Systemic Delivery of MicroRNA-101 Potently Inhibits Hepatocellular Carcinoma In Vivo by Repressing Multiple Targets

Zheng, Fang; Liao, Yiji; Cai, Mu Yan; Liu, Tian Hao; Chen, Shu Peng; Wu, Pei Hong; Wu, Long; Bian, Xiu Wu; Guan, Xin Yuan; Zeng, Yi Xin; Yuan, Yunfei; Kung, Hsiang Fu; Xie, Dan

doi:10.1371/journal.pgen.1004873

Cited by 89 publications

(70 citation statements)

References 46 publications

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“…Under-expression of miR-101 has been identified herein as well as in previous studies in liver cancer [66,67] and CCA [68]. Down- regulated miR-101 was associated with hepatitis B virus infection [69].…”

Section: Figuresupporting

confidence: 75%

Integrative Analysis of Transcriptome and MicroRNome Profiles in Cholangiocarcinoma

Severino¹,

Hasimoto²,

Rodrigues³

et al. 2017

J Cancer Sci Ther

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Aim: To identify deregulated expression of miRNAs and target genes in cholangiocarcinoma (CCA), as well as drug-gene interactions that may be useful for patient treatment. Methods:We analyzed quantitative transcriptome and miRNA deep sequencing expression data from 45 samples, 36 CCA and 9 histologically normal biliary tissues, obtained from the public repository The Cancer Genome Atlas (TCGA). Bioinformatic methods were used to identify and integrate differential expression of miRNA and transcriptome profiles in CCA vs. normal tissues. Deregulated miRNA and corresponding target genes were identified and mapped into miRNA-mRNA networks. Results:Results showed 64 differentially expressed miRNAs (48 over and 16 under-expressed) between CCA and corresponding normal biliary tissues. Additionally, 432 genes (180 over and 252 under-expressed) were identified between CCA and normal samples. We identified individual miRNAs with the largest number of gene targets. Among these, miR-125a was over-expressed and had the highest number of direct interactions with 33 mRNA targets. miRNAs miR-122 and miR-139 were the under-expressed miRNAs with the highest number of interactions (9 targets each). miR-122 was found to modulate the expression of the transcription factor FOXM1, known to be involved in tumorigenesis and the matrix metalloproteinase MMP7, an important mediator of tumor invasion. miR-148 and miR-194 were predicted to modulate NQO1, which is up-regulated in cancer and associated with treatment resistance in cholangiocarcinoma. Conclusion:The novelty of our study is the identification of complex deregulated networks of miRNAs and target genes in CCA. miRNAs with a large number of targets may have a higher functional impact on cell regulation. These findings contribute for a better understanding of CCA biology. Identified miRNAs and target genes are potential candidates for the design of validation strategies towards the characterization of clinically applicable biomarkers; such biomarkers may be useful for the development of molecularly-targeted therapeutics that can benefit patients.

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Section: Figuresupporting

confidence: 75%

Integrative Analysis of Transcriptome and MicroRNome Profiles in Cholangiocarcinoma

Severino¹,

Hasimoto²,

Rodrigues³

et al. 2017

J Cancer Sci Ther

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“…The binding site for miR-101 at 3′-UTR of SUB1 is indicated (Figure 1a). MiR-101 is known to play tumor suppressor function by targeting several oncogenes including EZH2, 11 proteasome assembly factor POMP, 13 Cyclooxygenase-2 (COX2), 12 and others, we sought to determine its role in SUB1 regulation. We treated prostate cancer cell line DU145 with precursor miRNA, miR-101 and tested some of the potential targets.…”

Section: Resultsmentioning

confidence: 99%

MicroRNA-101 regulated transcriptional modulator SUB1 plays a role in prostate cancer

et al. 2016

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MicroRNA-101, a tumor suppressor microRNA is often down-regulated in cancer and is known to target multiple oncogenes. Some of the genes that are negatively regulated by miR-101 expression include histone methyltransferase EZH2, COX2, POMP, CERS6, STMN1, MCL-1 and ROCK2, among others. In the present study, we show that mir-101 targets transcriptional coactivator SUB1 homolog (Saccharomyces cerevisiae)/PC4 (positive cofactor 4) and regulates its expression. SUB1 is known to play diverse role in vital cell processes such as DNA replication, repair and heterochromatinization. SUB1 is known to modulate transcription and acts as a mediator between the upstream activators and general transcription machinery. Expression profiling in several cancers revealed SUB1 overexpression, suggesting a potential role in tumorigenesis. However, detailed regulation and function of SUB1 has not been elucidated. In this study, we show elevated expression of SUB1 in aggressive prostate cancer. Knockdown of SUB1 in prostate cancer cells resulted in reduced cell proliferation, invasion and migration in vitro, and tumor growth and metastasis in vivo. Gene expression analyses coupled with chromatin immunoprecipitation revealed that SUB1 binds to the promoter regions of several oncogenes such as polo-like kinase PLK1, C-MYC, serine threonine kinase BUB1B and regulates their expression. Additionally, we observed SUB1 down-regulated CDKN1B expression. PLK1 knockdown or use of PLK1 inhibitor can mitigate oncogenic function of SUB1 in benign prostate cancer cells. Thus, our study suggests that miR-101 loss results in increased SUB1 expression and subsequent activation of known oncogenes driving prostate cancer progression and metastasis. This study therefore demonstrates functional role of SUB1 in the prostate cancer and identifies its regulation, and potential downstream therapeutic targets of SUB1 in prostate cancer.

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“…These results suggest that serum miR-101 can serve as a potential non-invasive biomarker to differentiate HBV-HCC from HBV-LC. Recently, it was shown that enforced overexpression of miR-101 by lentivirus-mediated systemic delivery strongly inhibits HCC in vivo by repressing multiple molecular targets such as EZH2, STMN1, COX2 and ROCK2 and blocking angiogenesis and epithelial-mesenchymal transition of HCC cells (Zheng et al, 2015a).…”

Section: Mir-101mentioning

confidence: 99%

HepatomiRNoma: The proposal of a new network of targets for diagnosis, prognosis and therapy in hepatocellular carcinoma

Bronte

Fanale

et al. 2016

Critical Reviews in Oncology/Hematology

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Systemic Delivery of MicroRNA-101 Potently Inhibits Hepatocellular Carcinoma In Vivo by Repressing Multiple Targets

Cited by 89 publications

References 46 publications

Integrative Analysis of Transcriptome and MicroRNome Profiles in Cholangiocarcinoma

Integrative Analysis of Transcriptome and MicroRNome Profiles in Cholangiocarcinoma

MicroRNA-101 regulated transcriptional modulator SUB1 plays a role in prostate cancer

HepatomiRNoma: The proposal of a new network of targets for diagnosis, prognosis and therapy in hepatocellular carcinoma

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