J Cancer 2018; 9(8):1403-1413. doi:10.7150/jca.23849

Research Paper

Secretory Clusterin Mediates Oxaliplatin Resistance via the Gadd45a/PI3K/Akt Signaling Pathway in Hepatocellular Carcinoma

Xin Wang1*, Fang Zou1,2*, Jingtao Zhong3, Longtao Yue1, Fuhai Wang1, Honglong Wei1, Guangsheng Yang1, Tao Jin1, Xiaofeng Dong4, Jie Li1, Peng Xiu1,✉

1. Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, China
2. Department of Emergency Surgery, The People's Hospital of Linyi City, Linyi 276000, China
3. Department of General Surgery, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academic of Medicine Science, Jinan 250117, Shandong, China
4. Department of Hepatobiliary Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, China
* Xin Wang and Fang Zou are equal contributors to this paper.

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Citation:
Wang X, Zou F, Zhong J, Yue L, Wang F, Wei H, Yang G, Jin T, Dong X, Li J, Xiu P. Secretory Clusterin Mediates Oxaliplatin Resistance via the Gadd45a/PI3K/Akt Signaling Pathway in Hepatocellular Carcinoma. J Cancer 2018; 9(8):1403-1413. doi:10.7150/jca.23849. Available from http://www.jcancer.org/v09p1403.htm

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Abstract

Purpose: Systemic therapy has often been used for patients with advanced hepatocellular carcinoma (HCC). However, due to drug resistance, the use of cytotoxic chemotherapy in the treatment of patients with advanced HCC has typically demonstrated low response rates. Secretory clusterin (sCLU) is expressed in aggressive late-stage tumors and associated with resistance to chemotherapy, including that in HCC cases. The present research aimed to investigate the biological role of sCLU in HCC.

Methods: sCLU expression in HCC and normal tissues was examined using immunohistochemical staining, followed by analysis of the correlation between sCLU expression and clinical indicators. In addition, the role and internal mechanism of sCLU in cell proliferation and apoptosis were investigated in HCC cells.

Results: sCLU expression was significantly upregulated in HCC tissues; and was associated with histological grade and poor overall survival. The levels of sCLU were significantly increased in Bel7402, SMMC7721 and resistant HCC cells (Bel7404-OR). Inhibiting the activity of sCLU enhanced the chemosensitivity of Bel7402 and SMMC7721 cells. Downregulation of sCLU could increase the expression of Gadd45a in HCC cells. Overexpression of sCLU contributed to drug resistance in Bel7402, SMMC7721 and Bel7404-OR cells; whereas, overexpression of Gadd45a alone overcame drug resistance in the cells above. No significant expression changes of sCLU and Gadd45a were observed in HCC cells after the interference of a selective inhibitor of the PI3K/Akt signaling pathway. However, regulation of the expression of Gadd45a could influence the phosphorylation level of Akt; and further regulate the expression of Bcl-2 and Bax proteins involved in the mitochondrial apoptosis pathways.

Conclusions: The results demonstrate that sCLU/Gadd45a/PI3K/Akt signaling represents a novel pathway that could regulate drug resistance in a one-way manner in HCC cells.