Noggin is associated with a poor prognosis of gastric cancer by promoting the proliferation of gastric cancer cells via the upregulation of EGFR

Sun,Zhiwei; Gao,Xiangyu; Zabkiewicz,Catherine; Ruge,Fiona; Xie,Meng; Cai,Shuo; Sun,Ping‑Hui; Griffiths,Paul; Pugh,Matthew  R.; Ji,Jiafu; Jiang,Wen  G.; Ye,Lin

doi:10.3892/ijo.2020.5081

Noggin is associated with a poor prognosis of gastric cancer by promoting the proliferation of gastric cancer cells via the upregulation of EGFR

Authors:
- Zhiwei Sun
- Xiangyu Gao
- Catherine Zabkiewicz
- Fiona Ruge
- Meng Xie
- Shuo Cai
- Ping‑Hui Sun
- Paul Griffiths
- Matthew R. Pugh
- Jiafu Ji
- Wen G. Jiang
- Lin Ye
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Affiliations: Cardiff China Medical Research Collaborative, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff CF14 4XN, UK, Department of Histopathology, Morriston Hospital, Heol Maes Eglwys, Swansea SA6 6NL, UK, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Gastrointestinal Tumour Center, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
Published online on: June 16, 2020 https://doi.org/10.3892/ijo.2020.5081
Pages: 813-824

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Abstract

Noggin is an antagonist of bone morphogenetic proteins (BMP), being indispensable for certain developmental events. The present study aimed to examine the role of Noggin in the development and prognosis of gastric cancer (GC) and to elucidate the underlying mechanisms. The expression of Noggin in GC was evaluated by RT‑qPCR, immunohistochemistry and by the analyses of publicly available databases. The effects of Noggin on proliferation, cell cycle, adhesion, invasion, colony formation and tumour spheroid were examined following both the knockdown and overexpression of Noggin in GC cell lines. The involvement of epidermal growth factor receptor (EGFR) signalling was examined by western blot analysis and by using small molecule inhibitors. As a result, a higher expression of Noggin in GC was found to be associated with a poorer overall survival. Noggin overexpression promoted the proliferation and colony formation of GC cells by promoting cell cycle progression. The knockdown of Noggin in HGC27 cells exerted an opposite effect on proliferation, colony formation and cell cycle progression. Noggin expression positively correlated with EGFR expression in both GC cell line models and The Cancer Genome Atlas human GC cohort. Targeting EGFR and its downstream pathways diminished cell proliferation which was promoted by Noggin. Furthermore, Noggin overexpression resulted in an enhanced nuclear translocation of β‑catenin, leading to an upregulation of EGFR. Thus, the findings of the present study demonstrate that Noggin promotes the proliferation of GC cells by upregulating EGFR and enhancing a vicious circle formed by β‑catenin, EGFR, ERK and Akt.

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