miR-17-92 cluster promotes cholangiocarcinoma growth: evidence for PTEN as downstream target and IL-6/Stat3 as upstream activator.

[severe combined immunodeficiency]

miR-17 -92 is an oncogenic miRNA cluster implicated in the development of several cancers ; however , it remains unknown whether the miR-17 -92 cluster is able to regulate cholangiocarcinogenesis . This study was designed to investigate the biological functions and molecular mechanisms of the miR-17 -92 cluster in cholangiocarcinoma . In situ hybridization and quantitative RT-PCR analysis showed that the miR-17 -92 cluster is highly expressed in human cholangiocarcinoma cells compared with the nonneoplastic biliary epithelial cells . Forced overexpression of the miR-17 -92 cluster or its members , miR-92 a and miR-19 a , in cultured human cholangiocarcinoma cells enhanced tumor cell proliferation , colony formation , and invasiveness , in Â vitro . Overexpression of the miR-17 -92 cluster or miR-92 a also enhanced cholangiocarcinoma growth in Â vivo in hairless outbred mice with severe combined immunodeficiency (SHO-Prkdc (scid )Hr (hr )). The tumor -suppressor , phosphatase and tensin homolog deleted on chromosome 10 (PTEN ), was identified as a bona fide target of both miR-92 a and miR-19 a in cholangiocarcinoma cells via sequence prediction , 3 ' untranslated region luciferase activity assay , and Western blot analysis . Accordingly , overexpression of the PTEN open reading frame protein (devoid of 3 ' untranslated region ) prevented miR-92 a- or miR-19 a-induced cholangiocarcinoma cell growth . Microarray analysis revealed additional targets of the miR-17 -92 cluster in human cholangiocarcinoma cells , including APAF-1 and PRDM 2 . Moreover , we observed that the expression of the miR-17 -92 cluster is regulated by IL -6 /Stat 3 , a key oncogenic signaling pathway pivotal in cholangiocarcinogenesis . Taken together , our findings disclose a novel IL -6 /Stat 3 -miR-17 -92 cluster-PTEN signaling axis that is crucial for cholangiocarcinogenesis and tumor progression .

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Diseases presenting "colony formation" symptom

cholangiocarcinoma

severe combined immunodeficiency

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