Isovitexin Inhibits Stemness and Induces Apoptosis in Hepatocellular Carcinoma SK-Hep-1 Spheroids by Upregulating miR-34a Expression

Author(s):

Chang Xu, Xiaocheng Cao, XiaoZheng Cao, Lihua Liu, Yebei Qiu, Xiang Li, Lingli Zhou, Yingxia Ning, Kaiqun Ren* and Jianguo Cao*   Pages 1654 - 1663 ( 10 )

Abstract:

<P>Background: We previously demonstrated that isovitexin (apigenin-6-C-glucoside, ISOV) suppressed the stemness of human Hepatocellular Carcinoma (HCC) cells. However, the mechanism of its action remains to be deciphered. </P><P> Objective: The current study was to examine whether ISOV regulates the miR-34a expression and hence suppresses the stemness of HCC SK-Hep-1 cells. </P><P> Methods: After identification of the stemness, apoptosis resistance and decreased miR-34a expression of spheres from SK-Hep-1 cells (SK-SC), we utilized transfection of a miR-34a mimic or inhibitor to investigate the effects of ISOV on miR-34a, Bcl-2, Bax and Mcl-1 expression in order to understand the mechanism underlying ISOV-mediated repression of stemness and promotion of apoptosis. </P><P> Results: Our results demonstrated that SK-SC displayed higher stemness and resistance to apoptosis, as well as reduced miR-34a levels compared to SK-Hep-1 cells. ISOV suppressed sphere and colony formation, and decreased CD44+ cell populations. In addition, ABCG2, ALDH1, and NANOG mRNA levels were decreased, while there was a concomitant increase in miR-34a levels. With regards to apoptosis-related proteins, ISOV increased Bax protein levels, and reduced Bcl-2 and Mcl-1 protein levels in SK-SC. Importantly, there was a cooperative effect when miR-34a was overexpressed in the presence of ISOV in SK-SC, and down-regulation of miR-34a attenuated the effects of ISOV in SK-Hep-1 cells. </P><P> Conclusion: We suggest that ISOV-mediated miR-34a upregulation induces apoptosis and suppresses the stemness of SK-SC. Our data indicate that ISOV exhibits therapeutic potential for the treatment of HCC.</P>

Keywords:

Hepatocellular carcinoma, cancer stem cell, isovitexin, miR-34a, apoptosis, Bcl-2, Mcl-1, Bax.

Affiliation:

Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Medical College, Hunan Normal University, Changsha, Hunan 410013, Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Medical College, Hunan Normal University, Changsha, Hunan 410013, Department of Pharmacy, the Second Clinical Medical School of Jinan University, Shenzhen People’s Hospital, Shenzhen 518020, Department of Pharmacy, the Second Clinical Medical School of Jinan University, Shenzhen People’s Hospital, Shenzhen 518020, Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Medical College, Hunan Normal University, Changsha, Hunan 410013, Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Medical College, Hunan Normal University, Changsha, Hunan 410013, Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Medical College, Hunan Normal University, Changsha, Hunan 410013, Department of Gynecology and Obstetrics, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Medical College, Hunan Normal University, Changsha, Hunan 410013, Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Medical College, Hunan Normal University, Changsha, Hunan 410013

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