PMID- 32863943 OWN - NLM STAT- MEDLINE DCOM- 20210601 LR - 20211204 IS - 1838-7640 (Electronic) IS - 1838-7640 (Linking) VI - 10 IP - 21 DP - 2020 TI - m(6)A RNA modification modulates PI3K/Akt/mTOR signal pathway in Gastrointestinal Cancer. PG - 9528-9543 LID - 10.7150/thno.42971 [doi] AB - Rationale: Methylation at the N6 position of adenosine (m(6)A) is the most prevalent RNA modification within protein-coding mRNAs in mammals, and it is a reversible modification with various important biological functions. The formation and function of m(6)A are regulated by methyltransferases (writers), demethylases (erasers), and special binding proteins (readers) as key factors. However, the underlying modification mechanisms of m(6)A in gastrointestinal (GI) cancer remain unclear. Here, we performed comprehensive molecular profiling of the nine known m(6)A writer, eraser, and reader proteins in GI cancer. Methods: Data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were used. Gene alteration and pathway analysis were done in cBioportal. The protein network of m(6)A regulators and its related pathway members was analyzed in STRING online platform. Phylogenetic tree was constructed in MEGA7. m(6)A modification sites were predicted by SRAMP. m(6)A related SNPs were analyzed by m(6)ASNP. The modulation of m(6)A on its related pathway members was validated by m(6)A-seq, real-time PCR and phosphor-MAPK array. Results: We found that m(6)A regulators were mostly upregulated in GI cancer and their differential expression significantly influenced the overall survival of patients with GI cancer. The phosphatidylinositol-3-kinase (PI3K)/Akt and mammalian target of rapamycin (mTOR) signaling pathways were found to be potentially affected by m(6)A modification in most human cancers, including GI cancer, which was further verified by m(6)A-Seq and phospho-MAPK array. Conclusions: Our findings suggest that m(6)A RNA modification has a fundamental role in the regulation of PI3K/Akt and mTOR signaling pathway function in cancer. CI - (c) The author(s). FAU - Zhao, Qijie AU - Zhao Q AD - Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, PR China. AD - South Sichuan Institute of Translational Medicine, Luzhou, 646000, Sichuan, PR China. AD - Department of Pathophysiology, College of Basic Medical Science, Southwest Medical University, Luzhou, 646000, Sichuan, PR China. FAU - Zhao, Yueshui AU - Zhao Y AD - Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, PR China. AD - South Sichuan Institute of Translational Medicine, Luzhou, 646000, Sichuan, PR China. FAU - Hu, Wei AU - Hu W AD - Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, PR China. AD - Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong SAR, PR China. FAU - Zhang, Yan AU - Zhang Y AD - Department of Oncology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210000, PR China. FAU - Wu, Xu AU - Wu X AD - Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, PR China. AD - South Sichuan Institute of Translational Medicine, Luzhou, 646000, Sichuan, PR China. FAU - Lu, Jianwei AU - Lu J AD - Department of Oncology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210000, PR China. FAU - Li, Mingxing AU - Li M AD - Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, PR China. AD - South Sichuan Institute of Translational Medicine, Luzhou, 646000, Sichuan, PR China. FAU - Li, Wei AU - Li W AD - Clinical Medical Research Center, the Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, PR China. AD - Department of Breast and Thyroid Surgery, the Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, PR China. FAU - Wu, Weiqing AU - Wu W AD - Department of Breast and Thyroid Surgery, the Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, PR China. FAU - Wang, Jianhong AU - Wang J AD - Clinical Medical Research Center, the Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, PR China. AD - Department of Breast and Thyroid Surgery, the Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, PR China. FAU - Du, Fukuan AU - Du F AD - Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, PR China. AD - South Sichuan Institute of Translational Medicine, Luzhou, 646000, Sichuan, PR China. FAU - Ji, Huijiao AU - Ji H AD - Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, PR China. AD - South Sichuan Institute of Translational Medicine, Luzhou, 646000, Sichuan, PR China. FAU - Yang, Xiao AU - Yang X AD - Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, PR China. FAU - Xu, Zhenyu AU - Xu Z AD - Department of Pharmacy, Yijishan Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, PR China. FAU - Wan, Lin AU - Wan L AD - Department of Hematology and Oncology, The Children's Hospital of Soochow, Jiangsu, PR China. FAU - Wen, Qinglian AU - Wen Q AD - Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, PR China. FAU - Li, Xiang AU - Li X AD - Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, PR China. FAU - Cho, Chi Hin AU - Cho CH AD - Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, PR China. AD - South Sichuan Institute of Translational Medicine, Luzhou, 646000, Sichuan, PR China. FAU - Zou, Chang AU - Zou C AD - Clinical Medical Research Center, the Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, PR China. AD - Department of Breast and Thyroid Surgery, the Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, PR China. FAU - Shen, Jing AU - Shen J AD - Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, PR China. AD - South Sichuan Institute of Translational Medicine, Luzhou, 646000, Sichuan, PR China. FAU - Xiao, Zhangang AU - Xiao Z AD - Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, PR China. AD - South Sichuan Institute of Translational Medicine, Luzhou, 646000, Sichuan, PR China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200725 PL - Australia TA - Theranostics JT - Theranostics JID - 101552395 RN - 0 (RNA, Messenger) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - A549 Cells MH - Cell Line MH - Cell Line, Tumor MH - Gastrointestinal Neoplasms/*genetics MH - HCT116 Cells MH - HEK293 Cells MH - HeLa Cells MH - Humans MH - Mutation/genetics MH - Phosphatidylinositol 3-Kinase/*genetics MH - Phylogeny MH - Proto-Oncogene Proteins c-akt/*genetics MH - RNA, Messenger/*genetics MH - Signal Transduction/*genetics MH - TOR Serine-Threonine Kinases/*genetics PMC - PMC7449908 OTO - NOTNLM OT - PI3K/Akt signal pathway OT - bioinformatics OT - gastrointestinal cancer OT - m6A RNA methylation OT - mTOR signaling pathway COIS- Competing Interests: The authors have declared that no competing interest exists. EDAT- 2020/08/31 06:00 MHDA- 2021/06/02 06:00 PMCR- 2020/01/01 CRDT- 2020/09/01 06:00 PHST- 2019/12/11 00:00 [received] PHST- 2020/07/10 00:00 [accepted] PHST- 2020/09/01 06:00 [entrez] PHST- 2020/08/31 06:00 [pubmed] PHST- 2021/06/02 06:00 [medline] PHST- 2020/01/01 00:00 [pmc-release] AID - thnov10p9528 [pii] AID - 10.7150/thno.42971 [doi] PST - epublish SO - Theranostics. 2020 Jul 25;10(21):9528-9543. doi: 10.7150/thno.42971. eCollection 2020.