子宮頚部初期癌と関連病変におけるHPVの発癌性に関する分子生物学的研究 : とくに16型, 18型E6/E7 mRNA局在について (<シンポジウム>子宮頚部の初期癌ならびにその関連病変)

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Recent molecular biologic studies have shown that some type of human papillomavirus (HPV) is closely associated with uterine cervical cancer. In order to investigate the relationship between HPV DNA and cervical cancer, we studied the carcinogenesis of HPV in cervical cancer and related lesions by dot blot hybridization (D.B.H.), Southern blot hybridization (S.B.H.), in situ hybridization (I.S.H.) and polymerase chain reaction (P.C.R.). We also followed some HPV DNA, mRNA positive or negative cases of cervical dysplasia for more than 16 months prospectively. I. Analysis of HPV DNA HPV DNA were detected in cervical dysplasia and cancer and HPV positive rate increased as the grade of cervical dysplasia became higher by several molecular biologic analysis. Especially, the results of I.S.H. with biotinylated HPV DNA probes revealed that HPV DNA was located in the nuclei of koilocytosis, dysplastic cells and cancer cells. In analysis of HPV type in squamous epithelium, HPV 6/11 was the highest positive rate (21.1%) in mild dysplasia. On the other hand, HPV16 positive rate increased with the grade of dysplasia and 34.9% (15/42) of moderate dysplasia and 51.4% (18/35) of severe dysplasia were positive for HPV 16 DNA, respectively. And N/C ratio in HPV 16 positive cells significantly increased by measurement of micrometer. These findings suggest that HPV 16 is high risk HPV and associated with squamous epithelial neoplasia. About 50% of metaplasia close to cervical neoplasia with HPV DNA was positive for the same type of HPV. In columnar epithelium, several types of HPV DNA were detected in 46.7% (15/32) of cervical adenocarcinoma. Thirty one percent (10/32) of adenocarcinoma, 50% (4/8) of adenosquamous cell carcinoma were positive for HPV 18. This suggests an association between HPV 18 and adenocarcinoma and related lesions. We examined amplified DNA detection of HPV 16 and 18 E7 gene by P.C.R. method. HPV 16 and/or 18 DNA were detected in 25 of 43 cases of cervical scrapes obtained from cervical neoplasia, and we confirmed the P.C.R. is the useful method for the screening and the retrospective investigation of HPV infection. By the immunohistochemical and molecular biologic study, there was no correlation HPV DNA with c-myc product and c-myc gene amplification. II. Analysis of HPV mRNA (E6/E7, L1/L2) The early genes E6/E7 of HPV 16 and 18 were considered as one of the carcinogenic factors of uterine cervix. We investigated the localization of HPV E6/E7 and L1/L2 mRNA in cervical dysplasia and CIS with I.S.H. using antisense and sense biotinylated HPV RNA probes which were made by in vitro transcription. E6/E7 and L1/L2 mRNA were observed in the cytoplasm and nuclei of the dysplastic cells or cancer cells of HPV DNA positive cases by antisense HPV E6/E7 or L1/L2 RNA probe. III. Follow up study The persistent or progressive rate of cervical dysplasia increased in HPV DNA positive cases compared with HPV DNA negative cases by follow up study. In HPV DNA positive cases, especially cervical dysplasia which HPV 16 DNA and E6/E7 mRNA were detected significantly progressed in CIS. On the other hand, many cases of cervical dysplasia which were positive for HPV L1/L2 mRNA regress to the low grade of cervical neoplasia. We concluded that the difference of HPV E6/E7 and L1/L2 gene expression was the very important mechanism in the development of cervical dysplasia by the follow up study. These findings suggested that an association between DNA detection and E6/E7 gene expression of HPV high risk group and cervical carcinogenesis. We suppose the multiple steps' carcinogenesis which HPV 16 or 18 E6/E7 gene expression may alter the regulation of the host genes and induce the cervical cancer.
社団法人日本産科婦人科学会の論文
1990-08-01

子宮頚部初期癌と関連病変におけるHPVの発癌性に関する分子生物学的研究 : とくに16型, 18型E6/E7 mRNA局在について (<シンポジウム>子宮頚部の初期癌ならびにその関連病変)

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