miR-192, a prognostic indicator, targets the SLC39A6/SNAIL pathway to reduce tumor metastasis in human hepatocellular carcinoma
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Junwei Lian1,*, Ying Jing1,*, Qiongzhu Dong2,3,*, Lin Huan1, Di Chen1, Chunyang Bao4, Qifeng Wang4, Fangyu Zhao1, Jinjun Li1, Ming Yao1, Lunxiu Qin2,3,5, Linhui Liang2,4, Xianghuo He1,2,4
1State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
2Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
3Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200032, China
4Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China
5Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
*These authors contributed equally to this work
Xianghuo He, e-mail: [email protected]
Linhui Liang, e-mail: [email protected]
Lunxiu Qin, e-mail: [email protected]
Keywords: miR-192, SLC39A6, metastasis, prognosis, hepatocellular carcinoma
Received: April 24, 2015 Accepted: November 20, 2015 Published: December 14, 2015
Metastasis is one of the causes of cancer death. Functions and mechanisms of microRNAs (miRNAs) involved in hepatocellular carcinoma (HCC) metastasis are largely unknown. Here, a miRNA microarray analysis was performed in MHCC-97L, MHCC-97H and HCC-LM3 cells with gradually increasing metastatic potential to disclose crucial miRNAs involved in HCC metastasis. miR-192 expression decreased and negatively correlated with vascular invasion in HCC specimens. Gain and loss of function studies revealed that miR-192 significantly suppressed metastasis of HCC cells in vitro and in vivo. Solute carrier family 39 member 6 (SLC39A6) was identified as a direct and functional target of miR-192. In addition, SLC39A6 negatively correlated with miR-192 in HCC samples and promoted HCC cell migration and invasion. Moreover, miR-192 decreased SLC39A6 expression, subsequently downregulating SNAIL and upregulating E-cadherin expression. Suppression of migration and invasion caused by miR-192 overexpression was alleviated by exogenous Snail expression. Intriguingly, lower miR-192 expression and higher SLC39A6 expression significantly contributed to poorer outcomes in HCC patients. Multivariate analysis indicated that miR-192 was an independent and significant predictor of HCC patient overall survival. In conclusion, we newly determined that miR-192 targeted the SLC39A6/SNAIL pathway to reduce tumor metastasis in HCC cells. This axis provided insights into the mechanism underlying miRNA regulation of HCC metastasis and a novel therapeutic target for HCC treatment.
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