CAPS1 Negatively Regulates Hepatocellular Carcinoma Development through Alteration of Exocytosis-Associated Tumor Microenvironment

Ruyi Xue; Wenqing Tang; Pingping Dong; Shuqiang Weng; Lijie Ma; She Chen; Taotao Liu; Xizhong Shen; Xiaowu Huang; Si Zhang; Ling Dong

doi:10.3390/ijms17101626

CAPS1 Negatively Regulates Hepatocellular Carcinoma Development through Alteration of Exocytosis-Associated Tumor Microenvironment

Int J Mol Sci. 2016 Sep 27;17(10):1626. doi: 10.3390/ijms17101626.

Authors

Ruyi Xue¹, Wenqing Tang², Pingping Dong³, Shuqiang Weng⁴, Lijie Ma⁵, She Chen⁶, Taotao Liu⁷, Xizhong Shen⁸, Xiaowu Huang⁹, Si Zhang¹⁰, Ling Dong¹¹

Affiliations

¹ Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai 200032, China. xue.ruyi@zs-hospital.sh.cn.
² Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai 200032, China. wanjin1986@163.com.
³ Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai 200032, China. pingdongqy@163.com.
⁴ Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai 200032, China. weng.shuqiang@zs-hospital.sh.cn.
⁵ Department of Hepatic Surgery of Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China. 14211210033@fudan.edu.cn.
⁶ Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China. shechen@fudan.edu.cn.
⁷ Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai 200032, China. liu.taotao@zs-hospital.sh.cn.
⁸ Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai 200032, China. shen.xizhong@zs-hospital.sh.cn.
⁹ Department of Hepatic Surgery of Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China. huang.xiaowu@zs-hospital.sh.cn.
¹⁰ Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China. zhangsi@fudan.edu.cn.
¹¹ Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai 200032, China. dong.ling@zs-hospital.sh.cn.

Abstract

The calcium-dependent activator protein for secretion 1 (CAPS1) regulates exocytosis of dense-core vesicles (DCVs) in neurons and neuroendocrine cells. The role of CAPS1 in cancer biology remains unknown. The purpose of this study was to investigate the role of CAPS1 in hepatocellular carcinoma (HCC). We determined the levels of CAPS1 in eight hepatoma cell lines and 141 HCC specimens. We evaluated the prognostic value of CAPS1 expression and its association with clinical parameters. We investigated the biological consequences of CAPS1 overexpression in two hepatoma cell lines in vitro and in vivo. The results showed that loss of CAPS1 expression in HCC tissues was markedly correlated with aggressive tumor phenotypes, such as high-grade tumor node metastasis (TNM) stage (p = 0.003) and absence of tumor encapsulation (p = 0.016), and was associated with poor overall survival (p = 0.008) and high recurrence (p = 0.015). CAPS1 overexpression inhibited cell proliferation and migration by changing the exocytosis-associated tumor microenvironment in hepatoma cells in vitro. The in vivo study showed that CAPS1 overexpression inhibited xenograft tumor growth. Together, these results identified a previously unrecognized tumor suppressor role for CAPS1 in HCC development.

Keywords: calcium-dependent activator protein for secretion 1; exocytosis; hepatocellular carcinoma; membrane trafficking; prognosis; tumor microenvironment.