J Cancer 2020; 11(18):5309-5317. doi:10.7150/jca.45712

Research Paper

Depressive Disorder promotes Hepatocellular Carcinoma metastasis via upregulation of ABCG2 gene expression and maintenance of self-renewal

Hao Hu1,2*, Shao-Ju Luo1*, Zhi-rui Cao1*, Yingzi Wu4, Zhuomao Mo1, Yongdan Wang1, Ling Yu1, Yan Chen4, Liang Xu3✉, Shi-Jun Zhang1✉

1. The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, P. R. China.
2. Department of Oncology, First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou (510407), China.
3. The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, P. R. China.
4. Department of Chinese Medicine, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, Guangdong, P. R. China.
*These authors contributed equally to this work.

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Citation:
Hu H, Luo SJ, Cao Zr, Wu Y, Mo Z, Wang Y, Yu L, Chen Y, Xu L, Zhang SJ. Depressive Disorder promotes Hepatocellular Carcinoma metastasis via upregulation of ABCG2 gene expression and maintenance of self-renewal. J Cancer 2020; 11(18):5309-5317. doi:10.7150/jca.45712. Available from https://www.jcancer.org/v11p5309.htm

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Abstract

Depressive disorder (DD) is the leading cause of disability worldwide and is the most prevalent mood disorder. Accumulative evidence from epidemiological studies has shown that DD is a risk factor for cancer. However, the role and molecular mechanism of DD in hepatocellular carcinoma (HCC) are still unknown. In this study, 30 mice were randomly divided into two groups: the HCC group and the HCC-DD group. The DD mouse model of HCC was established by induction with reserpine every other day and with monthly doses of diethylnitrosamine (DEN). All of the molecular studies were based on primary cell culture, and the effects of DD on HCC cell proliferation and migration and cancer stem cell (CSC) self-renewal were determined by colony formation, wound healing, and sphere culture assays. We found that the CSC markers ABCG2 and CD133 were upregulated in HCC-DD primary cells compared with HCC primary cells. Moreover, HCC-DD primary cells were more aggressive in terms of metastasis and self-renewal than HCC primary cells. Further study revealed that DD promoted tumor growth and metastasis by activating the AKT signaling pathway followed by an increased ABCG2 expression. Taken together, our novel findings indicate that DD promotes proliferation, self-renewal, and metastasis by upregulating ABCG2 in the AKT pathway.

Keywords: Depressive disorder, Hepatocellular carcinoma, Metastasis, CSCs, ABCG2