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microRNA‐448 inhibits stemness maintenance and self‐renewal of hepatocellular carcinoma stem cells through the MAGEA6‐mediated AMPK signaling pathway
Author(s) -
Guo JunCheng,
Yang YiJun,
Zhang JianQuan,
Guo Min,
Xiang Li,
Yu ShuFeng,
Ping Huang,
Zhuo Liu
Publication year - 2019
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.28915
Subject(s) - ampk , cancer research , gene silencing , stem cell , cd44 , microrna , cancer stem cell , biology , microbiology and biotechnology , signal transduction , small interfering rna , protein kinase a , chemistry , cell , kinase , cell culture , transfection , biochemistry , genetics , gene
Hepatocellular carcinoma (HCC) occurs mainly in patients with chronic liver disease and cirrhosis. Increasing evidence has identified the involvement of microRNAs (miRNAs) acting as essential regulators in the progression of HCC. As predicted by microarray analysis, miR‐448 might potentially affect HCC progression by regulating the melanoma‐associated antigen (MAGEA). Therefore, the present investigation focused on exploring whether or not miR‐448 and MAGEA6 were involved in the self‐renewal and stemness maintenance of HCC stem cells. The interaction among miR‐448, MAGEA6, and the AMPK signaling pathway was evaluated. It was noted that miR‐448 targeted and downregulated MAGEA6, thus activating the AMP‐activated protein kinase (AMPK) signaling pathway in HCC. Furthermore, for the purpose of exploring the functional relevance of MAGEA6 and miR‐448 on the sphere formation, colony formation, and invasion and migration of HCC stem cells, the CD133 + CD44 + HCC stem cells were sorted and treated with the mimic or inhibitor of miR‐448, small interfering RNA (siRNA) against MAGEA6 or an AMPK activator AICAR. MAGEA6 silencing or miR‐448 overexpression was demonstrated to inhibit the abilities of sphere formation, colony formation, cell migration, and invasion of HCC cells. Afterwards, a rescue experiment was conducted and revealed that MAGEA6 silencing reversed the effects of miR‐448 inhibitor on stemness maintenance and self‐renewal of HCC stem cells. Finally, after the in vivo experiment was carried out, miR‐448 was observed to restrain the tumor formation and stemness in vivo. Altogether, miR‐448 activates the AMPK signaling pathway by downregulating MAGEA6, thus inhibiting the stemness maintenance and self‐renewal of HCC stem cells, which identifies miR‐448 as a new therapeutic strategy for HCC.