胃癌组织中Th1细胞因子与胃癌患者术后生存的研究
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摘要
检测Th1细胞因子在胃癌组织中的表达,分析其与胃癌患者术后生存的相关性及其临床意义。
选取2006年6月至2008年1月之间接受标准D2根治术并达到R0切除的胃腺癌患者58例,随访截止时间为2010年2月。运用荧光实时定量PCR(qRT-PCR)技术,检测所有患者的胃癌组织中Th1细胞因子TRAV10、IRF1、TBX21、CD3Z、GZMB、GNLY、GATA3和IFNG的mRNA的表达量,并分析其与胃癌患者术后生存的关系及其临床意义。
截止到末次随访时间,共有13例患者死亡(22.4%),均死于胃癌复发。中位随访期为30.5个月(1.0-43.0)。所有患者的1年生存率为84.5%,2年生存率为80.6%。卡方检验显示GNLY、GZMB和IFNG的mRNA表达与胃癌组织中脉管癌栓的形成数量呈负相关。单变量cox回归分析提示GNLY的mRNA表达水平(p=0.022)以及TRAV10等八个因子的mRNA表达水平均下调(p=0.001)与胃癌患者术后生存显著相关,而单个TRAV10、IRF1、TBX21、CD3Z、GZMB、GATA3和IFNG的mRNA表达水平与胃癌患者术后生存无统计学意义,K-M分析也提示GNLY的mRNA表达水平(p=0.012)以及TRAV10等八个因子的mRNA的综合表达水平(p<0.001)与胃癌患者术后生存显著相关,但多变量cox回归分析仅提示TRAV10等八个因子的mRNA表达水平均下调(p=0.05)有统计学意义,提示该因素是影响胃癌患者术后生存的独立因素。1、GNLY的mRNA表达水平与胃癌患者术后生存有相关性,但不是独立因素。2、在TRAV10、IRF1、TBX21、CD3Z、GZMB、GNLY、GATA3和IFNG的mRNA表达水平中,有任意因子上调的患者预后好于皆下调的患者,该指标为影响胃癌患者术后生存的独立因素。
3、GNLY、GZMB和IFNG的mRNA的单独表达上调与胃癌组织脉管癌栓的形成数量呈负相关。
To investigate the correlation and clinical significance of the expressions and effects of Thl cytokines on survival time of patients with gastric cancer after radical resection.
We selected specimens from 58 patients who underwent RO resections with extended lymph nodes dissection(D2) from June 2006 through January 2008 at Zhongshan Hospital (Shanghai, China). The date of last follow-up was February 2010. The expressions of Thl cytokines mRNA was detected in tumor tissues from 58 patients with gastric cancer by real-time polymerase chain reaction (RT-PCR) method. Prognostic effects of Thl cytokines were evaluated by Cox regression and Kaplan-Meier analysis using median values as cutoff.
At last follow-up,13 patients (22.4%) studied had died, all of whom died from the recurrence of gastric cancer. The median duration of follow-up were 30.5 months (range,1.0-43.0). The overall survival (OS) rates were 84.5% for 1 year,80.6% for 2 years, respectively, for the whole study. The mRNA expressions of GNLY, GZMB and IFNG are associated with tumor emboli. The mRNA expressions of TRAV10, IRF1, TBX21, CD3Z, GZMB, GATA3 and IFNG are not associated with OS. In the tumor sites, the lower mRNA expression of GNLY is associated with worse OS (Urivariate analysis HR 0.23, p=0.022), however, it is not an independent predictor. At the same time, the combination of mRNA expressions of eight cytokines is an independent factor for OS (Urivariate analysis HR 0.23,p=0.001; Mutlivariate analysis HR 0.17,p=0.05).1-year and 2-year OS rates were 98%,89.8% for the group with high mRNA expression of eight cytokines, compared with 66.7%,55.6% for the group with low mRNA expression (Logrank-testp<0.001).
1. The mRNA expression of GNLY is associated with OS, but it is not an independent factor.
2. The combination of mRNA expressions of the eight cytokines is an independent factor for OS.
3. The mRNA expression of GNLY, GZMB and IFNG is separately negatively correlated with tumor emboli.
选取2006年6月至2008年1月之间接受标准D2根治术并达到R0切除的胃腺癌患者58例,随访截止时间为2010年2月。运用荧光实时定量PCR(qRT-PCR)技术,检测所有患者的胃癌组织中Th1细胞因子TRAV10、IRF1、TBX21、CD3Z、GZMB、GNLY、GATA3和IFNG的mRNA的表达量,并分析其与胃癌患者术后生存的关系及其临床意义。
截止到末次随访时间,共有13例患者死亡(22.4%),均死于胃癌复发。中位随访期为30.5个月(1.0-43.0)。所有患者的1年生存率为84.5%,2年生存率为80.6%。卡方检验显示GNLY、GZMB和IFNG的mRNA表达与胃癌组织中脉管癌栓的形成数量呈负相关。单变量cox回归分析提示GNLY的mRNA表达水平(p=0.022)以及TRAV10等八个因子的mRNA表达水平均下调(p=0.001)与胃癌患者术后生存显著相关,而单个TRAV10、IRF1、TBX21、CD3Z、GZMB、GATA3和IFNG的mRNA表达水平与胃癌患者术后生存无统计学意义,K-M分析也提示GNLY的mRNA表达水平(p=0.012)以及TRAV10等八个因子的mRNA的综合表达水平(p<0.001)与胃癌患者术后生存显著相关,但多变量cox回归分析仅提示TRAV10等八个因子的mRNA表达水平均下调(p=0.05)有统计学意义,提示该因素是影响胃癌患者术后生存的独立因素。1、GNLY的mRNA表达水平与胃癌患者术后生存有相关性,但不是独立因素。2、在TRAV10、IRF1、TBX21、CD3Z、GZMB、GNLY、GATA3和IFNG的mRNA表达水平中,有任意因子上调的患者预后好于皆下调的患者,该指标为影响胃癌患者术后生存的独立因素。
3、GNLY、GZMB和IFNG的mRNA的单独表达上调与胃癌组织脉管癌栓的形成数量呈负相关。
To investigate the correlation and clinical significance of the expressions and effects of Thl cytokines on survival time of patients with gastric cancer after radical resection.
We selected specimens from 58 patients who underwent RO resections with extended lymph nodes dissection(D2) from June 2006 through January 2008 at Zhongshan Hospital (Shanghai, China). The date of last follow-up was February 2010. The expressions of Thl cytokines mRNA was detected in tumor tissues from 58 patients with gastric cancer by real-time polymerase chain reaction (RT-PCR) method. Prognostic effects of Thl cytokines were evaluated by Cox regression and Kaplan-Meier analysis using median values as cutoff.
At last follow-up,13 patients (22.4%) studied had died, all of whom died from the recurrence of gastric cancer. The median duration of follow-up were 30.5 months (range,1.0-43.0). The overall survival (OS) rates were 84.5% for 1 year,80.6% for 2 years, respectively, for the whole study. The mRNA expressions of GNLY, GZMB and IFNG are associated with tumor emboli. The mRNA expressions of TRAV10, IRF1, TBX21, CD3Z, GZMB, GATA3 and IFNG are not associated with OS. In the tumor sites, the lower mRNA expression of GNLY is associated with worse OS (Urivariate analysis HR 0.23, p=0.022), however, it is not an independent predictor. At the same time, the combination of mRNA expressions of eight cytokines is an independent factor for OS (Urivariate analysis HR 0.23,p=0.001; Mutlivariate analysis HR 0.17,p=0.05).1-year and 2-year OS rates were 98%,89.8% for the group with high mRNA expression of eight cytokines, compared with 66.7%,55.6% for the group with low mRNA expression (Logrank-testp<0.001).
1. The mRNA expression of GNLY is associated with OS, but it is not an independent factor.
2. The combination of mRNA expressions of the eight cytokines is an independent factor for OS.
3. The mRNA expression of GNLY, GZMB and IFNG is separately negatively correlated with tumor emboli.
引文
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[3]. Agnello D, Lankford CS, Bream J, et al. Cytokines and transcription factors that regulate T helper cell differentiation:new players and new insights [J]. J Clin Immunol 2003;23:147-61.
[4]. Pages F, Berger A, Camus M, et al. Effector memory T cells, early metastasis, and survival in colorectal cancer [J]. N Engl J Med 2005;353:2654-66.
[5]. Galon J, Fridman WH, Pages F. The adaptive immunologic microenvironment in colorectal cancer:a novel perspective [J]. Cancer Res 2007;67:1883-6.
[6]. Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection and immunosubversion [J]. Nat Rev Immunol 2006;6:715-27.
[7]. Restifo NP, Marincola FM, Kawakami Y, Taubenberger J, Yannelli JR, Rosenberg SA. Loss of functional beta 2-microglobulin in metastatic melanomas from five patients receiving immunotherapy [J]. J Natl Cancer Inst 1996;88:100-8.
[8]. Khong HT, Restifo NP. Natural selection of tumor variants in the generation of "tumor escape" phenotypes [J]. Nat Immunol 2002;3:999-1005.
[9]. Mantovani A, Romero P, Palucka AK, Marincola FM. Tumour immunity:effector response to tumour and role of the microenvironment [J]. Lancet 2008;371:771-83.
[10]. Krensky AM, Clayberger C. Granulysin:a novel host defense molecule [J]. Am J Transplant 2005;5:1789-92.
[11]. Andersen P, Pedersen MW, Woetmann A, et al. EGFR induces expression of IRF-1 via STAT1 and STAT3 activation leading to growth arrest of human cancer cells [J]. Int J Cancer 2008;122:342-9.
[12]. Moriyama Y, Nishiguchi S, Tamori A, et al. Tumor-suppressor effect of interferon regulatory factor-1 in human hepatocellular carcinoma [J]. Clin Cancer Res 2001;7:1293-8.
[13]. Ho IC, Pai SY. GATA-3-not just for Th2 cells anymore [J]. Cell Mol Immunol 2007;4:15-29.
[14]. Kouros-Mehr H, Bechis SK, Slorach EM, et al. GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model [J]. Cancer Cell 2008;13:141-52.
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