Reciprocal control of miR-197 and IL-6/STAT3 pathway reveals miR-197 as potential therapeutic target for hepatocellular carcinoma

Signal transducer and activator of transcription 3 (STAT3) is one of the key players in liver cancer. Increased levels of phosphorylated STAT3 (p-STAT3) have been detected in many cancers including hepatocellular carcinoma (HCC), and are usually associated with a more aggressive phenotype and poor prognosis. In addition to aberrant activation of STAT3, upregulation of total STAT3 was also detected in HCC, for which the underlying mechanisms and significance remain to be fully elucidated. Here we report that a reciprocal regulation exists between miR-197 and the IL-6/STAT3 inflammatory signaling pathway in HCC. We found that IL-6 stimulation increased total STAT3 expression at protein level but not mRNA level in HCC cells, suggesting the existence of post-transcriptional regulation of STAT3. Our study showed that IL-6/STAT3 pathway decreases expression of miR-197 in HCC, which amplifies IL-6/STAT3 pathway and contributes to HCC progression. miR-197 can significantly inhibit HCC growth both in vitro and in vivo. In addition, IL-6/STAT3-induced downregulation of miR-197 in HCC may be via affecting Drosha binding to primary miR-197 (pri-miR197) and thus reducing mature miR-197 generation. Our study suggests that miR-197 may serve as a potential therapeutic target for interfering with the IL-6/STAT3 inflammatory pathway in HCC.