乳腺癌组织中Toll样受体的表达及青岛地区乳腺癌Toll样受体基因多态性的研究
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摘要
背景和目的Toll样受体是近年来发现的跨膜信号传递受体,它作为一种重要的模式识别受体(PRRs)通过对病原相关分子模式(PAMP)在先天性免疫中发挥作用,并进一步调整获得性免疫系统,通过刺激信号的级联反应诱导炎症因子和细胞因子产生,在抗感染中其重要作用。近来发现多种肿瘤细胞表达具有多种功能活性的Toll样受体,Toll样受体在癌症的发生和发展中也发挥着重要作用,其活化有助于肿瘤细胞的免疫逃逸。Toll样受体基因多态性可以增加多种肿瘤的易感性。但Toll样受体在乳腺癌中的表达及其基因多态性研究的还比较少。本研究对青岛地区乳腺癌组织中TLRs(2,3,4和9)的表达及其与临床病理因素的关系进行了研究,并对乳腺癌患者中TLR2(-196to-174del), TLR3(c.1377C/T), TLR4Asp299Gly, TLR4Thr399Ile, TLR9(1486T/C)和TLR9(C2848T)的基因多态性进行分析比较,旨在探讨TLRs基因及其基因多态性在乳腺癌发生中的意义。
方法①采用RT-PCR和实时荧光定量PCR检测213例病理组织学确诊且新鲜的乳腺癌及相应癌旁组织标本中TLR2, TLR3, TLR4和TLR4mRNA的表达；分析它们与临床病理特征的关系。②PCR结合限制性片段长度多态性(restriction fragment length polymorphism, RFLP)方法检测分析青岛地区213例经病理组织学确诊的乳腺癌患者和200例健康对照女性(均为非肿瘤患者,年龄与实验组年龄相符)外周血DNA样本TLR2(-196to-174del), TLR3(c.1377C/T), TLR4Asp299Gly, TLR4Thr399Ile, TLR9(1486T/C)和TLR9(C2848T)的基因型;西部分PCR产物进行测序,DNAStar软件对序列进行对比分析,验训PCR-RFLP基因分型结果；采用病例西照研究法比较分析乳腺癌患者和对照组的基因型和等位基因频率。
结果①a.乳腺癌组织中TLRs的表达率明显高于相应癌旁组织(p<0.05)；TLR2表达与肿瘤的T分期和N分期无明显像关性,而与肿瘤的组织学分级以及ER、PR和抑癌基因p53的状态显著相关；TLR3表达与肿瘤的N分期、ER状态和PR状态无明显相关，而与肿瘤的组织学分级、T分期和抑癌基因p53的状态显著相关,抑癌基因p53的表达对TLR3有明显的诱导作用；TLR4表达与肿瘤的N分期和抑癌基因p53的表达无明显相关性,而与肿瘤的组织学分级、T分期和ER、PR的状态均显著相关；TLR9表达与肿瘤组织学分级、T分期、N分期以及ER、PR和抑癌基因p53的表达均无明显相关性。
b.乳腺癌组织TLRs表达水平明显高于癌旁组织(p<0.05)。
②a.乳腺癌患者TLR2(-174to-196) ins/del基因型(42.72%)和del/del基因型(22.54%)及del等位基因频率(43.90%)明显高于健康对照组(ins/del9%, del/del0.5%, del等位基因频率5%)。差异有统计学意义。
b. TLR3(c.1377C/T)各基因型及等位基因频率在乳腺癌患者和健康对照组两种人群中的分布均无显著性差异。
c.乳腺癌患者和健康对照组均未发现TLR4Asp299Gly和TLR4Thr399Ile的突变型。
d. TLR91486T/C各基因型及等位基因频率在乳腺癌患者和健康对照组两种人群中的分布均无显著性差异。但乳腺癌患者C等位基因频率(CT+CC基因型)高于健康对照组,处于差别有统计学意义的临界值(P=0.053, OR=1.317,95%CI=0.997-1.739)。
TLR9C2848T各基因型及等位基因频率在乳腺癌患者和健康对照组两种人群中的分布均无显著性差异。
结论①TLRs乳腺癌中高表达,TLRs可能成为乳腺癌治疗的新靶点。②TLR2(-174to-196)基因的多态性可能增加了青岛地区女性乳腺癌的易感性；扩大样本量对青岛地区乳腺癌患者TLR91486T/C位点的基因多态性做进一步研究分析,可能会更确切地了解其对青岛地区乳腺癌易感性的作用。
Background and objective:Toll-like receptors (TLRs) were identified as transmembrane signal transduction proteins in recent years. As a group of pattern recognition receptors (prrs), TLRs play important roles in the innate immunity by recognizing pathogen associated molecular patterns (PAMPs) and further modulate adaptive immune system. PAMPs trigger TLR signaling cascades, leading to the release of proinflammatory cytokines, and play critical roles in infectious diseases. TLRs were recently shown to be expressed by cancer cells, and that indicate TLRS also play an important role in the initiation and progression of cancer. TLR activation may be an important event in tumor cell immune evasion. TLRs gene polymorphisms have been related to increased susceptibility to cancer developmentment in various organs. However, the expression and gene polymorphisms of TLRs in breast cancer specimens have few characterized. The aim of this study was to investigate the expression and clinical relevance of TLR2,3,4and9in breast cancer and evaluated the possible association between TLR2(-196to-174del), TLR3(c.1377C/T), TLR4Asp299Gly, TLR4Thr399Ile, TLR9(1486T/C) and TLR9(C2848T) gene polymorphisms and breast cancer in Qingdao.
Method①The TLRs expression of213cases of breast cancer and its adjacent tissues were detected with RT-PCR and real-time PCR, and the relationship between TLRs and clinicopathological features of breast cancer were analyzed.②Peripheral blood samples were collected from213histopathologically confirmd breast cancer patients and200cancer-free, age-matched healthy femal controls from Qingdao. Genomic DNA was extracted and genotyped for TLR2,3,4and9uing polymerase chain reation-based restriction fragment length polymorphism (PCR-RFLP). Genotyp of some samples were analyzed by PCR and sequencing. The allelic and genotypic frequencies of TLRs SNPs were compared between patients and controls in a case-control study.
Results①a. The TLRs expression in breast cancer tissues was significantly higher than that in adjacent tissues (p<0.05). Expression of TLR2increased gradually with histological grade and the status of ER(+), PR(+) and p53gene(-)(P<0.05), but it had no correlation with the progress of T stages and N stages. Expression of TLR3increased gradually with histological grade, the progress of T stages and the status of p53gene(+)(P<0.05). but it had no correlation with the progress of N stages and the status of ER(+) and PR(+). Expression of TLR4increased gradually with histological grade, the progress of T stages and the status of ER(+) and PR(+)(P<0.05), but it had no correlation with the progress of N stages and the status of p53gene(+). Expression of TLR9showed no correlation with the all clinicopathological features.
b. Tumors showed higher expression levels of TLRs than that in adjacent tissues (p<0.05)
(2)a. As far as (-174to-196) in TLR2gene ins/del and del/del genotypes and del allele were significantly more frequent in breast cancer patients compared to healthy controls.
b. No significant difference of (c.1377C/T) genotypes and allele frequency was found between in breast cancer patients and healthy controls.
c. No TLR4Asp299Gly and TLR4Thr399Ile mutant genotype was detected in any breast cancer patients and healthy controls.
d. No significant difference of TLR91486T/C genotypes was found between in breast cancer patients and healthy controls, but the c allele frequency showed borderline significance(P=0.053, OR=1.317,95%CI=0.997-1.739). No'significant difference of TLR9C2848T genotypes and allele frequency was found between in breast cancer patients and healthy controls.
Conclusions①LRs overexpressed in breast cancer. TLRs may represent therapeu-tic targets in breast cancer.②(-174to-196del) of TLR2gene polymorphisms may confer an increased susceptibility to breast cancer development in Qingdao. However, the assosication between TLR91486T/C gene polymorphisms and susceptibility of breast cancer in Qingdao was uncertainty, and We should continue to survey it using appropriate way and larger samples.
方法①采用RT-PCR和实时荧光定量PCR检测213例病理组织学确诊且新鲜的乳腺癌及相应癌旁组织标本中TLR2, TLR3, TLR4和TLR4mRNA的表达；分析它们与临床病理特征的关系。②PCR结合限制性片段长度多态性(restriction fragment length polymorphism, RFLP)方法检测分析青岛地区213例经病理组织学确诊的乳腺癌患者和200例健康对照女性(均为非肿瘤患者,年龄与实验组年龄相符)外周血DNA样本TLR2(-196to-174del), TLR3(c.1377C/T), TLR4Asp299Gly, TLR4Thr399Ile, TLR9(1486T/C)和TLR9(C2848T)的基因型;西部分PCR产物进行测序,DNAStar软件对序列进行对比分析,验训PCR-RFLP基因分型结果；采用病例西照研究法比较分析乳腺癌患者和对照组的基因型和等位基因频率。
结果①a.乳腺癌组织中TLRs的表达率明显高于相应癌旁组织(p<0.05)；TLR2表达与肿瘤的T分期和N分期无明显像关性,而与肿瘤的组织学分级以及ER、PR和抑癌基因p53的状态显著相关；TLR3表达与肿瘤的N分期、ER状态和PR状态无明显相关，而与肿瘤的组织学分级、T分期和抑癌基因p53的状态显著相关,抑癌基因p53的表达对TLR3有明显的诱导作用；TLR4表达与肿瘤的N分期和抑癌基因p53的表达无明显相关性,而与肿瘤的组织学分级、T分期和ER、PR的状态均显著相关；TLR9表达与肿瘤组织学分级、T分期、N分期以及ER、PR和抑癌基因p53的表达均无明显相关性。
b.乳腺癌组织TLRs表达水平明显高于癌旁组织(p<0.05)。
②a.乳腺癌患者TLR2(-174to-196) ins/del基因型(42.72%)和del/del基因型(22.54%)及del等位基因频率(43.90%)明显高于健康对照组(ins/del9%, del/del0.5%, del等位基因频率5%)。差异有统计学意义。
b. TLR3(c.1377C/T)各基因型及等位基因频率在乳腺癌患者和健康对照组两种人群中的分布均无显著性差异。
c.乳腺癌患者和健康对照组均未发现TLR4Asp299Gly和TLR4Thr399Ile的突变型。
d. TLR91486T/C各基因型及等位基因频率在乳腺癌患者和健康对照组两种人群中的分布均无显著性差异。但乳腺癌患者C等位基因频率(CT+CC基因型)高于健康对照组,处于差别有统计学意义的临界值(P=0.053, OR=1.317,95%CI=0.997-1.739)。
TLR9C2848T各基因型及等位基因频率在乳腺癌患者和健康对照组两种人群中的分布均无显著性差异。
结论①TLRs乳腺癌中高表达,TLRs可能成为乳腺癌治疗的新靶点。②TLR2(-174to-196)基因的多态性可能增加了青岛地区女性乳腺癌的易感性；扩大样本量对青岛地区乳腺癌患者TLR91486T/C位点的基因多态性做进一步研究分析,可能会更确切地了解其对青岛地区乳腺癌易感性的作用。
Background and objective:Toll-like receptors (TLRs) were identified as transmembrane signal transduction proteins in recent years. As a group of pattern recognition receptors (prrs), TLRs play important roles in the innate immunity by recognizing pathogen associated molecular patterns (PAMPs) and further modulate adaptive immune system. PAMPs trigger TLR signaling cascades, leading to the release of proinflammatory cytokines, and play critical roles in infectious diseases. TLRs were recently shown to be expressed by cancer cells, and that indicate TLRS also play an important role in the initiation and progression of cancer. TLR activation may be an important event in tumor cell immune evasion. TLRs gene polymorphisms have been related to increased susceptibility to cancer developmentment in various organs. However, the expression and gene polymorphisms of TLRs in breast cancer specimens have few characterized. The aim of this study was to investigate the expression and clinical relevance of TLR2,3,4and9in breast cancer and evaluated the possible association between TLR2(-196to-174del), TLR3(c.1377C/T), TLR4Asp299Gly, TLR4Thr399Ile, TLR9(1486T/C) and TLR9(C2848T) gene polymorphisms and breast cancer in Qingdao.
Method①The TLRs expression of213cases of breast cancer and its adjacent tissues were detected with RT-PCR and real-time PCR, and the relationship between TLRs and clinicopathological features of breast cancer were analyzed.②Peripheral blood samples were collected from213histopathologically confirmd breast cancer patients and200cancer-free, age-matched healthy femal controls from Qingdao. Genomic DNA was extracted and genotyped for TLR2,3,4and9uing polymerase chain reation-based restriction fragment length polymorphism (PCR-RFLP). Genotyp of some samples were analyzed by PCR and sequencing. The allelic and genotypic frequencies of TLRs SNPs were compared between patients and controls in a case-control study.
Results①a. The TLRs expression in breast cancer tissues was significantly higher than that in adjacent tissues (p<0.05). Expression of TLR2increased gradually with histological grade and the status of ER(+), PR(+) and p53gene(-)(P<0.05), but it had no correlation with the progress of T stages and N stages. Expression of TLR3increased gradually with histological grade, the progress of T stages and the status of p53gene(+)(P<0.05). but it had no correlation with the progress of N stages and the status of ER(+) and PR(+). Expression of TLR4increased gradually with histological grade, the progress of T stages and the status of ER(+) and PR(+)(P<0.05), but it had no correlation with the progress of N stages and the status of p53gene(+). Expression of TLR9showed no correlation with the all clinicopathological features.
b. Tumors showed higher expression levels of TLRs than that in adjacent tissues (p<0.05)
(2)a. As far as (-174to-196) in TLR2gene ins/del and del/del genotypes and del allele were significantly more frequent in breast cancer patients compared to healthy controls.
b. No significant difference of (c.1377C/T) genotypes and allele frequency was found between in breast cancer patients and healthy controls.
c. No TLR4Asp299Gly and TLR4Thr399Ile mutant genotype was detected in any breast cancer patients and healthy controls.
d. No significant difference of TLR91486T/C genotypes was found between in breast cancer patients and healthy controls, but the c allele frequency showed borderline significance(P=0.053, OR=1.317,95%CI=0.997-1.739). No'significant difference of TLR9C2848T genotypes and allele frequency was found between in breast cancer patients and healthy controls.
Conclusions①LRs overexpressed in breast cancer. TLRs may represent therapeu-tic targets in breast cancer.②(-174to-196del) of TLR2gene polymorphisms may confer an increased susceptibility to breast cancer development in Qingdao. However, the assosication between TLR91486T/C gene polymorphisms and susceptibility of breast cancer in Qingdao was uncertainty, and We should continue to survey it using appropriate way and larger samples.
引文
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3. Tal G, Mandelberg A, Dalal I, Cesar K, Somekh E, Tal A, Oron A, Itskovich S, Ballin A, Houri S, Beigelman A, Lider O, Rechavi G, Amariglio N. Association between common Toll-like receptor 4 mutations and severe respiratory syncytial virus disease. J Infect Dis, 2004,189(11):2057-2063.
4. Mockenhaupt FP, Cramer JP, Hamann L, Stegemann MS, Eckert J, Oh NR, Otchwemah RN, Dietz E, Ehrhardt S, Schroder NW, Bienzle U, Schumann RR. Toll-like receptor (TLR) polymorphisms in African children:Common TLR-4 variants predispose to severe malaria. Proc NatlAca Sci U S A,2006,103(1):177-182.
5. Franchimont D, Vermeire S, El Housni H, Pierik M, Van Steen K, Gustot T, Quertinmont E, Abramowicz M, Van Gossum A, Deviere J, Rutgeerts P. Deficient host-bacteria interactions in inflammatory bowel disease? The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn's disease and ulcerative colitis. Gut,2004,53(7):987-992.
6. Montes AH, Asensi V, Alvarez V, Valle E, Ocana MG, Meana A, Carton JA, Paz J, Fierer J, Celada A. The Toll-like receptor 4 (Asp299Gly) polymorphism is a risk factor for Gram-negative and haematogenous osteomyelitis. Clin Exp Immunol.2006, 143(3):404-413.
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