Capillary morphogenesis gene 2 maintains gastric cancer stem-like cell phenotype by activating a Wnt/\u03b2-catenin pathway

Chengdong Ji,Youhong Cui,Lang Yang,Weijing Yi,Zhihua Zhou,Xia Zhang,Dongfang Xiang,Ji Ming Wang,Yanxia Wang,Yong Ren,Peng Zhang,Xiuwu Bian,Wei Cui,Feng Qian

doi:10.1038/s41388-018-0226-z

Abstract

A growing body of evidence shows that the development and progression of gastric cancer (GC) is mainly associated to the presence of gastric cancer stem-like cells (GCSLCs). However, it is unclear how GCSLC population is maintained. This study aimed to explore the role of capillary morphogenesis gene 2 (CMG2) in GCSLC maintenance and the relevance to GC progression. We found that CMG2 was highly expressed in GC tissues and the expression levels were associated with the invasion depth and lymph node metastasis of GC, and inversely correlated with the survival of GC patients. Sorted CMG2High GC cells preferentially clustered in CD44High stem-like cell population, which expressed high levels of stemness-related genes with increased capabilities of self-renewal and tumorigenicity. Depletion of CMG2 gene resulted in reduction of GCSLC population with attenuated stemness and decrease of invasive and metastatic capabilities with subdued epithelial–mesenchymal transition phenotype in GC cells. Mechanistically, CMG2 interacted with LRP6 in GCSLCs to activate a Wnt/β-catenin pathway. Thus, our results demonstrate that CMG2 promotes GC progression by maintaining GCSLCs and can serve as a new prognostic indicator and a target for human GC therapy.

Highlights

Gastric cancer (GC) is the third leading cause of cancerrelated death worldwide [1, 2]
Chip analysis of GC tumor-sphere cells, which possessed the characteristics of gastric cancer stem-like cells (GCSLCs) [20], capillary morphogenesis gene 2 (CMG2) was found to be markedly overexpressed in GC tumor-sphere-forming cells, suggesting that CMG2 may play an important role in GCSLC maintenance
CMG2 is highly expressed in GC tissues and the expression is correlated with the outcome of patients

Summary

Introduction

Gastric cancer (GC) is the third leading cause of cancerrelated death worldwide [1, 2]. Recent studies suggested that gastric cancer stem-like cells (GCSLCs) are responsible for the invasion and metastasis [5,6,7], and targeting GCSLCs has become a promising therapeutic strategy for GC. F Kaplan–Meier estimation indicating shorter overall survival time of patients with CMG2+ GC by multiple, recurring subcutaneous tumors, gingival hypertrophy, joint contractures, osteolysis, and osteoporosis [13]. CMG2 plays contradictory roles in cells of prostate cancer [17], breast cancer [18], and glioma [19]. Chip analysis of GC tumor-sphere cells, which possessed the characteristics of GCSLCs [20], CMG2 was found to be markedly overexpressed in GC tumor-sphere-forming cells, suggesting that CMG2 may play an important role in GCSLC maintenance

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Conclusion