{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T23:22:43Z","timestamp":1792624963175,"version":"4.5.0"},"reference-count":37,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2023,6,2]],"date-time":"2023-06-02T00:00:00Z","timestamp":1685664000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100007225","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007225","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Carcinogenesis"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Incessant ovulation is believed to be a potential cause of epithelial ovarian cancer (EOC). Our previous investigations have shown that insulin\u2010like growth factor\u00a0(IGF2) and hepatocyte growth factor\u00a0(HGF) in the ovulatory follicular fluid (FF) contributed to the malignant transformation initiated by p53 mutations. Here we examined the individual and synergistic impacts of IGF2 and HGF on enhancing the malignant properties of high\u2010grade serous carcinoma (HGSC), the most aggressive type of EOC, and its precursor lesion, serous tubal intraepithelial carcinoma (STIC). In a mouse xenograft co\u2010injection model, we observed that FF co\u2010injection induced tumorigenesis of STIC\u2010mimicking cells, FE25. Co\u2010injection with IGF2 or HGF partially recapitulated the tumorigenic effects of FF, but co\u2010injection with both resulted in a higher tumorigenic rate than FF. We analyzed the different transformation phenotypes influenced by these FF growth signals through receptor inhibition. The IGF signal was necessary for clonogenicity, while the HGF signal played a crucial role in the migration and invasion of STIC and HGSC cells. Both signals were necessary for the malignant phenotype of anchoring\u2010independent growth but had little impact on cell proliferation. The downstream signals responsible for these HGF activities were identified as the tyrosine\u2010protein kinase Met (cMET)\/mitogen\u2010activated protein kinase and cMET\/AKT pathways. Together with the previous finding that the FF\u2010IGF2 could mediate clonogenicity and stemness activities via the IGF\u20101R\/AKT\/mammalian target of rapamycin and IGF\u20101R\/AKT\/NANOG pathways, respectively, this study demonstrated the cooperation of the FF\u2010sourced IGF and HGF growth signals in the malignant transformation and progression of HGSC through both common and distinct signaling pathways. These findings help develop targeted prevention of HGSC.<\/jats:p>","DOI":"10.1002\/mc.23586","type":"journal-article","created":{"date-parts":[[2023,6,2]],"date-time":"2023-06-02T15:20:53Z","timestamp":1685719253000},"page":"1417-1427","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Insulin\u2010like growth factor (IGF) and hepatocyte growth factor (HGF) in follicular fluid cooperatively promote the oncogenesis of high\u2010grade serous carcinoma from fallopian tube epithelial cells: Dissection of the molecular effects"],"prefix":"10.1002","volume":"62","author":[{"given":"Tang\u2010Yuan","family":"Chu","sequence":"first","affiliation":[{"name":"Center for Prevention and Therapy of Gynecological Cancers, Department of Research, Buddhist Tzu Chi General Hospital, Hualien Tzu Chi Hospital Buddhist Tzu Chi Medical Foundation Hualien Taiwan, ROC"},{"name":"Department of Obstetrics &amp; Gynecology, Buddhist Tzu Chi General Hospital, Hualien Tzu Chi Hospital Buddhist Tzu Chi Medical Foundation Hualien Taiwan, ROC"},{"name":"Institute of Medical Science Tzu Chi University  Hualien Taiwan, ROC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aye Aye","family":"Khine","sequence":"additional","affiliation":[{"name":"Center for Prevention and Therapy of Gynecological Cancers, Department of Research, Buddhist Tzu Chi General Hospital, Hualien Tzu Chi Hospital Buddhist Tzu Chi Medical Foundation Hualien Taiwan, ROC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na\u2010Yi Yuan","family":"Wu","sequence":"additional","affiliation":[{"name":"Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine Central South University Changsha People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pao\u2010Chu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics &amp; Gynecology, Buddhist Tzu Chi General Hospital, Hualien Tzu Chi Hospital Buddhist Tzu Chi Medical Foundation Hualien Taiwan, ROC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung\u2010Chao","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Buddhist Tzu Chi General Hospital, Hualien Tzu Chi Hospital Buddhist Tzu Chi Medical Foundation Hualien Taiwan, ROC"},{"name":"School of Medicine, College of Medicine Tzu Chi University Hualien Taiwan, ROC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming\u2010Hsun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pathology, Buddhist Tzu Chi General Hospital, Hualien Tzu Chi Hospital Buddhist Tzu Chi Medical Foundation  Hualien Taiwan, ROC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsuan\u2010Shun","family":"Huang","sequence":"additional","affiliation":[{"name":"Center for Prevention and Therapy of Gynecological Cancers, 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