Shh蛋白水平与肺腺癌临床特征及预后的关系

Correlation Between Shh Protein Expression and Clinical Features and Prognosis of Lung Adenocarcinoma

目的分析肺腺癌患者肺组织内音猬因子(Sonic Hedgehog,Shh)蛋白表达情况及其与患者临床特征和预后的关系。方法收集2010年3月至2015年9月期间于华中科技大学同济医学院附属同济医院行肺腺癌切除术的235例患者基本信息、切除的肺组织样本及肿瘤病理资料。采用组织芯片和免疫组织化学法测定Shh蛋白在肺癌及癌旁组织中的表达情况,运用Wilcoxon秩和检验分析Shh蛋白在肺癌组织及癌旁组织的表达差异,多元Logistic回归和Cox比例风险回归模型分析其与患者临床病理特征及预后的关联。结果肺腺癌组织中Shh蛋白表达水平明显高于癌旁组织(P<0.01)。肺腺癌与癌旁组织中Shh蛋白表达量的差值(癌/癌旁Shh蛋白表达量差值)和肿瘤大小显著负相关,癌/癌旁Shh蛋白IOD/Area差值、阳性细胞率差值及染色强度评分差值每增加1个单位,肿瘤发展为>7 cm的风险分别降低43%、4%和46%,其OR及95%CI分别为0.57(0.35,0.94)、0.96(0.94,0.99)和0.54(0.35,0.86);随着癌/癌旁Shh蛋白阳性细胞率差值的增加,肺腺癌患者肿瘤大小发展为>7 cm的风险逐渐降低(P趋势=0.011)。Cox比例风险回归模型显示,癌/癌旁Shh蛋白IOD/Area差值每增加1个单位,肺腺癌患者术后发生死亡的风险降低14%,其风险比(HR)为0.86,95%CI:(0.74,0.99);分层分析发现在中/高分化类型肿瘤和发生远处转移的患者中,癌/癌旁Shh蛋白IOD/Area差值每增加1个单位,患者发生死亡的风险可分别降低19%和38%,其HR(95%CI)分别为0.81(0.67,0.99)和0.62(0.41,0.94)。结论肺腺癌及癌旁组织内Shh蛋白表达量的差值与肺腺癌患者肿瘤大小及术后死亡风险显著负相关,提示其可能是肺腺癌患者术后生存的保护因素,为早期评估肺腺癌患者预后提供了新思路。

Objective To analyze the expression of Sonic Hedgehog(Shh)protein in lung tissues and its association with the clinicopathologic features and prognosis of lung adenocarcinoma patients.Methods The basic information,resected lung tissue samples and tumor pathological data of 235 patients who had undergone lung adenocarcinoma resection were collected,and the expression of Shh protein in lung cancer tissues and paracancerous tissues of the patients was determined by tissue microarray and immunohistochemistry.The Wilcoxon rank-sum test was used to analyze the differences in the expression of Shh protein between lung cancerous tissues and paracancerous tissues.Multivariate logistic regression and Cox proportional risk regression models were used to analyze the association of Shh protein expression with pathological characteristics and prognosis of patients.Results The level of Shh protein in cancerous tissues of patients with lung adenocarcinoma was significantly higher than that in paracancerous tissues(P<0.01).The difference in Shh protein expression between cancerous tissues and paracancerous tissues of lung adenocarcinoma(difference in cancer/paracancer Shh protein expression)was negatively correlated with tumor size.For each unit increase in cancer/paracancer Shh protein IOD/Area difference,positive cell rate difference,and staining intensity score difference,the risks of tumor size developing larger than 7 cm were reduced by 43%,4%and 46%,and the OR and 95%CI were 0.57(0.35,0.94),0.96(0.94,0.99)and 0.54(0.35,0.86),respectively.As the difference in the rate of cancer/paracancer Shh protein-positive cells increased,the risk of tumor size developing larger than 7 cm in patients with lung adenocarcinoma was progressively reduced(P_(trend)=0.011).Cox proportional risk regression model analysis showed that for each unit increase in the difference in cancer/paracancer Shh IOD/Area value,the risk of postoperative mortality in lung adenocarcinoma patients could be reduced by 14%,with a hazard ratio(HR)and 95%CI of 0.86(0.74,0.99).Stratified analysis revealed that in patients with moderately or highly differentiated tumor cells or distant metastases,each unit increased in the cancer/paracancer Shh protein IOD/Area difference,the risks of death were reduced by 19%and 38%,respectively,with HR and 95%CI of 0.81(0.67,0.99)and 0.62(0.41,0.94),respectively.Conclusion The difference value of Shh protein expression between cancerous tissues and paracancerous tissues is negatively correlated with tumor size and risk of postoperative mortality in lung adenocarcinoma patients,suggesting that it may be a protective factor for postoperative survival,and providing a new idea for early assessment of prognosis in patients with lung adenocarcinoma.