SHP2 as a Potential Therapeutic Target in Diffuse-Type Gastric Carcinoma Addicted to Receptor Tyrosine Kinase 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...
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| Veröffentlicht in: | Cancers 2021-08, Vol.13 (17), p.4309 |
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| creator | Nagamura, Yuko Miyazaki, Makoto Nagano, Yoshiko Tomiyama, Arata Ohki, Rieko Yanagihara, Kazuyoshi Sakai, Ryuichi Yamaguchi, Hideki |
| description | 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. |
| doi_str_mv | 10.3390/cancers13174309 |
| format | Article |
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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.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers13174309</identifier><identifier>PMID: 34503119</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>Antibodies ; c-Met protein ; Cell adhesion & migration ; Cell growth ; Fibroblast growth factor receptor 2 ; Fibroblast growth factor receptors ; Fibrosis ; Gastric cancer ; Gene amplification ; Kinases ; Lung cancer ; Medical prognosis ; MET protein ; Mutation ; Peritoneum ; Phenotypes ; Phosphatase ; Phosphorylation ; Protein-tyrosine kinase receptors ; Protein-tyrosine-phosphatase ; Proteins ; Statistical analysis ; Stroma ; Therapeutic applications ; Therapeutic targets ; Tumor cell lines ; Xenografts</subject><ispartof>Cancers, 2021-08, Vol.13 (17), p.4309</ispartof><rights>2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 by the authors. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c464t-49520d61a5aabbf20f54ce4356c07208258009c2a8c1cf7b110ae35c13bce9ff3</citedby><cites>FETCH-LOGICAL-c464t-49520d61a5aabbf20f54ce4356c07208258009c2a8c1cf7b110ae35c13bce9ff3</cites><orcidid>0000-0002-7100-8400 ; 0000-0003-2944-6535 ; 0000-0003-2125-9655 ; 0000-0002-7775-6653</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430696/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430696/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids></links><search><creatorcontrib>Nagamura, Yuko</creatorcontrib><creatorcontrib>Miyazaki, Makoto</creatorcontrib><creatorcontrib>Nagano, Yoshiko</creatorcontrib><creatorcontrib>Tomiyama, Arata</creatorcontrib><creatorcontrib>Ohki, Rieko</creatorcontrib><creatorcontrib>Yanagihara, Kazuyoshi</creatorcontrib><creatorcontrib>Sakai, Ryuichi</creatorcontrib><creatorcontrib>Yamaguchi, Hideki</creatorcontrib><title>SHP2 as a Potential Therapeutic Target in Diffuse-Type Gastric Carcinoma Addicted to Receptor Tyrosine Kinase Signaling</title><title>Cancers</title><description>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.</description><subject>Antibodies</subject><subject>c-Met protein</subject><subject>Cell adhesion & migration</subject><subject>Cell growth</subject><subject>Fibroblast growth factor receptor 2</subject><subject>Fibroblast growth factor receptors</subject><subject>Fibrosis</subject><subject>Gastric cancer</subject><subject>Gene amplification</subject><subject>Kinases</subject><subject>Lung cancer</subject><subject>Medical prognosis</subject><subject>MET protein</subject><subject>Mutation</subject><subject>Peritoneum</subject><subject>Phenotypes</subject><subject>Phosphatase</subject><subject>Phosphorylation</subject><subject>Protein-tyrosine kinase receptors</subject><subject>Protein-tyrosine-phosphatase</subject><subject>Proteins</subject><subject>Statistical analysis</subject><subject>Stroma</subject><subject>Therapeutic applications</subject><subject>Therapeutic targets</subject><subject>Tumor cell lines</subject><subject>Xenografts</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkc1v1DAQxS1ERau2Z66WuHAJ9UfixBekaiktolIrGs7WxJlsXWXtYDug_e8xbYWgc5mR3k9P82YIecvZByk1O7PgLcbEJW9ryfQrciRYKyqldP36n_mQnKb0wErJQqr2DTmUdcMk5_qI_Lq7uhUUEgV6GzL67GCm_T1GWHDNztIe4hYzdZ5-ctO0Jqz6_YL0ElKORd5AtM6HHdDzcXQ240hzoN_Q4pJDpP0-huQ80q_OQ0J657YeZue3J-Rggjnh6XM_Jt8_X_Sbq-r65vLL5vy6srWqc1XrRrBRcWgAhmESbGpqi7VslC3xWCeajjFtBXSW26kdOGeAsrFcDhb1NMlj8vHJd1mHHY62JIwwmyW6HcS9CeDM_4p392YbfpqunFRpVQzePxvE8GPFlM3OJYvzDB7DmoxoWq4FrztZ0Hcv0IewxpL3kWJKMKlEoc6eKFtOkyJOf5fhzPz5q3nxV_kbf8KWiw</recordid><startdate>20210826</startdate><enddate>20210826</enddate><creator>Nagamura, Yuko</creator><creator>Miyazaki, Makoto</creator><creator>Nagano, Yoshiko</creator><creator>Tomiyama, Arata</creator><creator>Ohki, Rieko</creator><creator>Yanagihara, Kazuyoshi</creator><creator>Sakai, Ryuichi</creator><creator>Yamaguchi, Hideki</creator><general>MDPI AG</general><general>MDPI</general><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7TO</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-7100-8400</orcidid><orcidid>https://orcid.org/0000-0003-2944-6535</orcidid><orcidid>https://orcid.org/0000-0003-2125-9655</orcidid><orcidid>https://orcid.org/0000-0002-7775-6653</orcidid></search><sort><creationdate>20210826</creationdate><title>SHP2 as a Potential Therapeutic Target in Diffuse-Type Gastric Carcinoma Addicted to Receptor Tyrosine Kinase Signaling</title><author>Nagamura, Yuko ; 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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.</abstract><cop>Basel</cop><pub>MDPI AG</pub><pmid>34503119</pmid><doi>10.3390/cancers13174309</doi><orcidid>https://orcid.org/0000-0002-7100-8400</orcidid><orcidid>https://orcid.org/0000-0003-2944-6535</orcidid><orcidid>https://orcid.org/0000-0003-2125-9655</orcidid><orcidid>https://orcid.org/0000-0002-7775-6653</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Antibodies c-Met protein Cell adhesion & migration Cell growth Fibroblast growth factor receptor 2 Fibroblast growth factor receptors Fibrosis Gastric cancer Gene amplification Kinases Lung cancer Medical prognosis MET protein Mutation Peritoneum Phenotypes Phosphatase Phosphorylation Protein-tyrosine kinase receptors Protein-tyrosine-phosphatase Proteins Statistical analysis Stroma Therapeutic applications Therapeutic targets Tumor cell lines Xenografts |
| title | SHP2 as a Potential Therapeutic Target in Diffuse-Type Gastric Carcinoma Addicted to Receptor Tyrosine Kinase Signaling |
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