J Cancer 2020; 11(19):5578-5587. doi:10.7150/jca.44788

Research Paper

SSR2 overexpression associates with tumorigenesis and metastasis of Hepatocellular Carcinoma through modulating EMT

Xiaopeng Hong1#, Hui Luo2#, Genglong Zhu1, Xiaodong Guan1, Yingbin Jia1, Hailing Yu1, Xiufang Lv1, Ting Yu1, Huimin Lan2, Qianqian Zhang2, Hanjie Li2, Weiming Sun2, Xiaofang Huang2✉, Jian Li1✉

1. Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, P. R. China.
2. Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, P. R. China.
#These authors contributed equally to this article.

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Citation:
Hong X, Luo H, Zhu G, Guan X, Jia Y, Yu H, Lv X, Yu T, Lan H, Zhang Q, Li H, Sun W, Huang X, Li J. SSR2 overexpression associates with tumorigenesis and metastasis of Hepatocellular Carcinoma through modulating EMT. J Cancer 2020; 11(19):5578-5587. doi:10.7150/jca.44788. Available from http://www.jcancer.org/v11p5578.htm

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Abstract

Background: Hepatocellular carcinoma (HCC) is a common malignancy around the world. The molecular mechanisms underlying HCC tumorigenesis and metastasis are far from clear. Numerous studies have pointed out that signal sequence receptor (SSR) is an endoplasmic reticulum-related protein involved in protein folding and processing of eukaryotic cells. SSR2 is a subunit of SSR protein, but the role of SSR2 in hepatocellular carcinoma is largely unknown and warrants further study.

Materials and Methods: Several public databases were data mined to analyze the expression of four subunits of SSR between tumor and its peritumor counterparts. Also, the expression of SSR2 in our own collected tissues from HCC patients were analyzed by IHC and quantitative PCR. Survival analyses were conducted to delineate the prognostic value of SSR2. Clinical data were obtained followed by analysis based on SSR2 expression. Afterwards, cell proliferation, migration and invasion were detected by IncuCyte and trans-well assays, respectively. RNA interference was carried out by transfecting specific siRNA targeting SSR2 into cells using lipo2000. Western blot was applied to validate the knockdown effect and regulation on EMT-related proteins.

Results: We examined the expression of SSR and its correlation with recurrence and survival of patients. We discovered that SSR2 overexpression was negatively associated with survival of HCC patients from TCGA databases and the mutation of SSR2 was most among the four subunits of SSR protein. Additionally, in this study, we collected tumor and adjacent tissues from 125 cases of HCC patients. Through constructing tissue microarray, we have identified that SSR2 was highly expressed in HCC tumor tissues compared with adjacent normal tissues of hepatocellular carcinoma patients by immunohistochemistry assays. Furthermore, Kaplan-Meier survival analysis from our collected tissues revealed that the overexpression of SSR2 was inversely correlated with disease free survival and overall survival of HCC patients. We elucidated that SSR2 promotes proliferation, migration and invasion of HCC cells. SSR2 knockdown suppressed epithelial mesenchymal transition (EMT) of HCC cells.

Conclusions: These results collectively show that SSR2 is overexpressed in HCC tumor tissues, and it is an important factor in predicting survival of HCC patients. Additionally, it is involved in metastasis of HCC. These findings may help to exploit SSR2 as a novel factor in predicting prognosis and metastasis of HCC.

Keywords: hepatocellular carcinoma, tumorigenesis, SSR2, EMT