Research Papers:
Blocking of STAT3 activation by miR491 acting via EGFR is involved in metastasis of hepatocellular carcinoma cells through inhibiting cancer stem celllike properties
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Yang Liu1,*, Yawei Liu2,3,*, Fei Luo4,5, Feng Liu1, Litian Hu2, Yi Liu4,5, Jianping Zhang2, Qizhan Liu4,5 and Weimin Fan1
1Department of Orthopedics, The First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, Jiangsu, People’s Republic of China
2Department of General Surgery, The Second Affiliated Hospital, Nanjing Medical University, Nanjing 210011, Jiangsu, People’s Republic of China
3Department of General Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing 210008, Jiangsu, People’s Republic of China
4Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People’s Republic of China
5The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People’s Republic of China
*These authors have contributed equally to this work
Correspondence to:
Qizhan Liu, email: [email protected]
Weimin Fan, email: [email protected]
Keywords: hepatocellular carcinoma, miR-491, cancer stem cell-like properties, migration
Received: June 29, 2017 Accepted: August 04, 2017 Published: September 23, 2017
ABSTRACT
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. However, the mechanisms that contribute to tumor metastasis remain unclear. To determine the molecular mechanisms underlying the metastasis of HCC cells, HepG2 (very low migratory capacity), MHCC97L (low migratory capacity), and MHCC97H (high migratory capacity) cells, as well as HCC tissues and corresponding non-cancerous liver tissue were used to investigate the effects of microRNA-491 (miR-491) on the acquisition of cancer stem cell (CSC)-like properties, neoplastic capacity, and migration of HCC cells. In HCC specimens, miR-491 levels were down-regulated, EGFR levels were up-regulated, and STAT3 was activated, results that correlated with the clinical stage of HCC. Moreover, miR-491 levels inversely correlated with the migratory potential of HCC cell lines. In HepG2 cells, down-regulation of miR-491 levels increased the levels of EGFR and STAT3 phosphorylation. In contrast, an miR-491 mimic induced contrary changes in MHCC97H cells. In HCC cells, miR-491 inhibited the luciferase activities of an EGFR 3’UTR Luc construct, indicating that miR-491 directly regulates EGFR. The effects of miR-491 on the activation were blocked by EGFR siRNA or the pEGFP-EGFR plasmid. In HepG2 cells, down-regulation of miR-491 increased the levels of CSC-like markers (Bmi-1, Oct-4, CD133, and EPCAM) and the levels of metastasis markers (MMP-9 and MMP-2) and enhanced the acquisition of CSC-like properties, neoplastic capacity, and migration; these effects were blocked by STAT3 siRNA. In contrast, over-expression of miR-491 decreased the levels of Bmi-1, Oct-4, CD133, EPCAM, MMP-9, and MMP-2 and inhibited the acquisition of CSC-like properties, neoplastic capacity, and migration of MHCC97H cells; the effects were blocked by up-regulation of STAT3 levels. These results indicate that miR-491 influences CSC-like properties and metastasis of HCC cells by blocking the activation of STAT3 via EGFR, which provides a mechanism for preventing metastasis of HCCs.