Perturbation of MicroRNA‐370/Lin‐28 homolog A/nuclear factor kappa B regulatory circuit contributes to the development of hepatocellular carcinoma

MicroRNA 370 (miR‐370) is located within the DLK1/DIO3 imprinting region on human chromosome 14, which has been identified as a cancer‐associated genomic region. However, the role of miR‐370 in malignances remains controversial. Here, we report that miR‐370 was repressed in human hepatocellular carcinoma (HCC) tissues and hepatoma cell lines. Using gain‐of‐function and loss‐of‐function experiments, we demonstrated that miR‐370 inhibited the malignant phenotype of HCC cells in vitro. Overexpression of miR‐370 inhibited growth and metastasis of HCC cells in vivo. Moreover, the RNA‐binding protein, LIN28A, was identified as a direct functional target of miR‐370, which, in turn, blocked the biogenesis of miR‐370 by binding to its precursor. LIN28A also mediated the suppressive effects of miR‐370 on migration and invasion of HCC cells by post‐transcriptionally regulating RelA/p65, which is an important effector of the canonical nuclear factor kappa B (NF‐κB) pathway. Interleukin‐6 (IL‐6), a well‐known NF‐κB downstream inflammatory molecule, reduced miR‐370 but increased LIN28A levels in HCC. Furthermore, miR‐370 levels were inversely correlated with LIN28A and IL‐6 messenger RNA (mRNA) levels, whereas LIN28A mRNA expression was positively correlated with IL‐6 expression in human HCC samples. Interestingly, reduction of miR‐370 expression was associated with the development of HCC in rats, as well as with aggressive tumor behavior and short survival in HCC patients. Conclusions: These data demonstrate the involvement of a novel regulatory circuit consisting of miR‐370, LIN28A, RelA/p65 and IL‐6 in HCC progression. Manipulating this feedback loop may have beneficial effect in HCC treatment. (Hepatology 2013; 58:1977–1991)