J Cancer 2018; 9(2):358-366. doi:10.7150/jca.20266

Research Paper

Clinical Significance of Glycoprotein Non-metastatic B and Its Association with EGFR/HER2 in Gastrointestinal Cancer

Jesse Yu Tajima1, Manabu Futamura1✉, Siqin Gaowa1, Ryutaro Mori1, Toshiyuki Tanahashi1, Yoshihiro Tanaka1, Nobuhisa Matsuhashi1, Takao Takahashi1, Kazuya Yamaguchi1, Tatsuhiko Miyazaki2, Kazuhiro Yoshida1

1. Department of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu, Japan;
2. Division of Pathology, Gifu University Hospital, Gifu, Japan.

Abstract

Glycoprotein non-metastatic B (GPNMB), a type I transmembrane glycoprotein, is overexpressed in melanoma and breast cancer and promotes cancer-cell invasion and motility. We previously reported cross-talk between GPNMB and human epidermal growth factor receptor 2 (HER2) in breast cancer, suggesting that GPNMB might play an important role in resistance to anti-HER2 therapy in breast cancer. Here, we clarified the association between GPNMB and HER-family proteins in gastrointestinal cancer by examining their relationships using gastric and colorectal cancer cell lines. We found that GPNMB depletion of by small-interfering RNA increased epidermal growth factor receptor (EGFR) expression and phosphorylation through AKT8 virus oncogene cellular homolog (AKT) and mitogen-activated protein kinase (MAPK) pathways. Additionally, treatment with cetuximab (CTX) also increased GPNMB expression, and combination therapy consisting of GPNMB depletion and CTX treatment significantly suppressed cell growth in colorectal cancer cell lines, but not in gastric cancer cell lines. Furthermore, we also evaluated changes in GPNMB expression in vivo, with immunohistochemistry detecting GPNMB overexpression in a colorectal cancer patient following anti-EGFR therapy. These results suggested possible cross-talk between GPNMB and EGFR, and that GPNMB might play an important role in resistance to anti-EGFR therapy in gastrointestinal cancer.

Keywords: GPNMB, gastrointestinal cancer, cross-talk, molecular-targeted therapy, drug resistance

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How to cite this article:
Tajima JY, Futamura M, Gaowa S, Mori R, Tanahashi T, Tanaka Y, Matsuhashi N, Takahashi T, Yamaguchi K, Miyazaki T, Yoshida K. Clinical Significance of Glycoprotein Non-metastatic B and Its Association with EGFR/HER2 in Gastrointestinal Cancer. J Cancer 2018; 9(2):358-366. doi:10.7150/jca.20266. Available from http://www.jcancer.org/v09p0358.htm