Maternal deletion of Meg3 and a small portion of its promoter abolishes expression from all the MEGs in the region[32]; therefore, it is believed that all Megs are transcribed from the Meg3 promoter as one long transcript. However, Fiore et al.[34] reported that the transcription factor, myocyte enhancing factor 2 (Mef2), could activate the transcription of the miR-379-656 cluster through direct binding to the upstream of the cluster. In this study, we found that ectopic expression of HNF4α did not elevate expression of all MEGs in this region (data not shown), but transactivated the expression of the miR-379-656 cluster. These data
suggest that these MEGs are regulated by gene-specific elements, C646 mouse in addition to Meg3 control of the one giant polycistronic RNA. miR-134 was first identified as a brain-specific microRNA, and HDAC inhibitor is implicated in the control of neuronal microstructure.[35] Silencing miR-134 results in neuroprotection
and prolongs seizure-suppressive actions in mice.[36] miR-134 also regulates the differentiation of mouse embryonic stem cells.[37] Overexpression of miR-134 induces cell cycle arrest in human pituitary tumor cells.[18] In the present study, we found that the level of miR-134 transcription in the liver gradually reduced during the development of HCC in a chemically induced HCC rat model. A reduction of miR-134 levels was also observed in the majority of human HCC tumor samples, and was associated with aggressive phenotypes of the disease. More interestingly, malignant phenotypes of HCC cells could be manipulated by changing miR-134 expression, both in vitro and in vivo. Together, these results suggest that miR-134 plays a crucial role in the carcinogenesis and progression of HCC and prompt the exploration of antitumor effects of other miRNAs in this cluster. Previous studies have revealed that miR-134 can target Nanog, Sox2, c-Myc, nuclear receptor liver receptor homolog 1, and Oct4.[17, 37, check details 38] These genes are important for the proliferation and fate-determining properties of stem/progenitor
cells and are also involved in hepatocarcinogenesis. The proto-oncogene KRAS is a central regulator of intracellular signal transduction pathways in malignant transformation, including PI3K-AKT, vascular endothelial growth factor, Wnt-β-catenin, and nuclear factor kappa B (NF-κB) pathways. It has been reported that KRAS is not frequently mutated and only one of 35 tumors had up-regulation of KRAS in human HCC.[39] However, KRAS was found to be up-regulated in most of HCC samples in this study (Supporting Fig. 7). Evidence suggests that KRAS is a bona fide target of several miRNAs (including let-7, miR-30C, miR-143, and miR-96) that can inhibit cancer cell proliferation and metastasis.[40-43] This study demonstrates that KRAS is a direct target of miR-134.
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