Regulation of placenta growth factor by microRNA-125b in hepatocellular cancer.

microRNAs (miRNAs) are a class of small noncoding RNAs that can regulate gene expression by translation repression or mRNA degradation. Our aim was to evaluate the role of aberrantly expressed miRNAs in hepatocellular cancer (HCC). miRNA expression in HCC tissues and cells was evaluated by qPCR array and Taqman miRNA assay. Cell proliferation, motility, invasion, and the angiogenesis index were quantitated using commercial assays. DNA methylation status, matrix metalloproteinases (MMPs) mRNA expression was quantitated by real-time PCR analysis. miRNA profiling identified a decrease in miR-125b expression in HCC tumor tissues and cell lines. The expression of miR-125b was significantly increased by the methylation inhibitor 5-aza-2'-deoxycytidine in HCC cells but not in normal controls, suggesting that the expression of miR-125b could be epigenetically modulated. Methylation-specific PCR revealed hypermethylation status of miR-125b in HCC cells compared to non-malignant controls. Cell proliferation, anchorage-independent growth, cell migration, invasion, and angiogenesis were significantly decreased by the introduction of miR-125b precursor in HCC cell lines. Placenta growth factor was identified as a target of miR-125b by bioinformatics analysis and experimentally verified using luciferase reporter constructs. Overexpression of miR-125b in HCC cells decreased PIGF expression, and altered the angiogenesis index. Furthermore, modulation of miR-125b also distorted expression of MMP-2 and -9, the mediators of enzymatic degradation of the extracellular matrix. Our studies showing epigenetic silencing of miR-125b contributes to an invasive phenotype provide novel mechanistic insights and identify a potential target mechanism that could be manipulated for therapeutic benefit in HCC.

Alpini G ，Glaser SS ，Zhang JP ，Francis H ，Han Y ，Gong J ，Stokes A ，Francis T ，Hughart N ，Hubble L ，Zhuang SM ，Meng F ... -  《-》

MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer.

Meng F ，Henson R ，Wehbe-Janek H ，Ghoshal K ，Jacob ST ，Patel T ... -  《-》

Sirtuin7 oncogenic potential in human hepatocellular carcinoma and its regulation by the tumor suppressors MiR-125a-5p and MiR-125b.

Sirtuins are nicotinamide adenine dinucleotide oxidized form (NAD(+) )-dependent deacetylases and function in cellular metabolism, stress resistance, and aging. For sirtuin7 (SIRT7), a role in ribosomal gene transcription is proposed, but its function in cancer has been unclear. In this study we show that SIRT7 expression was up-regulated in a large cohort of human hepatocellular carcinoma (HCC) patients. SIRT7 knockdown influenced the cell cycle and caused a significant increase of liver cancer cells to remain in the G1 /S phase and to suppress growth. This treatment restored p21(WAF1/Cip1) , induced Beclin-1, and repressed cyclin D1. In addition, sustained suppression of SIRT7 reduced the in vivo tumor growth rate in a mouse xenograft model. To explore mechanisms in SIRT7 regulation, microRNA (miRNA) profiling was carried out. This identified five significantly down-regulated miRNAs in HCC. Bioinformatics analysis of target sites and ectopic expression in HCC cells showed that miR-125a-5p and miR-125b suppressed SIRT7 and cyclin D1 expression and induced p21(WAF1/Cip1) -dependent G1 cell cycle arrest. Furthermore, treatment of HCC cells with 5-aza-2'-deoxycytidine or ectopic expression of wildtype but not mutated p53 restored miR-125a-5p and miR-125b expression and inhibited tumor cell growth, suggesting their regulation by promoter methylation and p53 activity. To show the clinical significance of these findings, mutations in the DNA binding domain of p53 and promoter methylation of miR-125b were investigated. Four out of nine patients with induced SIRT7 carried mutations in the p53 gene and one patient showed hypermethylation of the miR-125b promoter region. Our findings suggest the oncogenic potential of SIRT7 in hepatocarcinogenesis. A regulatory loop is proposed whereby SIRT7 inhibits transcriptional activation of p21(WAF1/Cip1) by way of repression of miR-125a-5p and miR-125b. This makes SIRT7 a promising target in cancer therapy. (HEPATOLOGY 2013).

Kim JK ，Noh JH ，Jung KH ，Eun JW ，Bae HJ ，Kim MG ，Chang YG ，Shen Q ，Park WS ，Lee JY ，Borlak J ，Nam SW ... -  《-》

MiRNA199a-3p suppresses tumor growth, migration, invasion and angiogenesis in hepatocellular carcinoma by targeting VEGFA, VEGFR1, VEGFR2, HGF and MMP2.

Ghosh A ，Dasgupta D ，Ghosh A ，Roychoudhury S ，Kumar D ，Gorain M ，Butti R ，Datta S ，Agarwal S ，Gupta S ，Krishna Dhali G ，Chowdhury A ，Schmittgen TD ，Kundu GC ，Banerjee S ... -  《Cell Death & Disease》

MiR-324-5p Suppresses Hepatocellular Carcinoma Cell Invasion by Counteracting ECM Degradation through Post-Transcriptionally Downregulating ETS1 and SP1.

Cao L ，Xie B ，Yang X ，Liang H ，Jiang X ，Zhang D ，Xue P ，Chen D ，Shao Z ... -  《-》