食管鳞状细胞癌癌变过程中HPV16/18 E6蛋白与PIK3CA、PIK3CB突变的相关性及其临床意义

Correlation of HPV16/18 E6 protein with PIK3CA and PIK3CB mutations in esophageal squamous cell carcinoma and its clinical significance

目的探讨HPV感染与PIK3CA、PIK3CB突变在食管鳞状细胞癌(esophageal squamous cell carcinoma,ESCC)癌变过程中的表达差异及其临床意义。方法采用免疫组化EnVision法检测32例食管正常黏膜、35例食管低级别异型增生(low-grade intraepithelial neoplasia,LGIN)、34例食管高级别异型增生(high-grade intraepithelial neoplasia,HGIN)及137例ESCC中HPV16/18 E6蛋白、p53、PIK3CA、PIK3CB的表达,并分析蛋白表达之间的相关性及与临床病理特征的关系。结果HPV16/18 E6蛋白在食管正常黏膜组、LGIN组、HGIN组、ESCC组的阳性率分别为0、8.6%、26.5%、29.9%,HPV16/18 E6蛋白在ESCC和HGIN中的表达高于食管正常黏膜和LGIN(P<0.05);p53蛋白在食管正常黏膜组、LGIN组、HGIN组、ESCC组的阳性率分别为9.4%、28.6%、50.0%、68.6%,p53在HGIN中的表达高于食管正常黏膜(P<0.05);PIK3CA蛋白在食管正常黏膜组、LGIN组、HGIN组、ESCC组的阳性率分别为9.4%、17.1%、26.5%、25.5%;PIK3CB蛋白在食管正常黏膜组、LGIN组、HGIN组、ESCC组的阳性率分别为6.3%、14.3%、23.5%、21.9%,PIK3CA和PIK3CB蛋白在ESCC中的表达高于食管正常黏膜(P<0.05)。HPV16/18 E6蛋白表达与肿瘤发病部位、分化程度、淋巴结转移相关(P<0.05);p53表达与肿瘤浸润深度、淋巴结转移相关(P<0.05);PIK3CA、PIK3CB表达与肿瘤淋巴结转移相关(P<0.05)。ESCC组中HPV16/18 E6与p53的表达呈正相关(r=0.202,P=0.018);HPV 16/18 E6与PIK3CA在HGIN、ESCC组中的表达均呈正相关(r=0.368,P=0.021;r=0.198,P=0.018);HPV 16/18 E6与PIK3CB的表达无关(P>0.05)。HPV16/18 E6、p53、PIK3CA和淋巴结转移与ESCC预后相关,HPV16/18 E6是ESCC的良好预后因素,p53、PIK3CA和淋巴结转移是ESCC的不良预后因素。结论HPV感染与ESCC的发生密切相关,其可能通过异常激活PI3K/Akt信号通路而促进肿瘤的发生、发展,联合检测HPV16/18 E6蛋白和PIK3CA突变对ESCC的预后判断和优化治疗具有重要意义。

Purpose To investigate the difference of HPV infection and PIK3CA,PIK3CB mutation in esophageal squamous cell carcinoma and its clinical significance.Methods The expression of HPV16/18 E6 protein,p53,PIK3CA and PIK3CB in 32 cases of normal esophageal mucosa,35 cases of low-grade intraepithelial neoplasia(LGIN),34 cases of high-grade intraepithelial neoplasia(HGIN)and 137 cases of esophageal squamous cell carcinoma was detected by immunohistochemical method,and their correlations with clinicopathological factors were analyzed.Results The positive expression rates of HPV16/18 E6 protein in normal esophageal mucosa,LGIN group,HGIN group and ESCC group were 0,8.6%,26.5%and 29.9%respectively.The expression of HPV16/18 E6 protein in squamous cell carcinoma and HGIN was higher than that in normal mucosa and LGIN(P<0.05).The positive expression rates of p53 protein in normal esophageal mucosa,LGIN group,HGIN group and ESCC group were 9.4%,28.6%,50.0%and 68.6%respectively.The expression of p53 in squamous cell carcinoma was higher than that in normal mucosa and LGIN(P<0.05).The expression of p53 in HGIN was higher than that in normal esophageal mucosa group(P<0.05).The positive expression rates of PIK3CA protein in normal esophageal mucosa,LGIN group,HGIN group and ESCC group were 9.4%,17.1%,26.5%and 25.5%respectively.The positive expression rates of PIK3CB protein in normal esophageal mucosa,LGIN group,HGIN group and ESCC group were 6.3%,14.3%,23.5%and 21.9%respectively.The expression rates of PIK3CA and PIK3CB protein in squamous cell carcinoma were higher than those in normal mucosa(P<0.05).In squamous cell carcinoma,the expression of HPV16/18 E6 protein was significantly correlated with tumor location,differentiation and lymph node metastasis.p53 was significantly correlated with tumor invasion depth and lymph node metastasis.PIK3CA and PIK3CB were significantly correlated with lymph node metastasis(P<0.05).The expression of HPV16/18 E6 was positively correlated with that of p53(r=0.202,P=0.018).The expression of HPV16/18 E6 and PIK3CA was positively correlated in esophageal high-grade dysplasia group and canceration group(r=0.368,P=0.021 and r=0.198,P=0.018).There was no significant correlation between HPV16/18 E6 and PIK3CB expression(P>0.05).HPV16/18 E6,p53,PIK3CA and lymph node metastasis were associated with the prognosis of esophageal cancer.HPV16/18 E6 was a good prognostic factor of esophageal cancer,while p53,PIK3CA and lymph node metastasis were poor prognostic factors of esophageal cancer.Conclusion HPV infection is closely related to the occurrence of esophageal squamous cell carcinoma,which may promote the occurrence and development of esophageal squamous cell carcinoma through abnormal activation of PI3K/Akt signaling pathway.Combined detection of HPV16/18 E6 protein and PIK3CA mutation is of great significance for prognosis judgment and optimal treatment of esophageal squamous cell carcinoma.