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 MS-275 purchase 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 Inhibitor Library cost 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) Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, especially in Asia.[1] Most HCCs develop on a background of chronic inflammation caused by hepatitis virus, toxins, metabolic impairment, or autoimmune hepatopathy.[2] Inflammatory molecules can provide signals that promote the proliferation and metastasis of HCC cells.[2, 3] The transcription factor, nuclear selleck products factor kappa B (NF-κB), is a key modulator of inflammatory response and plays a pivotal role in the regulation of inflammatory signal

transduction pathways in the liver.[4] Activation of NF-κB is also widely viewed as a link between inflammation and the pathogenesis of various cancers, including HCC.[4, 5] MicroRNAs (miRNAs) are a class of small noncoding RNA molecules that regulate post-transcriptional events.[6] Aberrant expression of many miRNAs is implicated in the onset and development of HCC.[7, 8] MicroRNA 370 (miR-370) is located within the DLK1/DIO3 imprinting region on human chromosome 14.[9] It was first cloned from human embryonic stem cells, but had a very low expression level.[10] Several studies have identified the DLK1/DIO3 domain as a cancer-associated genomic region,[11] implicating the involvement of miR-370 in cancer pathogenesis. Nevertheless, the role of miR-370 in malignances remains controversial. Substantial evidence demonstrates that miR-370 serves as a tumor suppressor in malignant cholangiocytes,[12, 13] leukemia cells,[14] and oral squamous carcinoma cells.