Abstract
microRNAs, frequently deregulated in human cancer, have been implicated in the progression of hepatocarcinogenesis. Here, we show that microRNA (miR)-137 is significantly down-regulated in hepatocellular carcinoma (HCC). Its decreased expression is associated with vein invasion, incomplete Involucrum, and distant metastasis. Multivariate analysis suggests that miR-137 is an independent indicator for poor survival. We next show that over-expression of miR-137 suppresses cell proliferation, migration and invasion in vitro. Conversely, miR-137 inhibition promotes HCC cell growth. We also identify AKT2 as a key target of miR-137 in this context. Statistical data reveal a reverse correlation of AKT2 and miR-137 expression in HCC patients. Silencing of AKT2 phenotypically copied miR-137-induced phenotypes, whereas re-expression of AKT2 reversed the suppressive effects of miR-137. Further investigations showed that miR-137 exerted its anti-tumour activity via inhibiting the AKT2/mTOR pathway. Moreover, we demonstrate that FoxD3 directly binds to the promoter of miR-137 and activates its transcription. In vivo studies confirm that FoxD3-regulated miR-137 inhibited HCC growth and metastasis via targeting AKT2. Together, our findings indicate that miR-137 is a valuable biomarker for HCC prognosis and the FoxD3/miR-137/AKT2 regulatory network plays an important role in HCC progression.
Highlights
Hepatocellular carcinoma (HCC) is the third leading cause for cancer-related death worldwide [1]
We demonstrated that the FoxD3/miR-137/AKT2 regulatory network played an important role in HCC progression
Down-regulation of miR-137 is associated with metastasis and poor prognosis in HCC
Summary
Hepatocellular carcinoma (HCC) is the third leading cause for cancer-related death worldwide [1]. Accumulating studies have suggested that deregulation of miRNAs have been linked to the development of a wide range of human diseases, including cancers. MicroRNA functions as either oncogene or tumour suppressor in different types of cancer [5]. In HCC, studies have focused on the effect of miRNAs on tumour growth and metastasis. MiR-26a inhibits [6], whereas www.impactjournals.com/oncotarget miR-17-5p promotes tumour growth and metastasis in HCC [7]. MiR-137 functions primarily as an anti-tumour miRNA and is dysregulated in multiple types of cancer, including head and neck cancer [8] and colorectal cancer [9]. Liang et al demonstrated that transcriptional factor HMGA1 influenced miR-137 expression in colorectal cancer [9]. The mechanism of miR-137 deregulation and its regulatory networks in HCC remain elusive
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have