KISS1蛋白在转移性胃癌中的表达及其与患者临床特征和预后的关系
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摘要
目的探讨KISS1蛋白在转移性胃癌(MGC)中的表达及其与患者临床特征和预后的关系。方法收集63例MGC患者手术切除的胃癌组织及其中50例癌旁组织(距离阴性切缘>5 cm)标本,另收集同期60例非转移性胃癌(NMGC)患者手术切除的胃癌组织标本,采用免疫组织化学方法检测KISS1蛋白的表达情况。结果KISS1蛋白表达于肿瘤细胞的细胞质中,其在MGC、NMGC及癌旁组织中的阳性表达率分别为23.8%(15/63)、43.3%(26/60)和82.0%(41/50),三者比较,差异有统计学意义(χ2=38.468,P﹤0.05)。其中,MGC组织和NMGC组织中KISS1蛋白的阳性表达率均低于癌旁组织(P﹤0.05);MGC组织和NMGC组织中KISS1蛋白的阳性表达率比较,差异无统计学意义(P﹥0.05)。MGC组织中KISS1蛋白的阳性表达率与胃癌大体类型、有无脉管癌栓及浸润深度有关(P﹤0.05)。63例MGC患者均获得术后随访,MGC患者的生存时间为4~27个月,中位总生存时间为8个月,1年生存率为25.4%(16/63)。其中,KISS1蛋白阳性表达MGC患者的中位生存时间为13个月,1年生存率为53.3%(8/15);KISS1蛋白阴性表达MGC患者的中位生存时间为8个月,1年生存率为16.7%(8/48);两者的总体生存情况比较,差异有统计学意义(χ2=6.290,P=0.012)。Cox比例风险回归模型分析显示,KISS1蛋白阳性表达是影响MGC患者生存的独立预后因素(HR:0.442,95%CI:0.239~0.818,P=0.009)。KISS1蛋白阳性表达NMGC患者的中位无瘤生存时间为27个月,1、2、3年无瘤生存率分别为95.7%、60.3%及43.5%;KISS1蛋白阴性表达NMGC患者的中位无瘤生存时间为16个月,1、2、3年无瘤生存率分别为70.4%、20.8%及15.6%;两者的总体无瘤生存情况比较,差异有统计学意义(χ2=12.176,P﹤0.01)。结论 KISS1蛋白在MGC患者的胃癌组织中低表达,与胃癌侵袭、转移及预后密切相关,NMGC患者中KISS1蛋白阴性表达者无瘤生存期短,KISS1蛋白有望成为预测预后的标志物。
Objective To investigate the expression of KISS1 in patients with metastatic gastric cancer(MGC) and its association with clinical features and prognosis. Method The specimens of surgical resection of MGC tissues from63 patients with MGC and 50 adjacent normal tissues(distance from resection margin>5 cm) among these 63 patients,and 60 specimens of non-metastatic gastric cancer(NMGC) tissues from 60 patients with NMGC were collected. Expressions of KISS1 protein were detected by immunohistochemistry. Result Expression of KISS1 protein was located in the cytoplasm of tumor tissue cells. The positive expression rates of KISS1 protein in MGC, NMGC tissues and adjacent normal tissues were 23.8%(15/63), 43.3%(26/60) and 82.0%(41/50), respectively, the difference was statistically significant(χ2=38.468, P<0.05). The positive expression rates of KISS1 protein in MGC and NMGC tissues were significantly lower than that in adjacent normal tissues(P<0.05); however, there was no statistical difference in positive expression rate of KISS1 protein between MGC and NMGC tissues(P>0.05). The positive expression rate of KISS1 protein was significantly related to general type, vascular thrombosis and the depth of invasion(P<0.05). All 63 patients with MGC were followed up, the range of survival time was 4 to 27 months, the median overall survival time was 8 months, 1-year survival rate was 25.4%(16/63). In MGC patients with positive expression of KISS1 protein, median survival time was13 months, 1-year survival rate was 53.3%(8/15); and in MGC patients with negative expression of KISS1 protein, median survival time was 8 months, 1-year survival rate was 16.7%(8/48); there was significant differences in the overall survival(χ2=6.290, P=0.012). Cox regression analysis showed that positive KISS1 protein expression was independent prognostic factors of MGC(HR: 0.442, 95%CI: 0.239-0.818, P=0.009). In NMGC patients with positive expression of KISS1 protein, median tumor-free survival time was 27 months; 1-, 2-and 3-year tumor-free survival rates were 95.7%,60.3% and 43.5%, respectively. In NMGC patients with negative expression of KISS1 protein, median tumor-free survival time was 16 months; 1-, 2-and 3-year tumor-free survival rates were 70.4%, 20.8% and 15.6%, respectively; there was significant difference in the tumor-free survival(χ2=12.176, P<0.01). Conclusion The reduced expression of KISS1 protein in gastric cancer tissue is closely associated with invasion, metastasis and poor prognosis of MGC patients, also closely associated with short tumor-free survival in NMGC patients. Expression of KISSl protein is expected to become a marker for predicting the prognosis of patients with gastric cancer.
Objective To investigate the expression of KISS1 in patients with metastatic gastric cancer(MGC) and its association with clinical features and prognosis. Method The specimens of surgical resection of MGC tissues from63 patients with MGC and 50 adjacent normal tissues(distance from resection margin>5 cm) among these 63 patients,and 60 specimens of non-metastatic gastric cancer(NMGC) tissues from 60 patients with NMGC were collected. Expressions of KISS1 protein were detected by immunohistochemistry. Result Expression of KISS1 protein was located in the cytoplasm of tumor tissue cells. The positive expression rates of KISS1 protein in MGC, NMGC tissues and adjacent normal tissues were 23.8%(15/63), 43.3%(26/60) and 82.0%(41/50), respectively, the difference was statistically significant(χ2=38.468, P<0.05). The positive expression rates of KISS1 protein in MGC and NMGC tissues were significantly lower than that in adjacent normal tissues(P<0.05); however, there was no statistical difference in positive expression rate of KISS1 protein between MGC and NMGC tissues(P>0.05). The positive expression rate of KISS1 protein was significantly related to general type, vascular thrombosis and the depth of invasion(P<0.05). All 63 patients with MGC were followed up, the range of survival time was 4 to 27 months, the median overall survival time was 8 months, 1-year survival rate was 25.4%(16/63). In MGC patients with positive expression of KISS1 protein, median survival time was13 months, 1-year survival rate was 53.3%(8/15); and in MGC patients with negative expression of KISS1 protein, median survival time was 8 months, 1-year survival rate was 16.7%(8/48); there was significant differences in the overall survival(χ2=6.290, P=0.012). Cox regression analysis showed that positive KISS1 protein expression was independent prognostic factors of MGC(HR: 0.442, 95%CI: 0.239-0.818, P=0.009). In NMGC patients with positive expression of KISS1 protein, median tumor-free survival time was 27 months; 1-, 2-and 3-year tumor-free survival rates were 95.7%,60.3% and 43.5%, respectively. In NMGC patients with negative expression of KISS1 protein, median tumor-free survival time was 16 months; 1-, 2-and 3-year tumor-free survival rates were 70.4%, 20.8% and 15.6%, respectively; there was significant difference in the tumor-free survival(χ2=12.176, P<0.01). Conclusion The reduced expression of KISS1 protein in gastric cancer tissue is closely associated with invasion, metastasis and poor prognosis of MGC patients, also closely associated with short tumor-free survival in NMGC patients. Expression of KISSl protein is expected to become a marker for predicting the prognosis of patients with gastric cancer.
引文
[1]Dassen AE,Lemmens VE,van de Poll-Franse LV,et al.Trends in incidence,treatment and survival of gastric adenocarcinoma between 1990 and 2007:a population-based study in the Netherlands[J].Eur J Cancer,2010,46(6):1101-1110.
[2]Yamada Y,Higuchi K,Nishikawa K,et al.Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naive patients with advanced gastric cancer[J].Ann Oncol,2015,26(1):141-148.
[3]Chang YR,Han DS,Kong SH,et al.The value of palliative gastrectomy in gastric cancer with distant metastasis[J].Ann Surg Oncol,2012,19(4):1231-1239.
[4]Wang W,Yang ZL,Liu JQ,et al.Overexpression of MTA1and loss of KAI-1 and Ki SS-1 expressions are associated with invasion,metastasis,and poor-prognosis of gallbladder adenocarcinoma[J].Tumori,2014,100(6):667-674.
[5]Pinilla L,Castellano JM,Romero M,et al.Delayed puberty in spontaneously hypertensive rats involves a primary ovarian failure independent of the hypothalamic Ki SS-1/GPR54/Gn RH system[J].Endocrinology,2009,150(6):2889-2897.
[6]Lee JH,Welch DR.Suppression of metastasis in human breast carcinoma MDA-MB-435 cells after transfection with the metastasis suppressor gene,Ki SS-1[J].Cancer Res,1997,57(12):2384-2387.
[7]Shahed A,Young KA.Differential ovarian expression of Ki SS-1 and GPR-54 during the estrous cycle and photoperiod induced recrudescence in Siberian hamsters(Phodopus sungorus)[J].Mol Reprod Dev,2009,76(5):444-452.
[8]Lee JH,Miele ME,Hicks DJ,et al.Ki SS-1,a novel human malignant melanoma metastasis-suppressor gene[J].J Natl Cancer Inst,1996,88(23):1731-1737.
[9]Wu S,Yu L,Wang D,et al.Aberrant expression of CD133in non-small cell lung cancer and its relationship to vasculogenic mimicry[J].BMC Cancer,2012,12:535.
[10]Pentheroudakis G,Kostadima L,Dova L,et al.A twisted kiss:in vitro and in vivo evidence of genetic variation and suppressed transcription of the metastasis-suppressor gene Ki SS1 in early breast cancer[J].Neoplasma,2010,57(1):47-54.
[11]Kostadima L,Pentheroudakis G,Pavlidis N.The missing kiss of life:transcriptional activity of the metastasis suppressor gene Ki SS1 in early breast cancer[J].Anticancer Res,2007,27(4B):2499-2504.
[12]Chen SQ,Chen ZH,Lin SY,et al.KISS1 methylation and expression as predictors of disease progression in colorectal cancer patients[J].World J Gastroenterol,2014,20(29):10071-10081.
[13]Navenot JM,Fujii N,Peiper SC.Ki SS1 metastasis suppressor gene product induces suppression of tyrosine kinase receptor signaling to Akt,tumor necrosis factor family ligand expression,and apoptosis[J].Mol Pharmacol,2009,75(5):1074-1083.
[14]Ji K,Ye L,Mason MD,et al.The Kiss-1/Kiss-1R complex as a negative regulator of cell motility and cancer metastasis(Review)[J].Int J Mol Med,2013,32(4):747-754.
[15]Makri A,Pissimissis N,Lembessis P,et al.The kisspeptin(Ki SS-1)/GPR54 system in cancer biology[J].Cancer Treat Rev,2008,34(8):682-692.
[16]周蕾,胡永莲,武世伍,等.Slug、ZEB1和KISS-1在胃腺癌中的表达及其临床意义[J].南方医科大学学报,2016,36(4):532-537.
[17]Guan-Zhen Y,Ying C,Can-Rong N,et al.Reduced protein expression of metastasis-related genes(nm23,KISS1,KAI1 and p53)in lymph node and liver metastases of gastric cancer[J].Int J Exp Pathol,2007,88(3):175-183.
[18]崔广飞,高凌.胃癌组织中Ki SS-1 m RNA及蛋白的表达[J].中国医学工程,2011,19(6):20-21;25.
[19]Dhar DK,Naora H,Kubota H,et al.Downregulation of Ki SS-1 expression is responsible for tumor invasion and worse prognosis in gastric carcinoma[J].Int J Cancer,2004,111(6):868-872.
[20]惠菲菲,刘凯,杨家和,等.同时性结直肠癌肝转移结直肠癌组织中Kiss-1蛋白和基质金属蛋白酶9蛋白的表达及意义[J].中华消化外科杂志,2016,15(2):153-160.
[21]Wang H,Jones J,Turner T,et al.Clinical and biological significance of KISS1 expression in prostate cancer[J].Am J Pathol,2012,180(3):1170-1178.
[22]Ulasov IV,Kaverina NV,Pytel P,et al.Clinical significance of KISS1 protein expression for brain invasion and metastasis[J].Cancer,2012,118(8):2096-2105.
[2]Yamada Y,Higuchi K,Nishikawa K,et al.Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naive patients with advanced gastric cancer[J].Ann Oncol,2015,26(1):141-148.
[3]Chang YR,Han DS,Kong SH,et al.The value of palliative gastrectomy in gastric cancer with distant metastasis[J].Ann Surg Oncol,2012,19(4):1231-1239.
[4]Wang W,Yang ZL,Liu JQ,et al.Overexpression of MTA1and loss of KAI-1 and Ki SS-1 expressions are associated with invasion,metastasis,and poor-prognosis of gallbladder adenocarcinoma[J].Tumori,2014,100(6):667-674.
[5]Pinilla L,Castellano JM,Romero M,et al.Delayed puberty in spontaneously hypertensive rats involves a primary ovarian failure independent of the hypothalamic Ki SS-1/GPR54/Gn RH system[J].Endocrinology,2009,150(6):2889-2897.
[6]Lee JH,Welch DR.Suppression of metastasis in human breast carcinoma MDA-MB-435 cells after transfection with the metastasis suppressor gene,Ki SS-1[J].Cancer Res,1997,57(12):2384-2387.
[7]Shahed A,Young KA.Differential ovarian expression of Ki SS-1 and GPR-54 during the estrous cycle and photoperiod induced recrudescence in Siberian hamsters(Phodopus sungorus)[J].Mol Reprod Dev,2009,76(5):444-452.
[8]Lee JH,Miele ME,Hicks DJ,et al.Ki SS-1,a novel human malignant melanoma metastasis-suppressor gene[J].J Natl Cancer Inst,1996,88(23):1731-1737.
[9]Wu S,Yu L,Wang D,et al.Aberrant expression of CD133in non-small cell lung cancer and its relationship to vasculogenic mimicry[J].BMC Cancer,2012,12:535.
[10]Pentheroudakis G,Kostadima L,Dova L,et al.A twisted kiss:in vitro and in vivo evidence of genetic variation and suppressed transcription of the metastasis-suppressor gene Ki SS1 in early breast cancer[J].Neoplasma,2010,57(1):47-54.
[11]Kostadima L,Pentheroudakis G,Pavlidis N.The missing kiss of life:transcriptional activity of the metastasis suppressor gene Ki SS1 in early breast cancer[J].Anticancer Res,2007,27(4B):2499-2504.
[12]Chen SQ,Chen ZH,Lin SY,et al.KISS1 methylation and expression as predictors of disease progression in colorectal cancer patients[J].World J Gastroenterol,2014,20(29):10071-10081.
[13]Navenot JM,Fujii N,Peiper SC.Ki SS1 metastasis suppressor gene product induces suppression of tyrosine kinase receptor signaling to Akt,tumor necrosis factor family ligand expression,and apoptosis[J].Mol Pharmacol,2009,75(5):1074-1083.
[14]Ji K,Ye L,Mason MD,et al.The Kiss-1/Kiss-1R complex as a negative regulator of cell motility and cancer metastasis(Review)[J].Int J Mol Med,2013,32(4):747-754.
[15]Makri A,Pissimissis N,Lembessis P,et al.The kisspeptin(Ki SS-1)/GPR54 system in cancer biology[J].Cancer Treat Rev,2008,34(8):682-692.
[16]周蕾,胡永莲,武世伍,等.Slug、ZEB1和KISS-1在胃腺癌中的表达及其临床意义[J].南方医科大学学报,2016,36(4):532-537.
[17]Guan-Zhen Y,Ying C,Can-Rong N,et al.Reduced protein expression of metastasis-related genes(nm23,KISS1,KAI1 and p53)in lymph node and liver metastases of gastric cancer[J].Int J Exp Pathol,2007,88(3):175-183.
[18]崔广飞,高凌.胃癌组织中Ki SS-1 m RNA及蛋白的表达[J].中国医学工程,2011,19(6):20-21;25.
[19]Dhar DK,Naora H,Kubota H,et al.Downregulation of Ki SS-1 expression is responsible for tumor invasion and worse prognosis in gastric carcinoma[J].Int J Cancer,2004,111(6):868-872.
[20]惠菲菲,刘凯,杨家和,等.同时性结直肠癌肝转移结直肠癌组织中Kiss-1蛋白和基质金属蛋白酶9蛋白的表达及意义[J].中华消化外科杂志,2016,15(2):153-160.
[21]Wang H,Jones J,Turner T,et al.Clinical and biological significance of KISS1 expression in prostate cancer[J].Am J Pathol,2012,180(3):1170-1178.
[22]Ulasov IV,Kaverina NV,Pytel P,et al.Clinical significance of KISS1 protein expression for brain invasion and metastasis[J].Cancer,2012,118(8):2096-2105.