Abstract
Increasing evidence indicates that dysregulation of microRNAs (miRNAs) plays critical roles in malignant transformation and tumor progression. Previously, we have shown that microRNA-451 (miR-451) inhibits growth, increases chemo- or radiosensitivity and reverses epithelial to mesenchymal transition (EMT) in lung cancer. However, the roles of miR-451 in hepatocelluar carcinoma (HCC) progression and metastasis are still largely unknown. Reduced miR-451 in HCC tissues was observed to be significantly correlated with advanced clinical stage, metastasis and worse disease-free or overall survival. Through gain- and loss-of function experiments, we demonstrated that miR-451 inhibited cell growth, induced G0/G1 arrest and promoted apoptosis in HCC cells. Importantly, miR-451 could inhibit the migration and invasion in vitro, as well as in vivo metastasis of HCC cells through regulating EMT process. Moreover, the oncogene c-Myc was identified as a direct and functional target of miR-451 in HCC cells. Knockdown of c-Myc phenocopied the effects of miR-451 on EMT and metastasis of HCC cells, whereas overexpression of c-Myc partially attenuated the functions of miR-451 restoration. Furthermore, miR-451 downregulation-induced c-Myc overexpression leads to the activation of Erk1/2 signaling, which induces acquisition of EMT phenotype through regulation of GSK-3β/snail/E-cadherin and the increased expression of MMPs family members in HCC cells. Collectively, these data demonstrated that miR-451 is a novel prognostic biomarker for HCC patients and that function as a potential metastasis inhibitor in HCC cells through activation of the Erk1/2 signaling, at least partially by targeting c-Myc. Thus, targeting miR-451/c-Myc/Erk1/2 axis may be a potential strategy for the treatment of metastatic HCC.
Highlights
Hepatocellular carcinoma (HCC) is the fifth common cause of cancer related death worldwide [1]
The expression of miR-451 is significantly downregulated in hepatocelluar carcinoma (HCC) tissues when compared to the adjacent non-tumor tissues, and reduced miR-451 was observed to be significantly associated with advanced TNM stage, lymph node metastasis, vascular invasion and higher Edmondson grade in additional 88 HCC tissues (Figure 1a-1b and Table 3)
The Kaplan-Meier survival plots revealed an association of lower miR-451 expression levels with shorter disease-free survival (DFS) and overall survival www.impactjournals.com/oncotarget (OS), and multivariate Cox regression analysis indicated that reduced miR-451 was an independent poor prognostic factor for HCC patients (P=0.009; Figure 1c and Table 4)
Summary
Hepatocellular carcinoma (HCC) is the fifth common cause of cancer related death worldwide [1]. Researches on EMT and its roles in HCC tumorigenesis and metastasis will provide a novel perspective from clinical and translational standpoints. Evidences suggesting miR-451 possibly involved in proliferation and migration of HCC [23, 24], the clinicopathological and prognostic values of miR-451 and its roles in EMT and metastasis of HCC cells remain largely unclear. We showed that reduced miR-451 was correlated with higher incidence of metastasis and poor survival of HCC patients. Restoration of miR-451 could reverse EMT and inhibit metastasis of HCC cells in vitro and in vivo. Our findings highlight the critical roles of miR-451 dysregulation in inhibiting metastasis of HCC through regulation of EMT process
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