Roles of phosphatidylinositol-3-kinases signaling pathway in inflammation-related cancer:Impact of rs10889677 variant and buparlisib in colitis-associated cancer  

作　　者：Nurul Nadirah Razali Raja Affendi Raja Ali Khairul Najmi Muhammad Nawawi Azyani Yahaya Norshafila Diana Mohd Rathi Norfilza Mohd Mokhtar 

机构地区：[1]Department of Physiology,Faculty of Medicine,Universiti Kebangsaan Malaysia,Cheras 56000,Kuala Lumpur,Malaysia [2]School of Medical and Life Sciences,Sunway University,Sunway City 47500,Malaysia [3]GUT Research Group,Faculty of Medicine,Universiti Kebangsaan Malaysia,Cheras 56000,Kuala Lumpur,Malaysia [4]Gastroenterology Unit,Department of Medicine,Faculty of Medicine,Universiti Kebangsaan Malaysia,Cheras 56000,Kuala Lumpur,Malaysia [5]Department of Pathology,Faculty of Medicine,Universiti Kebangsaan Malaysia,Cheras 56000,Kuala Lumpur,Malaysia

出　　处：《World Journal of Gastroenterology》2023年第40期5543-5556,共14页世界胃肠病学杂志（英文版）

基　　金：The Fundamental Research Grant Scheme,Ministry of Higher Education,Malaysia,No.FRGS/1/2018/SKK06/UKM/02/4.

摘　　要：BACKGROUND Phosphatidylinositol-3-kinases(PI3K)is a well-known route in inflammationrelated cancer.Recent discovery on PI3K-related genes revealed a potential variant that links ulcerative colitis(UC)and colorectal cancer(CRC)with colitisassociated cancer(CAC).PI3K/AKT pathway has been recommended as a potential additional therapeutic option for CRC due to its substantial role in modifying cellular processes.Buparlisib is a pan-class I PI3K inhibitor previously shown to reduce tumor growth.AIM To investigate the regulation of rs10889677 and the role of buparlisib in the PI3K signaling pathway in CAC pathogenesis.METHODS Genomic DNA from 32 colonic samples,including CAC(n=7),UC(n=10)and CRC(n=15),was sequenced for the rs10889677 mutation.The mutant and wildtype fragments were amplified and cloned in the pmirGLO vector.The luciferase activity of cloned vectors was assessed after transfection into the HT29 cell line.CAC mice were induced by a mixture of a single azoxymethane injection and three cycles of dextran sulphate sodium,then buparlisib was administered after 14 d.The excised colon was subjected to immunohistochemistry for Ki67 and Cleaved-caspase-3 markers and quantitative real-time polymerase chain reaction analysis for Pdk1 and Sgk2.RESULTS Luciferase activity decreased by 2.07-fold in the rs10889677 mutant,confirming the hypothesis that the variant disrupted miRNA binding sites,which led to an increase in IL23R expression and the activation of the PI3K signaling pathway.Furthermore,CAC-induced mice had a significantly higher disease activity index(P<0.05).Buparlisib treatment significantly decreased mean weight loss in CAC-induced mice(P<0.05),reduced the percentage of proliferating cells by 5%,and increased the number of apoptotic cells.The treatment also caused a downward trend of Pdk1 expression and significantly decreased Sgk2 expression.CONCLUSION Our findings suggested that the rs10889677 variant as a critical initiator of the PI3K signaling pathway,and buparlisib had the ability to prevent PI3K-non

关 键 词：Colitis-associated cancer Colorectal cancer Phosphatidylinositol 3-kinase Animal model LUCIFERASES RENILLA Phosphatidylinositol 3-kinase inhibitor 

分 类 号：R735[医药卫生—肿瘤]