GPAA1 promotes gastric cancer progression via upregulation of GPI-anchored protein and enhancement of ERBB signalling pathway

Journal of Experimental & Clinical Cancer Research

Bo Ni¹  Rong-Kun Li²  Li-Li Zhu³  Xue-Li Zhang³  Li-Peng Hu³  Qin Yang³  Jun Li³  Zhi-Gang Zhang³  Yan-Li Zhang³  Ya-Hui Wang³  Shu-Heng Jiang³  Xiao-Xin Zhang³  Xiao-Mei Yang³  Chun-Chao Zhu⁴  Qing Li⁵  Guang-Ang Tian⁵ 

[1] 0000 0004 0368 8293, grid.16821.3c, Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 200217, Shanghai, People’s Republic of China;0000 0004 0368 8293, grid.16821.3c, Department of Interventional Radiology, Tongren Hospital, School of Medicine, Shanghai Jiao Tong University, 200336, Shanghai, People’s Republic of China;0000 0004 0368 8293, grid.16821.3c, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 200240, Shanghai, People’s Republic of China;0000 0004 0368 8293, grid.16821.3c, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 200240, Shanghai, People’s Republic of China;0000 0004 0368 8293, grid.16821.3c, Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 200217, Shanghai, People’s Republic of China;0000 0004 0619 8943, grid.11841.3d, Shanghai Medical College of Fudan University, 200032, Shanghai, People’s Republic of China;

关键词: Gastric cancer;    GPAA1;    GPI-anchored proteins;    EGFR;    ERBB2;   

DOI  :  10.1186/s13046-019-1218-8

来源: publisher

【 摘 要 】

BackgroundGastric cancer is one of the deadliest malignant tumours, with a high incidence in China, and is regulated by aberrantly overexpressed oncogenes. However, existing therapies are insufficient to meet patients’ needs; thus, the identification of additional therapeutic targets and exploration of the underlying mechanism are urgently needed. GPAA1 is the subunit of the GPI transamidase that transfers the GPI anchor to proteins within the ER. The functional impacts of increased expression levels of GPAA1 in human cancers are not well understood.MethodsData mining was performed to determine the pattern of GPAA1 expression and the reason for its overexpression in tumour and adjacent normal tissues. In vitro and in vivo experiments evaluating proliferation and metastasis were performed using cells with stable deletion or overexpression of GPAA1. A tissue microarray established by the Ren Ji Hospital was utilized to analyse the expression profile of GPAA1 and its correlation with prognosis. Western blotting, an in situ proximity ligation assay, and co-immunoprecipitation (co-IP) were performed to reveal the mechanism of GPAA1 in gastric cancer.ResultsGPAA1 was a markedly upregulated oncogene in gastric cancer due to chromosomal amplification. GPAA1 overexpression was confirmed in specimens from the Ren Ji cohort and was associated with ERBB2 expression, predicting unsatisfactory patient outcomes. Aberrantly upregulated GPAA1 dramatically contributed to cancer growth and metastasis in in vitro and in vivo studies. Mechanistically, GPAA1 enhanced the levels of metastasis-associated GPI-anchored proteins to increase tumour metastasis and intensified lipid raft formation, which consequently promoted the interaction between EGFR and ERBB2 as well as downstream pro-proliferative signalling.ConclusionsGPAA1 facilitates the expression of cancer-related GPI-anchored proteins and supplies a more robust platform—the lipid raft—to promote EGFR-ERBB2 dimerization, which further contributes to tumour growth and metastasis and to cancer progression. GPAA1 could be a promising diagnostic biomarker and therapeutic target for gastric cancer.

【 授权许可】

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