子宫内膜癌中p-AKT与PTEN、P53、HER-2表达的相关性及意义

目的:探讨磷酸化蛋白激酶B(phosphorylated protein kinase B,p-AKT)、磷酸酶与张力蛋白同源物(phos-phatase and tensin homolog,PTEN)、P53、人表皮生长因子受体2(human epidermal growth factor receptor 2,HER-2)在子宫内膜癌组织中的表达变化特点、相关性及意义。方法:免疫组织化学法检测p-AKT及PTEN、P53、HER-2、Ki67在95例内膜癌组织中的表达并与临床病理特点及预后相对照。结果:(1)本组95例子宫内膜癌p-AKT阳性率为53.7%(51/95),Ⅰ型癌(53.6%)与Ⅱ型癌(54.5%)的表达率近似;p-AKT阳性与阴性组间预后差异无统计学意义(P=0.757)。(2)PTEN失表达率为56.8%(54/95),在Ⅰ型癌(60.7%,51/84)与Ⅱ型癌(27.3%,3/11)差异具有统计学意义(P=0.035);PTEN失表达组的预后显著优于正常表达组(P=0.015)。(3)p-AKT与PTEN表达无显著相关性(P=0.265),但分组分析显示p-AKT阳性时,PTEN失表达组与正常组间的预后差异失去统计学意义(P=0.148),而p-AKT阴性时,PTEN失表达组生存期较PTEN正常表达组长(P=0.055)。同时,p-AKT阳性与PTEN失表达对肿瘤增殖活性可能有协同促进作用:PTEN+/p-AKT+时的Ki67阳性率最高(40.0%),PTEN-/p-AKT-时的Ki67阳性率最低(8.7%),差异有统计学意义(P=0.015)。(4)p-AKT表达与P53、HER-2阳性亦未见相关性(P0.05),Ⅱ型癌P53、HER-2阳性表达(100.0%,45.5%)显著高于Ⅰ型癌(42.9%,6.0%)(P0.05),阳性者预后差,且两者表达正相关(r=0.209,P=0.041)。结论:p-AKT在两型内膜癌中均有较高比例的活化,p-AKT阳性表达可能削弱PTEN失表达对内膜癌生物学行为相对善良的提示作用,p-AKT+与PTEN+对肿瘤增殖活性可能有协同促进作用;p-AKT活化与Ⅰ、Ⅱ型内膜癌常见的分子异常(PTEN失表达、P53和HER-2表达)均无相关性,可能更多取决于其他因素的调节。以p-AKT为靶点的生物治疗在进展期内膜癌中的治疗价值值得进一步深入研究。

Correlations of p-AKT with PTEN, P53, HER-2 expressions in endometrial carcinoma and their relationship with patient survival

Objective: To investigate the correlation of phosphorylated protein kinase B(p-AKT) with phosphatase and tensin homolog(PTEN),P53,human epidermal growth factor receptor 2(HER-2) expressions in endometrial carcinoma and their significance.Methods: The expressions of p-AKT with PTEN,HER-2,P53 and Ki67 were assessed in 95 endometrial carcinomas using immunohistochemistry.The biomarker expressions correlated with clinicopathologic variables and with patient survival.Results:(1) p-AKT was positive in 53.7%(51/95) of tumors and was found to express almost similarly in endometrioid adenocarcinoma(EC) and non-enometrioid adenocarcinoma(NEC).There was no significant difference of patient survival between p-AKT positive and negative subgroups(P=0.757).(2) PTEN loss was found in 56.8%(54/95) of tumors,and occurred more often in EC(60.7%,51/84) than in NEC(27.3%,3/11),which was of statistical significance(P=0.035).The patients with PTEN loss had a longer survival than those without(P=0.015).(3) Although there was no significant correlation between p-AKT and PTEN expression,the extended analysis showed that the predictive value of PTEN loss in p-AKT positive subgroup(P=0.148) was lower than that in p-AKT negative expression subgroup(P=0.055).Meanwhile p-AKT positive and PTEN loss might have synergic effect on tumor proliferation,Ki67 positive rate was highest in PTEN+/p-AKT+ subgroup(40.0%) and lowest in PTEN-/p-AKT-subgroup(8.7%),which was of significant difference(P=0.015).(4) No correlation was found between p-AKT expression and P53 or HER-2 status(P>0.05).On the other hand,HER-2 and P53 positive correlated significantly(r=0.209,P=0.041) and occurred more frequently in NEC(45.5%,100.0%) than in EC(6.0%,42.9%)(P <0.05),which were found to predict poor survival(P<0.05).Conclusion: p-AKT was activated equally in EC and NEC.p-AKT positive alone might have limited effect on patient survival,however,p-AKT expression might lower the predictive value of PTEN loss in endometrial carcinoma.Moreover,p-AKT positive and PTEN loss might have synergic effect on tumor proliferation.On the other hand,as p-AKT expression did not have any correlations with PTEN,P53 and HER-2 status in this cohort,there might be other important factors involved in p-AKT activation in endometrial carcinoma.In sum,further investigation should be conducted in the targeted therapy based on p-AKT and associated molecular mechanism in advanced endometrial carcinoma.