Integrative Omics Uncovers Low Tumorous Magnesium Content as A Driver Factor of Colorectal Cancer  

作　　者：Rou Zhang Meng Hu Yu Liu Wanmeng Li Zhiqiang Xu Siyu He Ying Lu Yanqiu Gong Xiuxuan Wang Shan Hai Shuangqing Li Shiqian Qi Yuan Li Yang Shu Dan Du Huiyuan Zhang Heng Xu Zongguang Zhou Peng Lei Hai-Ning Chen Lunzhi Dai 

机构地区：[1]National Clinical Research Center for Geriatrics and General Practice Ward/International Medical Center Ward,General Practice Medical Center,State Key Laboratory of Biotherapy,West China Hospital,Sichuan University,Chengdu 610041,China [2]Institute of Digestive Surgery,West China Hospital,Sichuan University,Chengdu 610041,China [3]Colorectal Cancer Center,Department of General Surgery,West China Hospital,Sichuan University,Chengdu 610041,China [4]Advanced Mass Spectrometry Center,Research Core Facility,Frontiers Science Center for Disease-related Molecular Network,West China Hospital,Sichuan University,Chengdu 610041,China

出　　处：《Genomics, Proteomics & Bioinformatics》2024年第4期99-117,共19页基因组蛋白质组与生物信息学报（英文版）

基　　金：supported by the National Key R&D Program of China(Grant No.2022YFA1303200);the National Natural Science Foundation of China(Grant Nos.82073221,31870826,and 82073246);the Sichuan Provincial Science and Technology Project(Grant No.2021YFS0134);the National Clinical Research Center for Geriatrics of West China Hospital(Grant No.Z2021JC005);the 135 Project for Disciplines of Excellence of West China Hospital(Grant Nos.ZYYC23013,ZYYC23025,ZYGD20006,and 2016105).

摘　　要：Magnesium(Mg)deficiency is associated with increased risk and malignancy in colorectal cancer(CRC),yet the underlying mechanisms remain elusive.Here,we used genomic,proteomic,and phosphoproteomic data to elucidate the impact of Mg deficiency on CRC.Genomic analysis identified 160 genes with higher mutation frequencies in Low-Mg tumors,including key driver genes such as KMT2C and ERBB3.Unexpectedly,initiation driver genes of CRC,such as TP53 and APC,displayed higher mutation frequencies in High-Mg tumors.Additionally,proteomic and phosphoproteomic data indicated that low Mg content in tumors may activate epithelial–mesenchymal transition(EMT)by modulating inflammation or remodeling the phosphoproteome of cancer cells.Notably,we observed a negative correlation between the phosphorylation of DBN1 at S142(DBN1S142p)and Mg content.A mutation in S142 to D(DBN1S142D)mimicking DBN1S142p up-regulated MMP2 and enhanced cell migration,while treatment with MgCl2 reduced DBN1S142p,thereby reversing this phenotype.Mechanistically,Mg2þattenuated the DBN1–ACTN4 interaction by decreasing DBN1S142p,which in turn enhanced the binding of ACTN4 to F-actin and promoted F-actin polymerization,ultimately reducing MMP2 expression.These findings shed new light on the crucial role of Mg deficiency in CRC progression and suggest that Mg supplementation may be a promising preventive and therapeutic strategy for CRC.

关 键 词：Magnesium deficiency Colorectal cancer Genome instability Tumor metastasis Phosphorylation. 

分 类 号：R735.37[医药卫生—肿瘤]