Abstract
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-miR-197) 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.
Highlights
hepatocellular carcinoma (HCC) is one of the most common human malignant tumors in the world and the second leading cause of cancer-related death in China.[1]
Our results showed that p-Signal transducer and activator of transcription 3 (STAT3) and total STAT3 levels were quickly increased after IL-6 stimulation in HCC cells, which was consistent with previous studies.[2,20]
STAT3 mRNA levels remained unchanged throughout IL-6 stimulation, indicating that IL-6 stimulation rapidly increased STAT3 expression at protein level but not at mRNA level in HCC cells, and suggesting that IL-6-induced upregulation of total STAT3 may be modulated at post-transcriptional level rather than transcriptional level
Summary
HCC is one of the most common human malignant tumors in the world and the second leading cause of cancer-related death in China.[1]. It is urgent to explore the molecular mechanisms underlying tumorigenesis and progression of HCC. Dysregulation of coding and non-coding gene expression was considered to be the main cause of HCC.[2,3,4,5,6]. STATs, which mostly exist in the cytoplasm, are key transcription factors mediating cytokine and growth factor signaling pathways.[7] So far, seven STAT members have been identified in mammals.[8,9,10] After cytokine binding, the receptors are quickly phosphorylated by Jak kinases. STATs are phosphorylated, dimerized and translocated into the nucleus where they regulate expression of target genes.[11] STAT3, one of the most extensively studied STAT members, has been proven to be constitutively activated in various cancers including HCC.[12,13] Activated
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