脂联素分子受体3在转化生长因子-β介导的食管-胃交界腺癌发生和转移中的临床意义

Clinical significance of progestin and adipo Q receptor 3 in transforming growth factor-mediated tumorigenesis and metastasis of esophageal-gastric junction adenocarcinoma

目的观察脂联素分子受体3(PAQR3)在食管-胃交界腺癌组织中的表达并探讨其临床意义,特别是PAQR3表达水平与转化生长因子-β(TGF-β)通路介导肿瘤转移的相关性。方法采用免疫组织化学检测180例食管-胃交界腺癌(SiewertⅡ型)手术组织标本中肿瘤组织及配对的癌旁正常组织中PAQR3、TGF-β、p-Smad2、p-Smad3、p53、细胞核增殖抗原(Ki-67)及上皮-间充质转化(EMT)相关蛋白表达水平;分析PAQR3表达与患者临床病理特征和预后的关系,探讨PAQR3表达与TGF-β通路、EMT过程之间的相关性。组间比较采用单因素方差分析。结果78.3%(141/180)食管-胃交界腺癌组织的PAQR3蛋白呈低水平表达,显著低于癌旁正常胃组织(1.1%,2/180)。癌组织中PAQR3表达水平与幽门螺杆菌感染(χ^(2)=73.383,P<0.01)、肿瘤大小(χ^(2)=51.207,P<0.01)、肿瘤分化(χ^(2)=82.303,P<0.01)、静脉浸润(χ^(2)=7.639,P<0.01)、神经侵犯(χ^(2)=19.047,P<0.01)、浸润深度(χ^(2)=14.572,P<0.01)、淋巴结转移(χ^(2)=20.531,P<0.01)、远处转移(χ^(2)=49.787,P<0.01)及TNM分期(χ^(2)=147.120,P<0.01)均呈明显负相关;而与性别(χ^(2)=1.326,P>0.05)、肿瘤诊断时年龄(χ^(2)=0.815,P>0.05)均无相关。癌组织中PAQR3低表达患者的平均总生存时间显著短于PAQR3正常或高表达患者,两者差异有统计学意义(χ^(2)=34.587,P<0.01)。癌组织中PAQR3蛋白低表达与TGF-β蛋白上调(r=-0.768,P<0.01)、p-Smad2蛋白上调(r=-0.771,P<0.01)、p-Smad3蛋白上调(r=-0.774,P<0.01)、波形蛋白(Vimentin)蛋白上调(r=-0.946,P<0.01)、Twist蛋白上调(r=-0.966,P<0.01)、Snail蛋白上调(r=-0.931,P<0.01)及SIP1蛋白上调(r=-0.932,P<0.01)呈明显负相关,与E-钙黏蛋白(E-cadherin)蛋白下调呈明显正相关(r=0.875,P<0.01)。结论食管-胃交界腺癌组织中PAQR3蛋白低表达与TGF-β信号通路及EMT激活密切相关,提示PAQR3下调可能是食管-胃交界腺癌转移发生的起始因素,机制上是通过TGF-β/Smad信号通路来实现。

Objective To investigate the expression of progestin and adipo Q receptor 3(PAQR3)in esophageal-gastric junction adenocarcinoma(EJA)tissues and the clinical significance,especially the correlation between PAQR3 expression levels and the tumor metastasis mediated by transforming growth factor(TGF)-βpathway.Methods The expression levels of PAQR3,TGF-β,p-Smad2,p-Smad3,p53,proliferation cell nuclear antigen(Ki-67)and epithelial-mesenchymal transition(EMT)-related proteins in tumor tissues and paired adjacent normal tissues of 180 EJA(type SiewertⅡ)patients were detected by immunohistochemistry.The relationship between PAQR3 expression and the clinicopathological characteristics and prognosis of the patients were studied,and the correlation between PAQR3 expression and TGF-βand EMT process was analyzed.Statistical analysis was performed using SPSS 19.0 statistical software,and the inter-group comparisons were performed using a one-way ANOVA.Results The low expression of PAQR3 protein was found in 78.3%(141/180)EJA tissues,significantly higher than that in paired adjacent normal tissues(1.1%,2/180).PAQR3 expression levels in cancer tissues was significantly negatively associated with helicobacter pylori infection(χ^(2)=73.383,P<0.01),tumor size(χ^(2)=51.207,P<0.01),tumor differentiation(χ^(2)=82.303,P<0.01),venous invasion(χ^(2)=7.639,P<0.01),neural invasion(χ^(2)=19.047,P<0.01),infiltration depth(χ^(2)=14.572,P<0.01),lymph node metastasis(χ^(2)=20.531,P<0.01),distant metastasis(χ^(2)=49.787,P<0.01),and TNM stage(χ^(2)=147.120,P<0.01);but not with sex(χ^(2)=1.326,P>0.05),age at tumor diagnosis(χ^(2)=0.815,P>0.05).The mean overall survival(OS)was significantly lower in EJA patients with low PAQR3 expression in cancer tissues than in those with normal or high PAQR3 expression,and the differences were statistically significant(χ^(2)=34.587,P<0.01).The expression level of PAQR3 protein in EJA tissues was negatively correlated with TGF-βexpression(r=-0.768,P<0.01),p-Smad2 expression(r=-0.771,P<0.01),p-Smad3 expression(r=-0.774,P<0.01),Vimentin expression(r=-0.946,P<0.01),Twist expression(r=-0.966,P<0.01),Snail expression(r=-0.931,P<0.01)and SIP1 expression(r=-0.932,P<0.01).However,a significantly positive correlation between PAQR3 protein expression levels and E-cadherin protein expression level in EJA tissues was found(r=0.875,P<0.01).Conclusion The low expression of PAQR3 protein in EJA tissues is closely related with TGF-βsignaling and EMT activation,suggesting that PAQR3 downregulation may be the initiation factor of EJA metastasis,mechanistically through the TGF-β/Smad signaling pathway.