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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

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*

Volume 20, Issue 14, 2020

Page: [1654 - 1663] Pages: 10

DOI: 10.2174/1871520620666200424123139

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Abstract

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.

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.

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.

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.

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.

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

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