Title The Roles of Hedgehog Pathway in Cervical Carcinoma

Objective:To determine the expression pattern and the extent of Hh signaling molecules in squamous cell carcinoma of uterine cervix and its precursor lesions;and to observe the effect of cyclopamine,a specific inhibitor of Hh signaling,on the morphology and growth of cultured HeLa cells and SiHa cells;and to explore the potential regulatory role of clinical diagnosis and pathological significance of Hh pathway in the pathogenesis,progression and treatment of carcinoma of uterine cervix and its precursor lesions.Methods:(1) 38 squamous cell carcinomas(SCC),23 cervical intraepithelial neoplasia(CIN)Ⅲ,10 CINⅡ,4 CINⅠand 32 normal cervical epithelia were immunohistochemically analyzed with anti-Shh,Ihh,Ptch,Smo,Gli-1,Gli-2, Gli-3 antibodies on paraffin blocks.(2) The DNA of 38 SCC was extracted and HPV16,18 were detected by PCR.(3) The morphological changes of HeLa cells and SiHa cells were observed under inverted microscope after the treatment of cyclopamine.The proliferation of both cells was measured by MTT assay. (4) Then the expression of several signaling molecules in them was observed by immuocytochemical method after the treatment of cyclopamine,so was the expression of Bax and Bcl-2.Results:(1) The expression of Hh signaling molecules was more enhanced in uterine cervical carcinoma than in aormal cervical epithelium,including carcinoma and its precursor lesions CINⅡ/Ⅲ.The staining pattern was mainly cytoplasmic except for Gli-1/2,whose expression was observed in both cytoplasm and nucleus.In case of Ihh,Ptch,Smo,Gli-1 and Gli-3,their expression in normal epithelium was completely absent or rare.Compared with those in normal epithelium,the expression of all the seven Hh signaling molecules was significantly increased in CINⅡ/Ⅲand carcinoma(P<0.05).The expression of Shh was increased for twice:the first increasing occurred in normal epithelium-CIN transition,and the second occurred during the progression of CIN to carcinoma.These results suggested that the Hh signaling pathways were extensively activated in carcinoma and CIN of uterine cervix. (2) In cases of 38 SCC,the positive rates of HPV16 was 71.1%,while HPV18 were all negative.The results showed that there was rare relationship between the infection of HPV16,18 and the expression of Hh signaling molecules.(3) The results showed that cyclopamine can inhibit the proliferation of HeLa cells and SiHa cells,and the rates of inhibition showed obvious additive or synergistic effects of the drugs.After the treatment of cyclopamine,the morphology of cells and the amount of cells were changed.(4) The immuocytochemical staining of the cyclopamine treated HeLa cells showed that the expression of Hh signaling molecules and Bcl-2 was significantly degraded comparing with the control group(tomatidine),however,Bax was enhanced.Conclusion:Hh signaling pathway was anormaly enhanced in carcinoma of uterine cervix and it participated the generation process of the carcinoma; cyclopamine may inhibit the proliferation of both ceils through inducing apoptosis.Therefor Hh signaling pathway may be regarded as a new target in the treatment of uterine cervix and its precursor lesions.

Category Oncology
Keywords cervical carcinoma, Cyclopamine, Hedgehog signaling pathway,
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Pages 105
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