The role of the HIF-1α/ALYREF/PKM2 axis in glycolysis and tumorigenesis of bladder cancer  

作　　者：Jing-Zi Wang Wei Zhu Jie Han Xiao Yang Rui Zhou Hong-Cheng Lu Hao Yu Wen-Bo Yuan Peng-Chao Li Jun Tao Qiang Lu Ji-Fu Wei Haiwei Yang 

机构地区：[1]Department of Urology,the First Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu 210000,P.R.China [2]Research Division of Clinical Pharmacology,the First Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu 210000,P.R.China

出　　处：《Cancer Communications》2021年第7期560-575,共16页癌症通讯（英文）

基　　金：supported by grants from the National Natural Science Foundation of China(81602235,81772711);the“333”project of Jiangsu Province(LGY2018055,LGY2016002);Key Provincial Talents Program of Jiangsu Province(ZDRCA2016006);the Priority Academic Program Development of Jiangsu Higher Education Institutions(JX10231801);the Provincial Initiative Program for Excellency Disciplines of Jiangsu Province(BE2016791).

摘　　要：Background:As a rate-limiting enzyme of glycolysis,pyruvate kinase muscle isozyme M2(PKM2)participates in tumor metabolism and growth.The regulatory network of PKM2 in cancer is complex and has not been fully studied in bladder cancer.The 5-methylcytidine(m5C)modification in PKM2 mRNA might participate in the pathogenesis of bladder cancer and need to be further clarified.This study aimed to investigate the biological function and regulatory mechanism of PKM2 in bladder cancer.Methods:The expression of PKM2 and Aly/REF export factor(ALYREF)was measured by Western blotting,qRT-PCR,and immunohistochemistry.The bioprocesses of bladder cancer cells were demonstrated by a series of experiments in vitro and in vivo.RNA immunoprecipitation,RNA-sequencing,and dualluciferase reporter assays were conducted to explore the potential regulatory mechanisms of PKM2 in bladder cancer.Results:In bladder cancer,we first demonstrated that ALYREF stabilized PKM2 mRNA and bound to its m5C sites in 3′-untranslated regions.Overexpression of ALYREF promoted bladder cancer cell proliferation by PKM2-mediated glycolysis.Furthermore,high expression of PKM2 and ALYREF predicted poor survival in bladder cancer patients.Finally,we found that hypoxia-inducible factor-1alpha(HIF-1α)indirectly up-regulated the expression of PKM2 by activating ALYREF in addition to activating its transcription directly.Conclusions:The m5C modification in PKM2 mRNA in the HIF-1α/ALYREF/PKM2 axis may promote the glucose metabolism of bladder cancer,providing a new promising therapeutic target for bladder cancer.

关 键 词：PKM2 ALYREF GLYCOLYSIS 5-methylcytidine modification bladder cancer HIF-1Α 

分 类 号：R73[医药卫生—肿瘤]