{"title":"Remote modulation of WWOX by an intronic variant associated with survival of Chinese gastric cancer patients","authors":"Lei Cheng, Yuanyuan Chang, Zuguang Xia, Yizhen Liu, Xiao Liu, Liwen Xiong, Chenchen Liu, Xiaodong Zhu, Mengyun Wang, Lixin Qiu","doi":"10.1002/ijc.34703","DOIUrl":null,"url":null,"abstract":"<p>The protein WWOX was reported to be involved in cancer progression via interaction with mTOR and DNA repair pathway. We previously reported noteworthy association of some single nucleotide polymorphisms (SNPs) in mTOR and DNA repair pathways with gastric cancer (GCa) patients' survival. We hypothesized that genetic variants in <i>WWOX</i> gene could predict the survival of GCa patients. By extracting <i>WWOX</i> genetic variants from our ongoing genome-wide association study including 796 GCa patients from an Eastern Chinese population, we identified 51 out of 1913 SNPs to be significantly associated with survival of GCa patients, which passed the false positive probability tests. In particular, the intronic variant rs9922483, a G>T change, was associated with 21% increased death risk for GCa patients (HR = 1.21, 95% CI = 1.04-1.42, <i>P</i> = .015). This locus was predicted to be involved in potential enhancer by bioinformatics analysis. Genotype-phenotype correlation analysis revealed decreased expression of <i>WWOX</i> by rs9922483 G>T change. Mechanistically, rs9922483 locus may exhibits long-range interaction with <i>WWOX</i> promoter, and the G>T change inhibited the transcriptional activity driven by <i>WWOX</i> promoter in luciferase reporter system. Especially, the G>T change had an allele-specific negative effect on NR3C1 binding, and NR3C1 promoted the expression of <i>WWOX</i> in GCa cells. Further functional analysis indicated an increase in proliferation, migration and invasion of GCa cells by knockdown of <i>WWOX</i>. In conclusion, <i>WWOX</i> genetic variants may modulate survival of Chinese GCa patients by exerting remote regulatory effect on <i>WWOX</i> expression. Our results highlight the <i>cis</i>-regulatory effect of genetic variants on genes and survival modulation for GCa patients.</p>","PeriodicalId":180,"journal":{"name":"International Journal of Cancer","volume":"154 2","pages":"307-319"},"PeriodicalIF":5.7000,"publicationDate":"2023-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Cancer","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ijc.34703","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
The protein WWOX was reported to be involved in cancer progression via interaction with mTOR and DNA repair pathway. We previously reported noteworthy association of some single nucleotide polymorphisms (SNPs) in mTOR and DNA repair pathways with gastric cancer (GCa) patients' survival. We hypothesized that genetic variants in WWOX gene could predict the survival of GCa patients. By extracting WWOX genetic variants from our ongoing genome-wide association study including 796 GCa patients from an Eastern Chinese population, we identified 51 out of 1913 SNPs to be significantly associated with survival of GCa patients, which passed the false positive probability tests. In particular, the intronic variant rs9922483, a G>T change, was associated with 21% increased death risk for GCa patients (HR = 1.21, 95% CI = 1.04-1.42, P = .015). This locus was predicted to be involved in potential enhancer by bioinformatics analysis. Genotype-phenotype correlation analysis revealed decreased expression of WWOX by rs9922483 G>T change. Mechanistically, rs9922483 locus may exhibits long-range interaction with WWOX promoter, and the G>T change inhibited the transcriptional activity driven by WWOX promoter in luciferase reporter system. Especially, the G>T change had an allele-specific negative effect on NR3C1 binding, and NR3C1 promoted the expression of WWOX in GCa cells. Further functional analysis indicated an increase in proliferation, migration and invasion of GCa cells by knockdown of WWOX. In conclusion, WWOX genetic variants may modulate survival of Chinese GCa patients by exerting remote regulatory effect on WWOX expression. Our results highlight the cis-regulatory effect of genetic variants on genes and survival modulation for GCa patients.
据报道,蛋白质WWOX通过与mTOR和DNA修复途径的相互作用参与癌症的进展。我们之前报道了mTOR和DNA修复通路中一些单核苷酸多态性(snp)与胃癌(GCa)患者生存的显著关联。我们假设WWOX基因的遗传变异可以预测GCa患者的生存。通过从我们正在进行的全基因组关联研究中提取WWOX遗传变异,包括来自中国东部人群的796例GCa患者,我们确定了1913个snp中有51个与GCa患者的生存显著相关,并通过了假阳性概率检验。特别是,G>T改变的内含子变异rs9922483与GCa患者死亡风险增加21%相关(HR = 1.21, 95% CI = 1.04-1.42, P = 0.015)。生物信息学分析预测该位点与潜在增强子有关。基因型-表型相关分析显示,rs9922483的G>T变化导致WWOX的表达降低。机制上,rs9922483位点可能与WWOX启动子存在远程相互作用,G>T的改变抑制了荧光素酶报告系统中WWOX启动子驱动的转录活性。特别是G>T的改变对NR3C1结合有等位基因特异性的负性影响,NR3C1促进了GCa细胞中WWOX的表达。进一步的功能分析表明,敲低WWOX可增加GCa细胞的增殖、迁移和侵袭。综上所述,WWOX基因变异可能通过远程调控WWOX的表达来调节中国GCa患者的生存。我们的研究结果强调了遗传变异对GCa患者基因和生存调节的顺式调控作用。
期刊介绍:
The International Journal of Cancer (IJC) is the official journal of the Union for International Cancer Control—UICC; it appears twice a month. IJC invites submission of manuscripts under a broad scope of topics relevant to experimental and clinical cancer research and publishes original Research Articles and Short Reports under the following categories:
-Cancer Epidemiology-
Cancer Genetics and Epigenetics-
Infectious Causes of Cancer-
Innovative Tools and Methods-
Molecular Cancer Biology-
Tumor Immunology and Microenvironment-
Tumor Markers and Signatures-
Cancer Therapy and Prevention