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

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

doi:10.3390/ijms17101626

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.

Highlights

Liver cancer is the fifth most frequently diagnosed cancer, and the second most frequent cause of cancer death worldwide [1]
Loss of calcium-dependent activator protein for secretion 1 (CAPS1) compared with peritumoral tissues was perceived in 85% (120 of 141) of hepatocellular carcinoma (HCC) samples, compared with peritumoral tissues
CAPS1 expression was determined by Western blotting in eight HCC cell lines, as well as a normal liver cell line, L-02 (Figure 1D)

Summary

Introduction

Liver cancer is the fifth most frequently diagnosed cancer, and the second most frequent cause of cancer death worldwide [1]. Hepatocellular carcinoma (HCC) represents the most common histological subtype, accounting for 70%–85% of the total liver cancer occurrence worldwide [2]. HCC is asymptomatic in its early stages, and even after tumor resection the survival and recurrence are extremely discouraging. Prognostic prediction is a vital component in clinical management of HCC patients. Current clinicopathologic factors, such as α-fetoprotein (AFP), tumor node metastasis (TNM) stage, and Barcelona clinic liver cancer (BCLC) stage, cannot accurately predict the outcome of HCC patients. It is important to identify novel prognostic factors for HCC [3]

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