HOTAIR遗传变异及基因-环境交互作用与肝癌临床特征的关联性分析
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摘要
目的探讨长链非编码RNA HOX转录反义RNA(LncRNA HOTAIR)遗传变异及基因-环境交互作用与肝癌预后相关临床特征的关系。方法选取广东省南方医科大学顺德医院2010年10月-2016年10月收治的原发性肝癌新发患者923例,采用TaqMan荧光定量PCR技术检测HOTAIR rs17105613 T> C、rs12427129 C> T和rs3816153 G> T基因型。采用χ~2检验分析肝癌临床特征分布的差异,应用logistic回归模型分析HOTAIR遗传变异对肝癌TNM分期、门静脉癌栓和发病年龄的影响。结果校正环境因素后,隐性遗传模式下rs17105613和rs3816153与肝癌TNM分期均有统计学关联(P值均<0. 05),且rs12427129与吸烟对肝癌发病年龄存在统计学意义的相乘交互作用(P=0. 029)和临界统计学意义的相加交互作用(P=0. 092)。结论 HOTAIR rs17105613和rs3816153可能与肝癌TNM分期有关,rs12427129与吸烟交互作用可能对肝癌发病年龄有影响,因此HOTAIR遗传变异可能促进肝癌细胞的侵袭和转移。
Objective To investigate the association of the genetic variation of the long non-coding RNA HOX transcript antisense RNA(HOATIR) and gene-environment interaction with prognosis-related clinical features of liver cancer. Methods A total of 923 patients with primary liver cancer Shunde Hospital of Southern Medical University were admitted to a hospital from October 2010 to October 2016 were enrolled in this study. TaqMan quantitative PCR was used to detect HOTAIR rs17105613 T > C,rs12427129 C > T,and rs3816153 G> T genotypes. The chi-square test was used to analyze the difference in the distribution of clinical features of liver cancer,and the logistic regression model was used to analyze the influence of the genetic variation of HOTAIR on the TNM stage of liver cancer,portal vein tumor thrombus,and age of onset. Results After the adjustment for environmental factors,rs17105613 and rs3816153 were significantly associated with TNM stage in the recessive mode(P < 0. 05),and there was a statistically significant multiplicative interaction between rs12427129 and smoking on the age of onset of liver cancer(P = 0. 029),as well as an additive interaction with critical statistical significance(P = 0.092). Conclusion HOTAIR rs17105613 and rs3816153 may be associated with TNM stage of liver cancer. The interaction between rs12427129 and smoking may influence the age of onset of liver cancer. Therefore,the genetic variation of HOTAIR may promote the invasion and metastasis of hepatoma cells.
Objective To investigate the association of the genetic variation of the long non-coding RNA HOX transcript antisense RNA(HOATIR) and gene-environment interaction with prognosis-related clinical features of liver cancer. Methods A total of 923 patients with primary liver cancer Shunde Hospital of Southern Medical University were admitted to a hospital from October 2010 to October 2016 were enrolled in this study. TaqMan quantitative PCR was used to detect HOTAIR rs17105613 T > C,rs12427129 C > T,and rs3816153 G> T genotypes. The chi-square test was used to analyze the difference in the distribution of clinical features of liver cancer,and the logistic regression model was used to analyze the influence of the genetic variation of HOTAIR on the TNM stage of liver cancer,portal vein tumor thrombus,and age of onset. Results After the adjustment for environmental factors,rs17105613 and rs3816153 were significantly associated with TNM stage in the recessive mode(P < 0. 05),and there was a statistically significant multiplicative interaction between rs12427129 and smoking on the age of onset of liver cancer(P = 0. 029),as well as an additive interaction with critical statistical significance(P = 0.092). Conclusion HOTAIR rs17105613 and rs3816153 may be associated with TNM stage of liver cancer. The interaction between rs12427129 and smoking may influence the age of onset of liver cancer. Therefore,the genetic variation of HOTAIR may promote the invasion and metastasis of hepatoma cells.
引文
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[27]LIU S.Study of prognosis and long-term survival impact factors of liver cancer[J].J Liaoning Med Univ,2014,35(2):101-103.(in Chinese)刘森.肝癌的预后及长期生存影响因素的研究进展[J].辽宁医学院学报,2014,35(2):101-103.
[28]WU MC,LEE S,CAI T,et al.Rare-variant association testing for sequencing data with the sequence kernel association test[J].Am J Hum Genet,2011,89(1):82-93.
[29]SZULAKOWSKI P,CROWTHER AJ,JIMENEZ LA,et al.The effect of smoking on the transcriptional regulation of lung inflammation in patients with chronic obstructive pulmonary disease[J].Am J Respir Crit Care Med,2006,174(1):41-50.
[2]CHEN WQ,ZHENG RS,ZHANG SW,et al.Report of cancer incidence and mortality in China,2013[J].China Cancer,2017,26(1):1-7.(in Chinese)陈万青,郑荣寿,张思维,等.2013年中国恶性肿瘤发病和死亡分析[J].中国肿瘤,2017,26(1):1-7.
[3]ZHENG RS,ZUO TT,ZENG HM,et al.Mortality and survival analysis of liver cancer in China[J].Chin J Oncol,2015,37(9):697-702.(in Chinese)郑荣寿,左婷婷,曾红梅,等.中国肝癌死亡状况与生存分析[J].中华肿瘤杂志,2015,37(9):697-702.
[4]GUO XD,SUN SS,LI WD,et al.Clinical features of patients with Barcelona Clinic Liver Cancer stage C primary liver cancer and related prognostic factors:An analysis of 140 cases[J].J Clin Hepatol,2018,34(7):1456-1461.(in Chinese)郭晓笛,孙莎莎,李文东,等.140例BCLC分期C期原发性肝癌患者的临床特征及预后影响因素分析[J].临床肝胆病杂志,2018,34(7):1456-1461.
[5]DISTEFANO JK.Long noncoding RNAs in the initiation,progression,and metastasis of hepatocellular carcinoma[J].Noncoding RNA Res,2017,2(3-4):129-136.
[6]KAPRANOV P,CHENG J,DIKE S,et al.RNA maps reveal new RNA classes and a possible function for pervasive transcription[J].Science,2007,316(5830):1484-1488.
[7]GIBB EA,BROWN CJ,WAN LL.The functional role of long non-coding RNA in human carcinomas[J].Mol Cancer,2011,10(1):38.
[8]RINN JL,KERTESZ M,WANG JK,et al.Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs[J].Cell,2007,129(7):1311-1323.
[9]SUN YS,QU Q,PAN JH,et al.Role of lncRNAs in colorectal cancer[J].Chin J Clin Pharmacol Ther,2017,22(2):222-227.(in Chinese)孙跃胜,屈强,潘江华,等.长链非编码RNA在结直肠癌中的作用[J].中国临床药理学与治疗学,2017,22(2):222-227.
[10]GUPTA RA,NILAY S,WANG KC,et al.Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis[J].Nature,2010,464(7291):1071-1076.
[11]LI Z,ZHANG F,CAI HB,et al.Association of the peripheral blood long non-coding RNA HOTAIR with postoperative prognosis of ovarian cancer and its significance[J].Trauma Crit Med,2018,6(5):291-293.(in Chinese)李蓁,张帆,蔡红兵,等.外周血长链非编码RNA-同源盒基因反义转录RNA与卵巢癌术后转归关系及意义[J].创伤与急危重病医学,2018,6(5):291-293.
[12]NAKAGAWA T,ENDO H,YOKOYAMA M,et al.Large noncoding RNA HOTAIR enhances aggressive biological behavior and is associated with short disease-free survival in human non-small cell lung cancer[J].Biochem Biophys Res Commun,2013,436(2):319-324.
[13]ENDO H,SHIROKI T,NAKAGAWA T,et al.Enhanced expression of long non-coding RNA HOTAIR is associated with the development of gastric cancer[J].PLo S One,2013,8(10):e77070.
[14]WANG PH.Significant association of long non-coding RNAs HOTAIR genetic polymorphisms with cancer recurrence and patient survival in patients with uterine cervical cancer[J].Int J Med Sci,2018,15(12):1312-1319.
[15]BAYRAM S,SUMBUL AT,DADASE.A functional HOTAIRrs12826786 C>T polymorphism is associated with breast cancer susceptibility and poor clinicopathological characteristics in a Turkish population:A hospital-based case-control study[J].Tumour Biol,2015,37(4):5577-5584.
[16]Ministry of Health of the People's Republic of China.Diagnosis,management,and treatment of hepatocellular carcinoma(V2011)[J].J Clin Hepatol,2011,27(11):1141-1159.(in Chinese)中华人民共和国卫生部.原发性肝癌诊疗规范(2011年版)[J].临床肝胆病杂志,2011,27(11):1141-1159.
[17]BOYLE AP,HONG EL,HARIHARAN M,et al.Annotation of functional variation in personal genomes using RegulomeDB[J].Genome Res,2012,22(9):1790-1797.
[18]WARD LD,KELLIS M.HaploReg v4:Systematic mining of putative causal variants,cell types,regulators and target genes for human complex traits and disease[J].Nucleic Acids Res,2016,44(D1):d877-d881.
[19]XU Z,TAYLOR JA.SNP info:Integrating GWAS and candidate gene information into functional SNP selection for genetic association studies[J].Nucleic Acids Res,2009,37(suppl-2):w600-w605.
[20]LI X,WU Z,MEI Q,et al.Long non-coding RNA HOTAIR,a driver of malignancy,predicts negative prognosis and exhibits oncogenic activity in oesophageal squamous cell carcinoma[J].Br J Cancer,2013,109(8):2266-2278.
[21]XU ZY,YU QM,DU YA,et al.Knockdown of long non-coding RNA HOTAIR suppresses tumor invasion and reverses epithelial-mesenchymal transition in gastric cancer[J].Int J Biol Sci,2013,9(6):587-597.
[22]GAO JZ,LI J,DU JL,et al.Long non-coding RNA HOTAIRis a marker for hepatocellular carcinoma progression and tumor recurrence[J].Oncol Lett,2016,11(3):1791-1798.
[23]DAI D,HU DH,ZHENG JJ.Expression and significance of peripheral blood lymphocyte transcription factors in patients with liver cancer[J].Chin J Gerontol,2018,38(1):140-142.(in Chinese)戴丹,胡东辉,张建军.肝癌患者外周血淋巴细胞转录因子的表达及意义[J].中国老年学杂志,2018,38(1):140-142.
[24]SHEN WL.Study on the different types of CTCF-mediated chromatin interactions[D].Academy of Military Medical Sciences,2015.(in Chinese)沈文龙.CTCF介导不同类型染色质相互作用的研究[D].中国人民解放军军事医学科学院,2015.
[25]TIAN T,LI C,XIAO J,et al.Quantitative assessment of the polymorphisms in the HOTAIR lncRNA and cancer risk:A meta-analysis of 8 case-control studies[J].PLo S One,2016,11(3):e152296.
[26]LI YW.Progress in long-chain non-coding RNA HOTAIR in malignant tumors[J].Prog Biochem Biophys,2015,42(3):228-235.(in Chinese)李雨薇.长链非编码RNA HOTAIR在恶性肿瘤中的研究进展[J].生物化学与生物物理进展,2015,42(3):228-235.
[27]LIU S.Study of prognosis and long-term survival impact factors of liver cancer[J].J Liaoning Med Univ,2014,35(2):101-103.(in Chinese)刘森.肝癌的预后及长期生存影响因素的研究进展[J].辽宁医学院学报,2014,35(2):101-103.
[28]WU MC,LEE S,CAI T,et al.Rare-variant association testing for sequencing data with the sequence kernel association test[J].Am J Hum Genet,2011,89(1):82-93.
[29]SZULAKOWSKI P,CROWTHER AJ,JIMENEZ LA,et al.The effect of smoking on the transcriptional regulation of lung inflammation in patients with chronic obstructive pulmonary disease[J].Am J Respir Crit Care Med,2006,174(1):41-50.