Wenfeng Hua1, Yuan Zhao2, Xiaohan Jin3, Danyang Yu2, Jing He4, Dan Xie5, Ping Duan6. 1. Department of Laboratory Medicine and Central Laboratories, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China. Electronic address: huawf@gd2h.org.cn. 2. Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China. 3. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China. 4. Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China. 5. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China. Electronic address: xiedan@sysucc.org.cn. 6. Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: dppddpp@126.com.
Abstract
OBJECTIVE: As the most prevalent internal modification in mammalian messenger RNA, N6‑methyladenosine (m6A) plays an important role in posttranscriptional gene regulation. METTL3 is a key component of the m6A methyltransferase complex and has recently been shown to play important roles in cancer development and progression. The current study was aimed to explore the function and underlying mechanism of METTL3 in ovarian cancer. METHODS: METTL3 expression was assessed by immunohistochemistry in 162 ovarian carcinoma patients. Stable cell lines with METTL3 gene overexpression or knockdown were established to investigate the function of METTL3 in ovarian cancer in vitro and in vivo. RESULTS: METTL3 was frequently upregulated in ovarian carcinoma and that a high level of METTL3 was significantly associated with tumor grade (P = 0.001), pT status (P = 0.002), pN/pM status (P < 0.001), FIGO stage (P < 0.001), and overall survival rate (P < 0.001). Stable overexpression of METTL3 in the OVCAR3 and COV504 cell lines significantly increased cellular proliferation, focus formation, motility, invasion, and tumor formation in nude mice. Silencing METTL3 expression in the SKOV3 and HO-8910 cell lines with short hairpin RNA effectively inhibited its oncogenic function. Further study found that METTL3 promoted epithelial-mesenchymal transition (EMT) by upregulating the receptor tyrosine kinase AXL. CONCLUSION: Our findings suggest that METTL3 plays very important oncogenic roles in ovarian carcinoma development and/or aggressiveness by stimulating AXL translation and EMT and that METTL3 may serve as a novel prognostic and/or therapeutic target of interest in ovarian cancer.
OBJECTIVE: As the most prevalent internal modification in mammalian messenger RNA, N6‑methyladenosine (m6A) plays an important role in posttranscriptional gene regulation. METTL3 is a key component of the m6A methyltransferase complex and has recently been shown to play important roles in cancer development and progression. The current study was aimed to explore the function and underlying mechanism of METTL3 in ovarian cancer. METHODS:METTL3 expression was assessed by immunohistochemistry in 162 ovarian carcinomapatients. Stable cell lines with METTL3 gene overexpression or knockdown were established to investigate the function of METTL3 in ovarian cancer in vitro and in vivo. RESULTS:METTL3 was frequently upregulated in ovarian carcinoma and that a high level of METTL3 was significantly associated with tumor grade (P = 0.001), pT status (P = 0.002), pN/pM status (P < 0.001), FIGO stage (P < 0.001), and overall survival rate (P < 0.001). Stable overexpression of METTL3 in the OVCAR3 and COV504 cell lines significantly increased cellular proliferation, focus formation, motility, invasion, and tumor formation in nude mice. Silencing METTL3 expression in the SKOV3 and HO-8910 cell lines with short hairpin RNA effectively inhibited its oncogenic function. Further study found that METTL3 promoted epithelial-mesenchymal transition (EMT) by upregulating the receptor tyrosine kinase AXL. CONCLUSION: Our findings suggest that METTL3 plays very important oncogenic roles in ovarian carcinoma development and/or aggressiveness by stimulating AXL translation and EMT and that METTL3 may serve as a novel prognostic and/or therapeutic target of interest in ovarian cancer.