CD44基因多态性与宫颈癌及非小细胞肺癌的相关性
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摘要
背景与目的:CD44分子是众多肿瘤细胞的标志分子,其表达水平与肿瘤细胞的恶性程度有关。该研究探讨CD44基因中的单核苷酸多态性(single nucleotide polymorphism,SNP)位点与云南汉族人群宫颈癌和非小细胞肺癌(non-small cell lung cancer,NSCLC)易感性的相关性。方法:选取了CD44基因中的两个SNP位点rs13347和rs8193,采用TagMan基因分型的方法,分析这两个多态性位点在497例宫颈癌患者和500例健康对照个体以及483例NSCLC患者和471例健康对照个体中的分布特征,并分析CD44基因中的多态性位点与云南汉族人群宫颈癌和NSCLC的相关性。结果:rs13347和rs8193位点等位基因和基因型在宫颈癌组和对照组中的分布频率的差异无统计学意义(P>0.05)。而在NSCLC组和对照组的比较中:rs13347和rs8193位点等位基因在NSCLC组和对照组中的分布频率的差异有统计学意义(P=0.020和P=0.004);这两个位点基因型在NSCLC组和对照组中分布频率的差异有统计学意义(P=0.027和P=0.020);其中rs13347位点等位基因C在NSCLC组中的分布频率显著高于对照组,可能是NSCLC发生的风险因素(OR=1.250,95%CI:1.035～1.509),rs8193位点等位基因C在对照组中的分布频率显著高于NSCLC组,可能是NSCLC发生的保护性因素(OR=0.768,95%CI:0.641～0.921)。单倍型分析结果显示,rs13347C-rs8193T和rs13347T-rs8193C在NSCLC组和对照组中的分布频率差异有统计学意义(P=0.003和0.022);该结果说明单倍型rs13347C-rs8193T可能是云南汉族人群NSCLC发生的风险性因素(OR=1.316,95%CI:1.096～1.579)。结论:CD44基因中的两个SNP位点rs13347和rs8193可能与云南汉族人群宫颈癌发病风险无关,而可能与云南汉族人群NSCLC具有相关性。
Background and purpose: CD44 is a biomarker for many human malignant tumors, and the expression level of CD44 might be associated with malignancy of cancers. Thus, in the current study, we investigated the association between single nucleotide polymorphisms(SNP) in CD44 gene and cervical cancer and non-small cell lung cancer(NSCLC) in a Yunnan Han population.Methods: For cervical cancer, 497 patients and 500 healthy individuals were recruited. For NSCLC, 483 patients and 471 healthy individuals were recruited. Two SNP in CD44 gene(rs13347, rs8193) were genotyped using TaqMan assay. And the association between the two SNP and the tumors was analyzed. Results: For cervical cancer, the allelic and genotypic frequencies of rs13347 and rs8193 were not significantly different between patients with cervical cancer and control groups(P>0.05). For NSCLC, the allelic frequencies of rs13347 and rs8193 were significantly different between NSCLC and control groups(P=0.020 and P=0.004). The C allele of rs13347 occurred more frequently in NSCLC group than in control group and might be the risk factor for NSCLC(OR=1.250, 95% CI: 1.035-1.509). The C allele of rs8193 occurred significantly more frequently in control group compared with NSCLC group, and might be a protective factor for NSCLC(OR=0.768, 95% CI: 0.641-0.921). The genotypic frequencies of rs13347 and rs8193 were significantly different between NSCLC and control groups(P=0.027 and P=0.020). Additionally, the results of haplotype analysis showed that rs13347 C-rs8193 T haplotype might be associated with higher risk of NSCLC(P=0.003, OR=1.316, 95% CI: 1.096-1.579). Conclusion: The two SNP in the CD44 gene(rs13347, rs8193) might be only associated with the risk of NSCLC, but not cervical cancer in the Yunnan Han population.
Background and purpose: CD44 is a biomarker for many human malignant tumors, and the expression level of CD44 might be associated with malignancy of cancers. Thus, in the current study, we investigated the association between single nucleotide polymorphisms(SNP) in CD44 gene and cervical cancer and non-small cell lung cancer(NSCLC) in a Yunnan Han population.Methods: For cervical cancer, 497 patients and 500 healthy individuals were recruited. For NSCLC, 483 patients and 471 healthy individuals were recruited. Two SNP in CD44 gene(rs13347, rs8193) were genotyped using TaqMan assay. And the association between the two SNP and the tumors was analyzed. Results: For cervical cancer, the allelic and genotypic frequencies of rs13347 and rs8193 were not significantly different between patients with cervical cancer and control groups(P>0.05). For NSCLC, the allelic frequencies of rs13347 and rs8193 were significantly different between NSCLC and control groups(P=0.020 and P=0.004). The C allele of rs13347 occurred more frequently in NSCLC group than in control group and might be the risk factor for NSCLC(OR=1.250, 95% CI: 1.035-1.509). The C allele of rs8193 occurred significantly more frequently in control group compared with NSCLC group, and might be a protective factor for NSCLC(OR=0.768, 95% CI: 0.641-0.921). The genotypic frequencies of rs13347 and rs8193 were significantly different between NSCLC and control groups(P=0.027 and P=0.020). Additionally, the results of haplotype analysis showed that rs13347 C-rs8193 T haplotype might be associated with higher risk of NSCLC(P=0.003, OR=1.316, 95% CI: 1.096-1.579). Conclusion: The two SNP in the CD44 gene(rs13347, rs8193) might be only associated with the risk of NSCLC, but not cervical cancer in the Yunnan Han population.
引文
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[3]DARAI E,WALKER-COMBROUZE F,BENIFLA J L,et al.E-cadherin and CD44 expression in cervical intraepithelial neoplasia:comparison between HIV-positive and HIV-negative women and correlation with HPV status[J].Gynecol Oncol,2000,76(1):56-62.
[4]ZOLLER M.CD44:can a cancer-initiating cell profit from an abundantly expressed molecule?[J].Nat Rev Cancer,2011,11(4):254-267.
[5]ZHOU J,NAGARKATTI P S,ZHONG Y,et al.Unique SNP in CD44 intron 1 and its role in breast cancer development[J].Anticancer Res,2010,30(4):1263-1272.
[6]SUENAGA M,YAMADA S,FUCHS B C,et al.CD44 single nucleotide polymorphism and isoform switching may predict gastric cancer recurrence[J].J Surg Oncol,2015,112(6):622-628.
[7]LIN X,YOU X,CAO X,et al.Association of single-nucleotide polymorphisms of CD44 gene with susceptibility to breast cancer in Chinese women[J].Med Sci Monit,2018,24:3077-3083.
[8]YADAV A,GUPTA A,RASTOGI N,et al.Association of cancer stem cell markers genetic variants with gallbladder cancer susceptibility,prognosis,and survival[J].Tumour Biol,2016,37(2):1835-1844.
[9]LI X P,ZHANG X W,ZHENG L Z,et al.Expression of CD44in pancreatic cancer and its significance[J].Int J Clin Exp Pathol,2015,8(6):6724-6731.
[10]BUKOWSKA B,MARCZAK A.Innovative therapy of ovarian cancer based on overexpression of CD44 receptor[J].Ginekol Pol,2015,86(5):388-391.
[11]JING F,KIM H J,KIM C H,et al.Colon cancer stem cell markers CD44 and CD133 in patients with colorectal cancer and synchronous hepatic metastases[J].Int J Oncol,2015,46(4):1582-1588.
[12]熊珊珊,邱前辉,詹建东,等.CD44在鼻咽癌侧群细胞中的表达及意义[J].临床耳鼻喉头颈外科杂志,2015,29(9):841-844.
[13]芮萌,李龙芸,刘丽华,等.p21、CD44v在肺癌组织中的表达及其意义[J].中国肺癌杂志,2000,3(2):111-114.
[14]SPEISER P,WANNER C,TEMPFER C,et al.CD44 is an independent prognostic factor in early-stage cervical cancer[J].Int J Cancer,1997,74(2):185-188.
[15]IBRAHIM E M,BLACKETT A D,TIDY J A,et al.CD44 is a marker of endocervical neoplasia[J].Int J Gynecol Pathol,1999,18(2):101-108.
[16]DALL P,HEKELE A,IKENBERG H,et al.Increasing incidence of CD44v7/8 epitope expression during uterine cervical carcinogenesis[J].Int J Cancer,1996,69(2):79-85.
[17]LUO Z,WU R R,LV L,et al.Prognostic value of CD44expression in non-small cell lung cancer:a systematic review[J].Int J Clin Exp Pathol,2014,7(7):3632-3646.
[18]SU C Y,LI Y S,HAN Y,et al.Correlation between expression of cell adhesion molecules CD44v6 and E-cadherin and lymphatic metastasis in non-small cell lung cancer[J].Asian Pac JCancer Prev,2014,15(5):2221-2224.
[19]CHOU Y E,HSIEH M J,HSIN C H,et al.CD44 gene polymorphisms and environmental factors on oral cancer susceptibility in Taiwan[J].PLoS One,2014,9(4):e93692.
[20]JIANG L,DENG J,ZHU X,et al.CD44 rs13347 C>Tpolymorphism predicts breast cancer risk and prognosis in Chinese populations[J].Breast Cancer Res,2012,14(4):R105.
[21]CHOU Y E,HSIEH M J,CHIOU H L,et al.CD44 gene polymorphisms on hepatocellular carcinoma susceptibility and clinicopathologic features[J].Biomed Res Int,2014,2014:231474.
[22]GERGER A,ZHANG W,YANG D,et al.Common cancer stem cell gene variants predict colon cancer recurrence[J].Clin Cancer Res,2011,17(21):6934-6943.
[23]MUMBREKAR K D,BOLA SADASHIVA S R,KABEKKODUS P,et al.Genetic variants in CD44 and MAT1A confer susceptibility to acute skin reaction in breast cancer patients undergoing radiation therapy[J].Int J Radiat Oncol Biol Phys,2017,97(1):118-127.
[24]ShI Y Y,HE L.SHEsis,a powerful software platform for analyses of linkage disequilibrium,haplotype construction,and genetic association at polymorphism loci[J].Cell Res,2005,15(2):97-98.
[25]世界癌症报告.中国新增病例全球第一[J].临床合理用药杂志,2014,7(9):170.
[26]YU G,LI H,WANG J,et al.miRNA-34a suppresses cell proliferation and metastasis by targeting CD44 in human renal carcinoma cells[J].J Urol,2014,192(4):1229-1237.
[27]DASARI S,RAJENDRA W,VALLURU L.Evaluation of soluble CD44 protein marker to distinguish the premalignant and malignant carcinoma cases in cervical cancer patients[J].Med Oncol,2014,31(9):139.
[28]GIVEHCHIAN M,WOEMER S M,LACROIX J,et al.Expression of CD44 splice variants in normal respiratory epithelium and bronchial carcinomas:no evidence for altered CD44 splicing in metastasis[J].Oncogene,1996,12(5):1137-1144.
[29]HIGASHIKAWA K,YOKOZAKI H,UE T,et al.Evaluation of CD44 transcription variants in human digestive tract carcinomas and normal tissues[J].Int J Cancer,1996,66(1):11-17.
[30]DE ROSSI G,MARRONI P,PAGANUZZI M,et al.Increased serum levels of soluble CD44 standard,but not of variant isoforms v5 and v6,in B cell chronic lymphocytic leukemia[J].Leukemia,1997,11(1):134-141.
[31]EMAK G,JENNINGS T,ROBINSON L,et al.Restricted patterns of CD44 variant exon expression in human papillary thyroid carcinoma[J].Cancer Res,1996,56(5):1037-1042.
[32]SLIUTZ G,TEMPFER C,WINKLER S,et al.Immunohistochemical and serological evaluation of CD44 splice variants in human ovarian cancer[J].Br J Cancer,1995,72(6):1494-1497.
[33]BRODERSEN P,VOINNET O.Revisiting the principles of microRNA target recognition and mode of action[J].Nat Rev Mol Cell Biol,2009,10(2):141-148.
[34]WU H,DENG J,ZHENG J,et al.Functional polymorphisms in the CD44 gene and acute myeloid leukemia cancer risk in a Chinese population[J].Mol Carcinog,2015,54(2):102-110.
[35]XIAO M,HU S,ZHANG L,et al.Polymorphisms of CD44gene and nasopharyngeal carcinoma susceptibility in a Chinese population[J].Mutagenesis,2013,28(5):577-582.
[36]SHI J,DUAN Y,PAN L,et al.Positive association between CD44 gene rs13347 C>T polymorphism and risk of cancer in Asians:a systemic review and meta-analysis[J].Onco Targets Ther,2016,9:3493-3500.
[37]LOU F,MA H N,XU L,et al.Two polymorphisms of CD443’UTR weaken the binding of miRNAs and associate with nasopharyngeal carcinoma in a Chinese population[J].Eur Rev Med Pharmacol Sci,2014,18(17):2444-2452.
[38]TULSYAN S,AGARWAL G,Lal P,et al.CD44 gene polymorphisms in breast cancer risk and prognosis:a study in North Indian population[J].PLoS One,2013,8(8):e71073.
[39]TERPE H J,STARK H,PREHM P,et al.CD44 variant isoforms are preferentially expressed in basal epithelial of non-malignant human fetal and adult tissues[J].Histochemistry,1994,101(2):79-89.
[2]JECK W R,SIEBOLD A P,SHARPLESS N E.Review:a Metaanalysis of GWAS and age-associated diseases[J].Aging Cell,2012,11(5):727-731.
[3]DARAI E,WALKER-COMBROUZE F,BENIFLA J L,et al.E-cadherin and CD44 expression in cervical intraepithelial neoplasia:comparison between HIV-positive and HIV-negative women and correlation with HPV status[J].Gynecol Oncol,2000,76(1):56-62.
[4]ZOLLER M.CD44:can a cancer-initiating cell profit from an abundantly expressed molecule?[J].Nat Rev Cancer,2011,11(4):254-267.
[5]ZHOU J,NAGARKATTI P S,ZHONG Y,et al.Unique SNP in CD44 intron 1 and its role in breast cancer development[J].Anticancer Res,2010,30(4):1263-1272.
[6]SUENAGA M,YAMADA S,FUCHS B C,et al.CD44 single nucleotide polymorphism and isoform switching may predict gastric cancer recurrence[J].J Surg Oncol,2015,112(6):622-628.
[7]LIN X,YOU X,CAO X,et al.Association of single-nucleotide polymorphisms of CD44 gene with susceptibility to breast cancer in Chinese women[J].Med Sci Monit,2018,24:3077-3083.
[8]YADAV A,GUPTA A,RASTOGI N,et al.Association of cancer stem cell markers genetic variants with gallbladder cancer susceptibility,prognosis,and survival[J].Tumour Biol,2016,37(2):1835-1844.
[9]LI X P,ZHANG X W,ZHENG L Z,et al.Expression of CD44in pancreatic cancer and its significance[J].Int J Clin Exp Pathol,2015,8(6):6724-6731.
[10]BUKOWSKA B,MARCZAK A.Innovative therapy of ovarian cancer based on overexpression of CD44 receptor[J].Ginekol Pol,2015,86(5):388-391.
[11]JING F,KIM H J,KIM C H,et al.Colon cancer stem cell markers CD44 and CD133 in patients with colorectal cancer and synchronous hepatic metastases[J].Int J Oncol,2015,46(4):1582-1588.
[12]熊珊珊,邱前辉,詹建东,等.CD44在鼻咽癌侧群细胞中的表达及意义[J].临床耳鼻喉头颈外科杂志,2015,29(9):841-844.
[13]芮萌,李龙芸,刘丽华,等.p21、CD44v在肺癌组织中的表达及其意义[J].中国肺癌杂志,2000,3(2):111-114.
[14]SPEISER P,WANNER C,TEMPFER C,et al.CD44 is an independent prognostic factor in early-stage cervical cancer[J].Int J Cancer,1997,74(2):185-188.
[15]IBRAHIM E M,BLACKETT A D,TIDY J A,et al.CD44 is a marker of endocervical neoplasia[J].Int J Gynecol Pathol,1999,18(2):101-108.
[16]DALL P,HEKELE A,IKENBERG H,et al.Increasing incidence of CD44v7/8 epitope expression during uterine cervical carcinogenesis[J].Int J Cancer,1996,69(2):79-85.
[17]LUO Z,WU R R,LV L,et al.Prognostic value of CD44expression in non-small cell lung cancer:a systematic review[J].Int J Clin Exp Pathol,2014,7(7):3632-3646.
[18]SU C Y,LI Y S,HAN Y,et al.Correlation between expression of cell adhesion molecules CD44v6 and E-cadherin and lymphatic metastasis in non-small cell lung cancer[J].Asian Pac JCancer Prev,2014,15(5):2221-2224.
[19]CHOU Y E,HSIEH M J,HSIN C H,et al.CD44 gene polymorphisms and environmental factors on oral cancer susceptibility in Taiwan[J].PLoS One,2014,9(4):e93692.
[20]JIANG L,DENG J,ZHU X,et al.CD44 rs13347 C>Tpolymorphism predicts breast cancer risk and prognosis in Chinese populations[J].Breast Cancer Res,2012,14(4):R105.
[21]CHOU Y E,HSIEH M J,CHIOU H L,et al.CD44 gene polymorphisms on hepatocellular carcinoma susceptibility and clinicopathologic features[J].Biomed Res Int,2014,2014:231474.
[22]GERGER A,ZHANG W,YANG D,et al.Common cancer stem cell gene variants predict colon cancer recurrence[J].Clin Cancer Res,2011,17(21):6934-6943.
[23]MUMBREKAR K D,BOLA SADASHIVA S R,KABEKKODUS P,et al.Genetic variants in CD44 and MAT1A confer susceptibility to acute skin reaction in breast cancer patients undergoing radiation therapy[J].Int J Radiat Oncol Biol Phys,2017,97(1):118-127.
[24]ShI Y Y,HE L.SHEsis,a powerful software platform for analyses of linkage disequilibrium,haplotype construction,and genetic association at polymorphism loci[J].Cell Res,2005,15(2):97-98.
[25]世界癌症报告.中国新增病例全球第一[J].临床合理用药杂志,2014,7(9):170.
[26]YU G,LI H,WANG J,et al.miRNA-34a suppresses cell proliferation and metastasis by targeting CD44 in human renal carcinoma cells[J].J Urol,2014,192(4):1229-1237.
[27]DASARI S,RAJENDRA W,VALLURU L.Evaluation of soluble CD44 protein marker to distinguish the premalignant and malignant carcinoma cases in cervical cancer patients[J].Med Oncol,2014,31(9):139.
[28]GIVEHCHIAN M,WOEMER S M,LACROIX J,et al.Expression of CD44 splice variants in normal respiratory epithelium and bronchial carcinomas:no evidence for altered CD44 splicing in metastasis[J].Oncogene,1996,12(5):1137-1144.
[29]HIGASHIKAWA K,YOKOZAKI H,UE T,et al.Evaluation of CD44 transcription variants in human digestive tract carcinomas and normal tissues[J].Int J Cancer,1996,66(1):11-17.
[30]DE ROSSI G,MARRONI P,PAGANUZZI M,et al.Increased serum levels of soluble CD44 standard,but not of variant isoforms v5 and v6,in B cell chronic lymphocytic leukemia[J].Leukemia,1997,11(1):134-141.
[31]EMAK G,JENNINGS T,ROBINSON L,et al.Restricted patterns of CD44 variant exon expression in human papillary thyroid carcinoma[J].Cancer Res,1996,56(5):1037-1042.
[32]SLIUTZ G,TEMPFER C,WINKLER S,et al.Immunohistochemical and serological evaluation of CD44 splice variants in human ovarian cancer[J].Br J Cancer,1995,72(6):1494-1497.
[33]BRODERSEN P,VOINNET O.Revisiting the principles of microRNA target recognition and mode of action[J].Nat Rev Mol Cell Biol,2009,10(2):141-148.
[34]WU H,DENG J,ZHENG J,et al.Functional polymorphisms in the CD44 gene and acute myeloid leukemia cancer risk in a Chinese population[J].Mol Carcinog,2015,54(2):102-110.
[35]XIAO M,HU S,ZHANG L,et al.Polymorphisms of CD44gene and nasopharyngeal carcinoma susceptibility in a Chinese population[J].Mutagenesis,2013,28(5):577-582.
[36]SHI J,DUAN Y,PAN L,et al.Positive association between CD44 gene rs13347 C>T polymorphism and risk of cancer in Asians:a systemic review and meta-analysis[J].Onco Targets Ther,2016,9:3493-3500.
[37]LOU F,MA H N,XU L,et al.Two polymorphisms of CD443’UTR weaken the binding of miRNAs and associate with nasopharyngeal carcinoma in a Chinese population[J].Eur Rev Med Pharmacol Sci,2014,18(17):2444-2452.
[38]TULSYAN S,AGARWAL G,Lal P,et al.CD44 gene polymorphisms in breast cancer risk and prognosis:a study in North Indian population[J].PLoS One,2013,8(8):e71073.
[39]TERPE H J,STARK H,PREHM P,et al.CD44 variant isoforms are preferentially expressed in basal epithelial of non-malignant human fetal and adult tissues[J].Histochemistry,1994,101(2):79-89.