子宫颈癌中Hedgehog信号通路蛋白表达与人乳头状瘤病毒16型感染的关系

目的 探讨Hedgehog(Hh)信号通路蛋白在宫颈癌及其癌前病变中的临床病理学意义,并分析其与人乳头状瘤病毒(HPV)16型感染的关系.方法 32例正常宫颈上皮、71例宫颈上皮内瘤变(CIN;CIN Ⅰ 28例,CIN Ⅱ 18例,CIN Ⅲ25例)和80例宫颈鳞状细胞癌共183例选自延边大学医院、延边妇幼保健院和延边肿瘤医院病理科存档蜡块.应用PCR技术检测上述组织中HPV16型的感染情况,并应用Shh、Ihh、Ptch和Smo 4种Hh信号通路蛋白抗体、组织芯片和免疫组织化学EnVision法检测Hh信号通路蛋白在上述病变组织中的表达情况.结果 Shh、Ihh、Ptch和Smo在正常宫颈黏膜上皮中为弱阳性,而在宫颈癌和CIN Ⅲ中呈强阳性,其表达率均显著高于正常宫颈黏膜上皮(P均<0.05).80例官颈癌标本中HPV16阳性率是77.5%(62/80),而且Shh蛋白的强阳性率在HPV16型阳性的宫颈癌组织中显著高于HPV16阴性组(P<0.05).结论 Hh信号通路蛋白过表达可以作为宫颈癌及其癌前病变的早期辅助诊断指标并有望成为宫颈癌靶向治疗的新靶点,而且Shh蛋白的过表达与HPV16型感染密切相关.

Relationship between hedgehog signaling pathway molecules and HPV16 infection in uterine cervical cancers

Objective To investigate the significance of sonic hedgehog (Shh), indian hedgehog (Ihh), smoothened (Smo) and patched (Ptch) expressions in uterine cervical lesions and their relationships with HPV type 16 infection. Methods Totally 183 cases of cervical lesions, including 32 non-neoplastic cervix, 71 cervical intraepithelial neoplasia (28 CIN Ⅰ , 18 CIN Ⅱ, and 25 CIN Ⅲ) and 80 squamous cell carcinomas (SCC) were selected from the Department of Pathology, Yanbian University Hospital, Yanbian Women Hospital, and Yanhian Tumor Hospital. Shh, Ihh, Ptch and Smo proteins expression were investigated by immunohistochemistry using tissue microarry platform, and the presence of HPV type 16 was detected by PCR method. Results Immunohistochemical staining showed that the frequencies of Shh, Ihh, Pteh and Smo expression were rare in normal cervical epithelium, but were strongly expressed in cervical cancer and its precursor lesions ( CIN Ⅱ/Ⅲ) (P<0.01, P<0.01, P<0.05, P<0.05, respectively). In cervical cancer, the expression rate of Shh (95%) was higher than that of CIN (CIN Ⅰ to CIN Ⅲ) (46.4%, 61.1%, 80.0%, respectively, P<0.05). HPV16 was positive in 77.5% of SCC. In cervical cancer, the expression of Shh was related with HPV16 infection (P<0.05), and the expression of Smo was correlated with lymph node metastasis (P<0.05). Conclusions Shh, Ihh, Ptch,and Smo genes may play important roles in the development of cervical cancer. Detection of Hedgehog signaling pathway molecules seems helpful for the early diagnosis of cervical cancer and its precursor lesions,and are potentially therapeutic targets as well.