免疫因子表达异常促进宫颈癌微环境免疫失衡

Aberrant Expressions of Immune Factors Facilitate the Disequilibrium of Immune Status in Cervical Cancer

目的评估叉头蛋白3(Fox P3)、趋化因子配体22(CCL22)、肿瘤坏死因子受体超家族成员40(OX40)和SMAD家族成员3(Smad3)在宫颈癌免疫微环境中的调节作用和对肿瘤发生的影响。方法采用qRT-PCR方法检测宫颈癌癌灶、癌旁和正常宫颈组织中Fox P3、CCL22、OX40和Smad3的mRNA表达水平。结果与正常宫颈组织相比,Fox P3和CCL22 mRNA在癌灶(P=0.000,P=0.002)和癌旁(P=0.048,P=0.040)的表达显著升高,两者在高级别鳞癌癌灶(P=0.019,P=0.020)和癌旁(P=0.023,P=0.031)中的表达明显高于低级别鳞癌。OX40和Smad3的mRNA在癌灶中的表达明显低于正常宫颈(P=0.000,P=0.015),两者在高级别鳞癌癌灶(P=0.018,P=0.030)和癌旁(P=0.027,P=0.014)中的表达明显低于低级别鳞癌。在宫颈癌灶和癌旁中,OX40 mRNA与Smad3 mRNA(r=0.384,P=0.002;r=0.288,P=0.023)、Fox P3 mRNA与CCL22 mRNA均呈正相关(r=0.353,P=0.000;r=0.307,P=0.000),CCL22 mRNA与OX40 mRNA呈负相关(r=-0.288,P=0.031;r=-0.263,P=0.037)。Fox P3和CCL22mRNA在HPV阳性的宫颈癌灶(P=0.024,P=0.039)和癌旁(P=0.032,P=0.034)中的表达明显高于阴性组,Smad3在HPV阳性宫颈癌灶中的表达明显低于HPV阴性组(P=0.017)。结论在宫颈癌发生的微环境中,存在免疫因子Fox P3、CCL22、OX40和Smad3的转录表达异常,这种表达偏移可能导致宫颈癌局部OX40和Smad3的正性调节被削弱,而Fox P3和CCL22的免疫抑制作用增强的免疫模式,共同参与促成局部免疫失衡和肿瘤的发生。

Objective To explore the expressions and co-relationship of immune factors forkhead box p3（ Fox P3）,chemokine（ C-C motif） ligand 22（ CCL22）,tumor necrosis factor receptor superfamily member40（ OX40）,and SMAD family member 3（ Smad3） in cervical carcinoma and investigate their immunomodulatory roles in cervical carcinogenesis.Methods Totally 30 cases of cervical carcinoma with adjacent tissues and20 cases of normal cervix were collected in this study.Fox P3,CCL22,OX40,and Smad3 mRNA expressions were detected by real-time polymerase chain reaction（ RT-PCR）.Results Compared to normal cervix,the expression levels of Fox P3 and CCL22 mRNA were elevated in neoplastic foci（ P = 0.000,P = 0.002） and tumor periphery（ P = 0.048,P = 0.040）.The mRNAs increased modestly in high-grade squamous cell carcinoma focal（ P = 0.019,P = 0.020） and periphery tissue（ P = 0.023,P = 0.031） in comparison with low-grade squamous cell carcinoma.The expression levels of OX40 and Smad3 mRNA were significantly lower in neoplastic foci（ P = 0.000,P = 0.015） than normal cervix.Compared to low-grade squamous cell carcinoma focal and periphery tissue,the mRNAs decreased moderately in high-grade squamous cell carcinoma（ P = 0.018, P =0.030; P = 0.027,P = 0.014）.In both neoplastic foci and tumor periphery,the mRNA expression level of CCL22 was positively correlated with Fox P3（ r = 0.353,P = 0.000; r = 0.307,P = 0.000） but negatively correlated with OX40（ r =-0.288,P = 0.031; r =-0.263,P = 0.037）,while OX40 was positively correlated with Smad3（ r = 0.384,P = 0.002; r = 0.288,P = 0.023）.The mRNA expressions of Fox P3 and CCL22 were increased in foci and pericarcinous tissues（ P = 0.024,P = 0.039; P = 0.032,P = 0.034） while Smad3 was decreased in neoplastic foci（ P = 0.017） in contrast to HPV negative corresponding group.Conclusion Fox P3 and CCL22 expressions increase while OX40 and Smad3 expression decrease at mRNA level in the microenvironment of cervical cancer,which may be associated with such immunological model that the immunosuppressive roles of Fox P3 and CCL22 enhance while the immunity-boosting roles of OX40 and Smad3 are impeded,contributing to the deterioration of immune disequilibrium in local site and cervical cancer carcinogenesis.