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Article

SHP2 as a Potential Therapeutic Target in Diffuse-Type Gastric Carcinoma Addicted to Receptor Tyrosine Kinase Signaling

1
Department of Cancer Cell Research, Sasaki Institute, Sasaki Foundation, Tokyo 101-0062, Japan
2
Department of Neurosurgery, National Defense Medical College, Saitama 359-8513, Japan
3
Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Tokyo 104-0045, Japan
4
Division of Biomarker Discovery, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba 277-8577, Japan
5
Department of Biochemistry, Kitasato University School of Medicine, Sagamihara 252-0374, Japan
*
Author to whom correspondence should be addressed.
Academic Editor: Levi J. Beverly
Cancers 2021, 13(17), 4309; https://doi.org/10.3390/cancers13174309
Received: 2 August 2021 / Revised: 23 August 2021 / Accepted: 23 August 2021 / Published: 26 August 2021
Diffuse-type gastric carcinoma (DGC) is characterized by rapid infiltrative growth associated with massive stroma and frequent peritoneal dissemination, which leads to poor patient outcomes. In this study, we found that the oncogenic tyrosine phosphatase SHP2 is tyrosine-phosphorylated downstream of the amplified receptor tyrosine kinases (RTKs) Met and fibroblast growth factor receptor 2 (FGFR2) in DGC cell lines. SHP2 knockdown or pharmacological inhibition selectively suppressed the growth of DGC addicted to amplified Met and FGFR2. Moreover, targeting SHP2 abrogated malignant phenotypes, including peritoneal dissemination, of Met-addicted DGC and could overcome acquired resistance to Met inhibitors. Our findings suggest that SHP2 is a potential target for the treatment of DGC addicted to amplified RTK signaling.
Diffuse-type gastric carcinoma (DGC) exhibits aggressive progression associated with rapid infiltrative growth, massive fibrosis, and peritoneal dissemination. Gene amplification of Met and fibroblast growth factor receptor 2 (FGFR2) receptor tyrosine kinases (RTKs) has been observed in DGC. However, the signaling pathways that promote DGC progression downstream of these RTKs remain to be fully elucidated. We previously identified an oncogenic tyrosine phosphatase, SHP2, using phospho-proteomic analysis of DGC cells with Met gene amplification. In this study, we characterized SHP2 in the progression of DGC and assessed the therapeutic potential of targeting SHP2. Although SHP2 was expressed in all gastric carcinoma cell lines examined, its tyrosine phosphorylation preferentially occurred in several DGC cell lines with Met or FGFR2 gene amplification. Met or FGFR inhibitor treatment or knockdown markedly reduced SHP2 tyrosine phosphorylation. Knockdown or pharmacological inhibition of SHP2 selectively suppressed the growth of DGC cells addicted to Met or FGFR2, even when they acquired resistance to Met inhibitors. Moreover, SHP2 knockdown or pharmacological inhibition blocked the migration and invasion of Met-addicted DGC cells in vitro and their peritoneal dissemination in a mouse xenograft model. These results indicate that SHP2 is a critical regulator of the malignant progression of RTK-addicted DGC and may be a therapeutic target. View Full-Text
Keywords: diffuse-type gastric carcinoma; peritoneal dissemination; SHP2; receptor tyrosine kinase; Met diffuse-type gastric carcinoma; peritoneal dissemination; SHP2; receptor tyrosine kinase; Met
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MDPI and ACS Style

Nagamura, Y.; Miyazaki, M.; Nagano, Y.; Tomiyama, A.; Ohki, R.; Yanagihara, K.; Sakai, R.; Yamaguchi, H. SHP2 as a Potential Therapeutic Target in Diffuse-Type Gastric Carcinoma Addicted to Receptor Tyrosine Kinase Signaling. Cancers 2021, 13, 4309. https://doi.org/10.3390/cancers13174309

AMA Style

Nagamura Y, Miyazaki M, Nagano Y, Tomiyama A, Ohki R, Yanagihara K, Sakai R, Yamaguchi H. SHP2 as a Potential Therapeutic Target in Diffuse-Type Gastric Carcinoma Addicted to Receptor Tyrosine Kinase Signaling. Cancers. 2021; 13(17):4309. https://doi.org/10.3390/cancers13174309

Chicago/Turabian Style

Nagamura, Yuko, Makoto Miyazaki, Yoshiko Nagano, Arata Tomiyama, Rieko Ohki, Kazuyoshi Yanagihara, Ryuichi Sakai, and Hideki Yamaguchi. 2021. "SHP2 as a Potential Therapeutic Target in Diffuse-Type Gastric Carcinoma Addicted to Receptor Tyrosine Kinase Signaling" Cancers 13, no. 17: 4309. https://doi.org/10.3390/cancers13174309

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