Cancer-associated fibroblasts-derived VCAM1 induced by H. pylori infection facilitates tumor invasion in gastric cancer.

Jiajia Shen, Jing Zhai, Qiang You, Guoxin Zhang, Mingfang He, Xuequan Yao, Lizong Shen

Oncogene 2020 Apr

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Cancer-associated fibroblasts (CAFs) play a major role in the progression of stomach cancer, but the related mechanisms are not fully understood. H. pylori infection is recognized as one of the strongest risk factors for gastric carcinoma, but its effects on CAFs remain unknown. We aimed to determine the causative relationship between H. pylori infection in fibroblasts and the promoted cancer pathogenesis and progression in gastric cancer. Primary CAFs and normal activated fibroblasts (NAFs) were generated from gastric cancer patients. Gene signature of H. pylori-infected human stomach fibroblasts was performed using the RNA-seq analysis. Spheroid cell invasion assay and zebrafish cell line-derived xenograft (zCDX) model were introduced to evaluate tumor invasion induced by CAFs. The molecule interactions were determined using the kinetic binding analysis with the Biolayer Interferometry (BLI). Clinical significance and relevance were also assessed using the database analyses. H. pylori infection activated stomach fibroblasts and caused multiple gene alterations, including vascular adhesion molecule 1 (VCAM1). H. pylori infection increased VCAM1 expression in CAFs in gastric carcinoma via activation of JAK/STAT1 signaling pathway, and VCAM1 levels were positively associated with tumor progression and dismal prognosis in stomach cancer patients. Furthermore, CAFs-derived VCAM1 molecularly interacted with integrin αvβ1/5 in gastric cancer cells facilitated tumor invasion in vitro and in vivo. Our results identify a novel mechanism underlying CAFs to promote tumor invasion during H. pylori infection. These studies facilitate us for a better understanding of the molecular process of gastric carcinoma progression, and provide the potential strategies for gastric cancer therapy.

Citation

Jiajia Shen, Jing Zhai, Qiang You, Guoxin Zhang, Mingfang He, Xuequan Yao, Lizong Shen. Cancer-associated fibroblasts-derived VCAM1 induced by H. pylori infection facilitates tumor invasion in gastric cancer. Oncogene. 2020 Apr;39(14):2961-2974