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

Oncogene volume 39, pages 2961–2974 (2020)Cite this article

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Abstract

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.

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Fig. 1: H. pylori infection activated human stomach fibroblasts and caused multiple gene alterations.
Fig. 2: H. pylori infection upregulated VCAM1 expression in human stomach fibroblasts via activation of JAK/STAT1 signaling pathway.
Fig. 3: VCAM1 was highly expressed in CAFs in gastric cancer tissues, and VCAM1 levels were associated with gastric cancer progression.
Fig. 4: VCAM1 in CAFs facilitated gastric tumor invasion.
Fig. 5: CAF-derived VCAM1 promoted gastric cancer cell invasion via interaction with integrin αvβ1/5 in gastric cancer cells.

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Acknowledgements

The authors would like to thank Dr Guiping Xie and Dr Yaohui Wang (Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine,) for their helps with sample collection and pathological assistance; Dr Jiaqi Wu (Institute of Translational Medicine, College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University) for stomach primary fibroblasts preparation and zCDX study.

Funding

This work was supported by the National Natural Science Foundation of China (Grant Nos. 81272711 and 81871959 to LS), the Priority Academic Program Development of Jiangsu Higher Education Institutions (JX10231801 to LS), the Key Medical Talents Program of Jiangsu Province (ZDRCA2016014 to LS), the Key R&D Program of Jiangsu Province (Social Development, BE2018758 to LS), the Programs of Jiangsu Province Hospital of Chinese Medicine (Y2018RC14 to LS and Y2018CX71 to JZ), and the Jiangsu Graduate Research Innovation Program (KYCX18_1479 to JS).

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  1. These authors contributed equally: Jiajia Shen, Jing Zhai

Authors and Affiliations

  1. Division of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, China

    Jiajia Shen & Lizong Shen

  2. Department of Surgical Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China

    Jing Zhai & Xuequan Yao

  3. Department of Geriatrics, Second Affiliated Hospital, Nanjing Medical University, Nanjing, 210003, China

    Qiang You

  4. Department of Gastroenterology, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, China

    Guoxin Zhang

  5. Institute of Translational Medicine, College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, 211800, China

    Mingfang He

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Shen, J., Zhai, J., You, Q. et al. Cancer-associated fibroblasts-derived VCAM1 induced by H. pylori infection facilitates tumor invasion in gastric cancer. Oncogene 39, 2961–2974 (2020). https://doi.org/10.1038/s41388-020-1197-4

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