Yu Liu1, Mingxu Da2,3. 1. The First Clinical Medical College, Lanzhou University, 222 Tianshui South Road, Lanzhou, 730000, China. 2. The First Clinical Medical College, Lanzhou University, 222 Tianshui South Road, Lanzhou, 730000, China. hxdamingxu@hotmail.com. 3. Department of Surgical Oncology, Gansu Provincial Hospital, Lanzhou, 730000, China. hxdamingxu@hotmail.com.
Abstract
PURPOSE: Wilms tumor 1 associated protein (WTAP) is a key RNA n6-methyladenosine (m6A) methylase, which predicts the occurrence of many diseases, such as liver fibrosis formation, coordinating cancer stem cell function, and promoting tumor development. Gastric cancer (GC) is one of the most common malignant tumors worldwide. However, the role of WTAP in GC development and drug resistance remains unclear. METHODS: Biological methods and data analysis were used to investigate the expression of WTAP in gastric carcinoma tissue. The expression of transforming growth factor-beta (TGF-β) and epithelial mesenchymal transition (EMT) in GC cells were detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB) with WTAP overexpression cell lines and WTAP knockout cell lines. Gradient concentrations of cisplatin (DDP), gradient cyclophosphamide (CTX), or radiation X-rays were added to WTAP overexpression cell lines and WTAP knockdown cell lines to observe the change of cell viability after radiotherapy and chemotherapy treatment. RESULTS: The expression of WTAP in gastric carcinoma tissue significantly increased as determined by bioinformatics analysis, and a high expression of WTAP was closely associated with poor prognosis of gastric cancer patients. Overexpression of WTAP promoted migration and EMT of GC cells and promoted the expression of TGF-β and the stability of mRNA. WTAP knockdown inhibited migration of GC cells and decreased TGF-β expression and stability of mRNA. In addition, WTAP promoted multiple chemotherapy resistance and radiotherapy resistance in GC. CONCLUSIONS: WTAP is a potential predictive biomarker for GC. Our findings revealed a novel mechanism by which WTAP regulates chemoradiotherapy resistance, extending the understanding of the m6A machinery in TGF-β induced EMT and metastasis in GC.
PURPOSE: Wilms tumor 1 associated protein (WTAP) is a key RNA n6-methyladenosine (m6A) methylase, which predicts the occurrence of many diseases, such as liver fibrosis formation, coordinating cancer stem cell function, and promoting tumor development. Gastric cancer (GC) is one of the most common malignant tumors worldwide. However, the role of WTAP in GC development and drug resistance remains unclear. METHODS: Biological methods and data analysis were used to investigate the expression of WTAP in gastric carcinoma tissue. The expression of transforming growth factor-beta (TGF-β) and epithelial mesenchymal transition (EMT) in GC cells were detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB) with WTAP overexpression cell lines and WTAP knockout cell lines. Gradient concentrations of cisplatin (DDP), gradient cyclophosphamide (CTX), or radiation X-rays were added to WTAP overexpression cell lines and WTAP knockdown cell lines to observe the change of cell viability after radiotherapy and chemotherapy treatment. RESULTS: The expression of WTAP in gastric carcinoma tissue significantly increased as determined by bioinformatics analysis, and a high expression of WTAP was closely associated with poor prognosis of gastric cancer patients. Overexpression of WTAP promoted migration and EMT of GC cells and promoted the expression of TGF-β and the stability of mRNA. WTAP knockdown inhibited migration of GC cells and decreased TGF-β expression and stability of mRNA. In addition, WTAP promoted multiple chemotherapy resistance and radiotherapy resistance in GC. CONCLUSIONS: WTAP is a potential predictive biomarker for GC. Our findings revealed a novel mechanism by which WTAP regulates chemoradiotherapy resistance, extending the understanding of the m6A machinery in TGF-β induced EMT and metastasis in GC.
Authors: Pedro J Batista; Benoit Molinie; Jinkai Wang; Kun Qu; Jiajing Zhang; Lingjie Li; Donna M Bouley; Ernesto Lujan; Bahareh Haddad; Kaveh Daneshvar; Ava C Carter; Ryan A Flynn; Chan Zhou; Kok-Seong Lim; Peter Dedon; Marius Wernig; Alan C Mullen; Yi Xing; Cosmas C Giallourakis; Howard Y Chang Journal: Cell Stem Cell Date: 2014-10-16 Impact factor: 24.633
Authors: H Bansal; Q Yihua; S P Iyer; S Ganapathy; D A Proia; D Proia; L O Penalva; P J Uren; U Suresh; J S Carew; A B Karnad; S Weitman; G E Tomlinson; M K Rao; S M Kornblau; S Bansal Journal: Leukemia Date: 2014-01-13 Impact factor: 11.528