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Theranostics 2020; 10(21):9528-9543. doi:10.7150/thno.42971 This issue Cite

Research Paper

m⁶A RNA modification modulates PI3K/Akt/mTOR signal pathway in Gastrointestinal Cancer

Qijie Zhao^1,2,3*, Yueshui Zhao^1,2*, Wei Hu^4,5*, Yan Zhang^6*, Xu Wu^1,2, Jianwei Lu⁶, Mingxing Li^1,2, Wei Li^7,8, Weiqing Wu⁸, Jianhong Wang^7,8, Fukuan Du^1,2, Huijiao Ji^1,2, Xiao Yang¹, Zhenyu Xu⁹, Lin Wan¹⁰, Qinglian Wen¹¹, Xiang Li¹, Chi Hin Cho^1,2, Chang Zou^7,8✉, Jing Shen^1,2✉, Zhangang Xiao^1,2✉

1. Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, PR China.
2. South Sichuan Institute of Translational Medicine, Luzhou, 646000, Sichuan, PR China.
3. Department of Pathophysiology, College of Basic Medical Science, Southwest Medical University, Luzhou, 646000, Sichuan, PR China.
4. Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, PR China.
5. Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
6. 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.
7. 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.
8. 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.
9. Department of Pharmacy, Yijishan Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, PR China.
10. Department of Hematology and Oncology, The Children's Hospital of Soochow, Jiangsu, PR China.
11. Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, PR China.
*These authors contributed equally to this work.

✉ Corresponding authors: Zhangang Xiao, Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, PR China; E-mail: zhangangxiaoedu.cn; xzg555898com. Jing Shen, Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, PR China; E-mail: crystal_straycom. Chang Zou, 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, P.R. China; E-mail: zouchang.cuhkcom; Fax: (86)755 22942850. More

Abstract

Rationale: Methylation at the N6 position of adenosine (m⁶A) 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 m⁶A are regulated by methyltransferases (writers), demethylases (erasers), and special binding proteins (readers) as key factors. However, the underlying modification mechanisms of m⁶A in gastrointestinal (GI) cancer remain unclear. Here, we performed comprehensive molecular profiling of the nine known m⁶A 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 m⁶A regulators and its related pathway members was analyzed in STRING online platform. Phylogenetic tree was constructed in MEGA7. m⁶A modification sites were predicted by SRAMP. m⁶A related SNPs were analyzed by m⁶ASNP. The modulation of m⁶A on its related pathway members was validated by m⁶A-seq, real-time PCR and phosphor-MAPK array.

Results: We found that m⁶A 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 m⁶A modification in most human cancers, including GI cancer, which was further verified by m⁶A-Seq and phospho-MAPK array.

Conclusions: Our findings suggest that m⁶A RNA modification has a fundamental role in the regulation of PI3K/Akt and mTOR signaling pathway function in cancer.

Keywords: m⁶A RNA methylation, gastrointestinal cancer, bioinformatics, PI3K/Akt signal pathway, mTOR signaling pathway

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