| Summary: | MicroRNAs (miRNAs) are negative regulators of gene expression, and miRNA
deregulation is found in various tumors. We previously reported that suppression
of adenine nucleotide translocase 2 (ANT2) by short hairpin RNA (shRNA) inhibits
hepatocellular carcinoma (HCC) development by rescuing miR-636 expression.
However, the tumor-suppressive mechanisms of ANT2 shRNA are still poorly
understood in HCC. Here, we hypothesized that miRNAs that are specifically
downregulated by ANT2 shRNA might function as oncomiRs, and we investigated the
roles of ANT2 shRNA-regulated miRNAs in the pathogenesis of HCC. Our data show
that miR-19a and miR-96, whose expression is regulated by ANT2 suppression, were
markedly upregulated in HCC cell lines and clinical samples. Ectopic expression
of miR-19a and miR-96 dramatically induced the proliferation and colony
formation of hepatoma cells in vitro, whereas inhibition of miR-19a and
miR-96 reduced these effects. To investigate the in vivo function, we
implanted miR-96-overexpressing HepG2 cells in a xenograft model and
demonstrated that the increase in miR-96 promoted tumor growth. We also found
that miR-19a and miR-96 inhibited expression of tissue inhibitor of
metalloproteinase-2. Taken together, our results suggest that ANT2-regulated
miR-19a and miR-96 play an important role in promoting the proliferation of
human HCC cells, and the knockdown of ANT2 directly downregulates miR-19a and
miR-96, ultimately resulting in the suppression of tumor growth.
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