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

Xiao-Xin Zhang,Rong-Kun Li,Qin Yang,Zhi-Gang Zhang,Chun-Chao Zhu,Ya-Hui Wang,Guang-Ang Tian,Shu-Heng Jiang,Li-Li Zhu,Bo Ni,Qing Li,Jun Li,Xue-Li Zhang,Yan-Li Zhang,Xiao-Mei Yang,Li-Peng Hu

doi:10.1186/s13046-019-1218-8

Abstract

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.

Highlights

Gastric cancer is one of the deadliest malignant tumours, with a high incidence in China, and is regulated by aberrantly overexpressed oncogenes
Chromosomal amplification resulting in aberrantly up-regulated GPI anchor attachment 1 (GPAA1) expression is correlated with poor prognosis in gastric cancer As previously mentioned, GPAA1 expression is extensively upregulated in liver cancer, breast cancer, head and neck cancer, and colorectal cancer
Copy number analysis of samples from The Cancer Genome Atlas (TCGA) using the cBioPortal database indicated that GPAA1 expression was extensively upregulated in various types of malignancies, such as lung, pancreas, uterine, liver and prostate cancers (Fig. 1a), and was upregulated in a considerable proportion of gastric cancers, oesophageal cancers and breast cancers (Fig. 1b)

Summary

Introduction

Gastric cancer is one of the deadliest malignant tumours, with a high incidence in China, and is regulated by aberrantly overexpressed oncogenes. Surgery, chemotherapy and targeted therapy, including Erb-B2 receptor tyrosine kinase 2 (ERBB2) and vascular endothelial growth factor receptor (VEGFR) inhibitors, are the effective gastric cancer therapies, but the long-term survival rate remains unsatisfactory [3]. Cancer is a lethal disease caused by the genetic alterations, including the upregulation of oncogenes and the downregulation of tumour suppressors [4]. Prostate stem cell antigen (PSCA), another type of GPI-AP, has been indicated to play an important role in tumorigenesis, proliferation and cell cycle progression via the upregulation of c-Myc expression [7]. Alkaline phosphatase (ALP), glypican-3 (GPC3), and carcinoembryonic antigen (CEA) have been identified as biomarkers of cancers [8,9,10]

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