{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T11:16:49Z","timestamp":1788779809735,"version":"build-2803163510"},"reference-count":42,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2018,12,14]],"date-time":"2018-12-14T00:00:00Z","timestamp":1544745600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2019,1]]},"abstract":"Malignant pleural mesothelioma (MPM<\/jats:styled-content>), a highly refractory tumor, is currently incurable due to the lack of an early diagnosis method and medication, both of which are urgently needed to improve the survival and\/or quality of life of patients. NF<\/jats:styled-content>2<\/jats:italic> is a tumor suppressor gene and is frequently mutated in MPM<\/jats:styled-content>. Using a CRISPR<\/jats:styled-content>\/Cas9 system, we generated an NF<\/jats:styled-content>2\u2010<\/jats:italic>knockout human mesothelial cell line, MeT\u20105A (NF<\/jats:styled-content>2\u2010KO<\/jats:styled-content>). In NF<\/jats:styled-content>2\u2010KO<\/jats:styled-content> cell clones, cell growth, clonogenic activity, migration activity, and invasion activity significantly increased compared with those in NF<\/jats:styled-content>2\u2010WT<\/jats:styled-content> cell clones. Complementary DNA<\/jats:styled-content> microarray analysis clearly revealed the differences in global gene expression profile between NF<\/jats:styled-content>2\u2010WT<\/jats:styled-content> and NF<\/jats:styled-content>2\u2010KO<\/jats:styled-content> cell clones. Quantitative PCR<\/jats:styled-content> analysis and western blot analysis showed that the upregulation of fibroblast growth factor receptor 2 (FGFR<\/jats:styled-content>2) was concomitant with the increases in phosphorylation levels of JNK<\/jats:styled-content>, c\u2010Jun, and retinoblastoma (Rb) in NF<\/jats:styled-content>2\u2010KO<\/jats:styled-content> cell clones. These increases were all abrogated by the exogenous expression of NF<\/jats:styled-content>2 in the NF<\/jats:styled-content>2\u2010KO<\/jats:styled-content> clone. In addition, the disruption of FGFR<\/jats:styled-content>2<\/jats:italic> in the NF<\/jats:styled-content>2\u2010KO<\/jats:styled-content> cell clone suppressed cell proliferation as well as the phosphorylation levels of JNK<\/jats:styled-content>, c\u2010Jun, and Rb. Notably, FGFR<\/jats:styled-content>2 was found to be highly expressed in NF<\/jats:styled-content>2\u2010negative human mesothelioma tissues (11\/12 cases, 91.7%) but less expressed in NF<\/jats:styled-content>2\u2010positive tissues. Collectively, these findings suggest that NF<\/jats:styled-content>2<\/jats:italic> deficiency might play a role in the tumorigenesis of human mesothelium through mediating FGFR<\/jats:styled-content>2 expression; FGFR<\/jats:styled-content>2 would be a candidate molecule to develop therapeutic and diagnostic strategies for targeting MPM<\/jats:styled-content> with NF<\/jats:styled-content>2<\/jats:italic> loss.<\/jats:p>","DOI":"10.1111\/cas.13871","type":"journal-article","created":{"date-parts":[[2018,11,12]],"date-time":"2018-11-12T08:10:09Z","timestamp":1542010209000},"page":"180-193","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Establishment and characterization of CRISPR<\/scp>\/Cas9\u2010mediated NF<\/scp>2<\/i>\u2212\/\u2212<\/i><\/sup> human mesothelial cell line: Molecular insight into fibroblast growth factor receptor 2 in malignant pleural mesothelioma"],"prefix":"10.1111","volume":"110","author":[{"given":"Md","family":"Wahiduzzaman","sequence":"first","affiliation":[{"name":"Department of Biochemistry Aichi Medical University School of Medicine Nagakute Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2165-7565","authenticated-orcid":false,"given":"Sivasundaram","family":"Karnan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Aichi Medical University School of Medicine Nagakute Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6296-2921","authenticated-orcid":false,"given":"Akinobu","family":"Ota","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Aichi Medical University School of Medicine Nagakute Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ichiro","family":"Hanamura","sequence":"additional","affiliation":[{"name":"Division of 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