J Cancer 2019; 10(25):6199-6206. doi:10.7150/jca.36301

Research Paper

Mortalin stabilizes CD151-depedent tetraspanin-enriched microdomains and implicates in the progression of hepatocellular carcinoma

Li-Xin Liu1,2*, Jia-Cheng Lu1*, Hai-Ying Zeng3*, Jia-Bin Cai1*, Peng-Fei Zhang1*, Xiao-Jun Guo1, Xiao-Yong Huang1, Rui-Zhao Dong1, Chi Zhang1, Qiang Kang2, Hao Zou2, Xin-Yu Zhang1, Lu Zhang1, Xiao-Wen Zhang2✉, Ai-Wu Ke1✉, Guo-Ming Shi1✉

1. Department of Liver Surgery and Liver transplantation of Liver Cancer Institute & Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
2. Department of Hepatobiliary Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China
3. Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
*These authors contributed equally to this work; none of the material appearing in this article has been previously presented or published in any form.

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Citation:
Liu LX, Lu JC, Zeng HY, Cai JB, Zhang PF, Guo XJ, Huang XY, Dong RZ, Zhang C, Kang Q, Zou H, Zhang XY, Zhang L, Zhang XW, Ke AW, Shi GM. Mortalin stabilizes CD151-depedent tetraspanin-enriched microdomains and implicates in the progression of hepatocellular carcinoma. J Cancer 2019; 10(25):6199-6206. doi:10.7150/jca.36301. Available from http://www.jcancer.org/v10p6199.htm

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Abstract

Background: Our previous studies showed that tetraspanin CD151 was implicated in the progression of hepatocellular carcinoma (HCC), mainly depending on the formation of functional complexes with molecular partners, including Mortalin. In this study, we investigate the role of mortalin in CD151-depedent progression of HCCs.

Methods: Immunofluorescent staining, western blot and quantitative real-time polymerase chain reaction (qRT-PCR) were used to investigate the expression and location of CD151 and Mortalin in four HCC cell lines with different metastatic ability. The relationship between Mortalin and CD151 was investigated in HCCLM3 cells using co-immunoprecipitation. CD151 or Mortalin expression in HCC cells were modified by transfection technology. Wound-healing assay and Transwell assay were used to assay the role of CD151 and Mortalin in cell migration and invasion. The expression and prognostic implication of CD151 and Mortalin in 187 cases of HCCs were analyzed.

Results: Expression of Mortalin in HCC cells was positive related to their metastatic ability and its tendency was in line with the expression of CD151. Immunofluorescent staining showed that Mortalin was located in cytoplasm, while positive staining for CD151 was observed in cytoplasm and membrane of HCC cells. co-IP revealed that Mortalin formed a complex with CD151. Down-regulation of Mortalin induced a moderate decreased CD151 protein, but not CD151 mRNA, while inhibition of CD151 did not influence the expression of Mortalin at the level of both protein and mRNA. Interference of Mortalin significantly inhibited the invasion and migration of HCC cells with high CD151 expression and partially restored the invasion and migration of HCC cells induced by CD151 over-expression. Clinically, high Mortalin expression correlated with malignant phenotype of HCC, such as microvascular invasion (p=0.017) and tumor diameter (p=0.001). HCC patients expressing high Mortalin were tend to have higher expression of CD151. HCC patients expressing high level of CD151 showed the poorer prognosis in a Mortalin-dependent manner.

Conclusions: Mortalin maybe stabilize of the structure of CD151-dependent tetraspanin-enriched microdomains and implicate in the progression of HCC.

Keywords: hepatocellular carcinoma, CD151, mortalin, tetraspanin-enriched microdomains, invasion