy is an area of emerging interest (48, 49). However, our study is, to our knowledge, the first to focus on the impact of a lncRNA on outcomes in a large prospective trial of AI therapy in women with early-stage breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Genetic Polymorphisms in the Long Noncoding RNA MIR2052HG Offer a Pharmacogenomic Basis for the Response of Breast Cancer Patients to Aromatase Inhibitor Therapy

et al. 2016

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Genetic risks in breast cancer remain only partly understood. Here we report the results of a genome-wide association study of germline DNA from 4,658 women, including 252 women experiencing a breast cancer recurrence, who were entered on the MA.27 adjuvant trial comparing the aromatase inhibitors (AI) anastrozole and exemestane. Single nucleotide polymorphisms (SNP) of top significance were identified in the gene encoding MIR2052HG, a long noncoding RNA of unknown function. Heterozygous or homozygous individuals for variant alleles exhibited a ~40% or ~63% decrease, respectively, in the hazard of breast cancer recurrence relative to homozygous wild-type individuals. Functional genomic studies in lymphoblastoid cell lines and ERα-positive breast cancer cell lines showed that expression from MIR2052HG and the ESR1 gene encoding estrogen receptor-α (ERα) was induced by estrogen and AI in a SNP-dependent manner. Variant SNP genotypes exhibited increased ERα binding to estrogen response elements, relative to wild-type genotypes, a pattern that was reversed by AI treatment. Further, variant SNPs were associated with lower expression of MIR2052HG and ERα. RNAi-mediated silencing of MIR2052HG in breast cancer cell lines decreased ERα expression, cell proliferation and anchorage-independent colony formation. Mechanistic investigations revealed that MIR2052HG sustained ERα levels both by promoting AKT/FOXO3-mediated ESR1 transcription and by limiting ubiquitin-mediated, proteasome-dependent degradation of ERα. Taken together, our results define MIR2052HS as a functionally polymorphic gene that affects risks of breast cancer recurrence in women treated with AI. More broadly, our results offer a pharmacogenomic basis to understand differences in the response of breast cancer patients to AI therapy.

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Section: Discussionmentioning

confidence: 99%

Genetic Polymorphisms in the Long Noncoding RNA MIR2052HG Offer a Pharmacogenomic Basis for the Response of Breast Cancer Patients to Aromatase Inhibitor Therapy

et al. 2016

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“…HCC is the fifth most prevalent malignancy and accounts for 85–90% of all primary liver cancer cases ( 29 ). A number of studies have reported that lncRNAs serve an important function in the regulation of gene expression in cancer development ( 30 – 32 ). The dysregulation of lncRNAs has been identified in various types of cancer, including HOTAIR in ovarian and colorectal cancer, GAS5 in breast cancer and MALAT1 in prostate cancer ( 33 – 35 ).…”

Section: Discussionmentioning

confidence: 99%

Long non-coding RNA CCAT2 functions as an oncogene in hepatocellular carcinoma, regulating cellular proliferation, migration and apoptosis

Zhou

et al. 2016

Oncology Letters

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An increasing number of studies have demonstrated that the dysregulation of long non-coding RNAs (lncRNAs) may serve an important role in tumor progression. Previous studies have reported that the lncRNA, colon cancer associated transcript 2 (CCAT2), was highly expressed in various tumors. However, the function of CCAT2 in hepatocellular carcinoma (HCC) has not yet been elucidated. The aim of the present study was to identify novel oncogene lncRNAs and investigate their physiological function and mechanism in HCC. Using reverse transcription-quantitative polymerase chain reaction, it was observed that CCAT2 was upregulated in HCC tissues and human HCC cell lines. Furthermore, the impacts of CCAT2 on cell proliferation, migration and apoptosis were analyzed using cell migration, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and enzyme-linked immunosorbent assay analysis respectively. The overexpression of CCAT2 using a synthesized vector significantly promoted cell migration and proliferation, and inhibited apoptosis of HCC cells in vitro. The suppression of CCAT2 expression resulted in opposing effects. To the best of our knowledge, the present study is the ﬁrst to demonstrate that CCAT2 functions as a oncogene in HCC. Further investigation is required to clarify the molecular mechanisms of this lncRNA in HCC development.

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“…Small RNAs or microRNAs (miRNAs) are endogenous, small (~18-24 nt), non-coding RNAs that are key regulators of gene expression. They function post-transcriptionally by binding to complementary sequences of the 3′-untranslated region (3′-UTR) of target mRNAs [21] and play an important role in the regulation of proliferation, differentiation, migration, and apoptosis [22]. The role of miRNA in brain development, neurodevelopmental disorders, and viral infections is well established [23][24][25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Zika virus E protein alters the properties of human fetal neural stem cells by modulating microRNA circuitry

et al. 2018

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Zika virus (ZV) infects neural stem cells (NSCs) and causes quiescence in NSCs, reducing the pool of brain cells, leading to microcephaly. Despite conscientious efforts, the molecular mechanisms for ZV-mediated effects on NSCs lack clarity. This study aimed to explore the underlying mechanisms for ZV-mediated induction of quiescence in the primary cultures of human fetal neural stem cells (fNSCs). We demonstrate that expression of ZV envelope (E) protein displays maximum quiescence in human fNSCs by accumulating cells in the G0/G1 phase of the cell cycle as compared to other non-structural proteins, viz. NS2A, NS4A and NS4B. E protein induces immature differentiation by induction of pro-neuronal genes in proliferating fNSCs, induces apoptosis in differentiating fNSCs 3 days post differentiation, and disrupts migration of cells from differentiating neurospheres. In utero electroporation of mouse brain with E protein shows drastic downregulation of proliferating cells in ventricular and subventricular zone regions. Global microRNA sequencing suggests that E protein modulates miRNA circuitry. Among differentially expressed miRNAs, we found 14 upregulated and 11 downregulated miRNAs. Mir-204-3p and mir-1273g-3p directly regulate NOTCH2 and PAX3 expression, respectively, by binding to their 3'UTR. Bioinformatic analysis using GO analysis for the targets of differentially expressed miRNAs revealed enrichment of cell cycle and developmental processes. Furthermore, WNT, CCKR, PDGF, EGF, p53, and NOTCH signaling pathways were among the top enriched pathways. Thus, our study provides evidence for the involvement of ZV E protein and novel insights into the molecular mechanism through identification of miRNA circuitry. Art work depicting the effect of Zika virus E protein on human fetal neural stem cells.

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The Inescapable Influence of Noncoding RNAs in Cancer

Cited by 45 publications

References 41 publications

Genetic Polymorphisms in the Long Noncoding RNA MIR2052HG Offer a Pharmacogenomic Basis for the Response of Breast Cancer Patients to Aromatase Inhibitor Therapy

Genetic Polymorphisms in the Long Noncoding RNA MIR2052HG Offer a Pharmacogenomic Basis for the Response of Breast Cancer Patients to Aromatase Inhibitor Therapy

Long non-coding RNA CCAT2 functions as an oncogene in hepatocellular carcinoma, regulating cellular proliferation, migration and apoptosis

Zika virus E protein alters the properties of human fetal neural stem cells by modulating microRNA circuitry

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