Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The functional association between intronic miRNAs and their host genes is still largely unknown. We found that three gene loci, which produced miR-26a and miR-26b, were embedded within introns of genes coding for the proteins of carboxy-terminal domain RNA polymerase II polypeptide A small phosphatase (CTDSP) family, including CTDSPL, CTDSP2 and CTDSP1. We conducted serum starvation-stimulation assays in primary fibroblasts and two-thirds partial-hepatectomies in mice, which revealed that miR-26a/b and CTDSP1/2/L were expressed concomitantly during the cell cycle process. Specifically, they were increased in quiescent cells and decreased during cell proliferation. Furthermore, both miR-26 and CTDSP family members were frequently downregulated in hepatocellular carcinoma (HCC) tissues. Gain- and loss-of-function studies showed that miR-26a/b and CTDSP1/2/L synergistically decreased the phosphorylated form of pRb (ppRb), and blocked G1/S-phase progression. Further investigation disclosed that miR-26a/b directly suppressed the expression of CDK6 and cyclin E1, which resulted in reduced phosphorylation of pRb. Moreover, c-Myc, which is often upregulated in cancer cells, diminished the expression of both miR-26 and CTDSP family members, enhanced the ppRb level and promoted the G1/S-phase transition. Our findings highlight the functional association of miR-26a/b and their host genes and provide new insight into the regulatory network of the G1/S-phase transition.
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PMID:MicroRNA-26a/b and their host genes cooperate to inhibit the G1/S transition by activating the pRb protein. 2221 Aug 97

Accumulating evidence demonstrates the important roles of microRNAs (miRNAs) in tumor development and progression. miR-26a has been reported to be downregulated in several types of cancers including hepatocellular carcinoma, but the underlying mechanism of how miR-26a is repressed remains largely unknown. In the present study, we performed western blot analysis, qRT-PCR, luciferase reporter assay and chromatin immunoprecipitation assay to investigate the relationship between miR-26a and the enhancer of zest homologue 2 (EZH2). CCK-8 assay and colony formation assay were carried out to explore the effect of miR-26a on HCC cells proliferation. We demonstrated that miR-26a was epigenetically repressed by EZH2-mediated H3K27 trimethylation within the miR-26a promoter. Moreover, we confirmed that EZH2 was also a direct target of miR-26a in HCC cells, thus, creating a double-negative feedback loop. Furthermore, miR-26a restoration increased the expressions of its host genes (CTDSPL and CTDSP2). Overexpression of EZH2 abrogated miR-26a induction of CTDSPL and CTDSP2. Restoring the balance of the double-negative feedback loop by miR-26a overpression or EZH2 silence significantly inhibited HCC cell growth. Overexpression of EZH2 rescued the growth inhibition effect of miR-26a. These findings suggest that an imbalanced double-negative feedback loop between EZH2 and miR-26a exists in HCC cells, which contributes to miR-26a deregulation and regulates tumor cells proliferation.
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PMID:A double-negative feedback loop between EZH2 and miR-26a regulates tumor cell growth in hepatocellular carcinoma. 2678 Oct 64