Identification and characterization of the genes responsible for the development of uterine cervical carcinoma : towards the molecular targetting.

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(1) Identification of pathways of cervical carcinogenesisCervical squamous cell carcinoma has been supposed to derive from reserve cells in squamo-columnar junction and develop stepwise through mild, moderate and severe dysplasia. Recent studies showed that type of HPV in severe dysplasia was different from that of mild dysplasia, implying that severe dysplasia does not necessarily develop through mild dysplasia. In our current study, we clarified that atypical immature metaplasia is formed by infection of malignant types of HPV, and that a new pathway from atypical immature metaplasia to severe dysplasia does exist.Adenosquamous carcinoma occupies about 1% of the uterine cervical carcinomas. Adenocarcinoma- and squamous cell carcinoma-parts are concurrently detected in adenosquamous carcinoma, however, it has been still unclear whether those two parts are formed separately form different original cells or develop from a single origin differentiating two cell types. We demonstrated ade … More nosquamous carcinoma of the uterine cervix was demonstrated to be a combination tumor originating from a single Stem cell by clonality analysis.(2) Identification of the genes regulating progression of cervical carcinomaThirty-two genes were identified as the genes responsible for development and progression of cervical carcinoma by DNA microarray analysis. Among them, Igfbp5 was shown to be significantly down-regulated from an early step of cervical carcinogenesis. Moreover, point mutation or amplification of PIK3CA gene was identified in 25% of cervical carcinoma cases. Inactivation of RUNX3 genes occurred in about 50% of uterine carcinoma. We also showed that B4-H7, a novel gene responsible for the development of ovarian cancer, plays a role in uterine carcinoma.(3) Analysis of epithelial-stromal interaction of cervical carcinomaWe demonstrated, in vitro and in vivo, that HB-EGF secreted by the stroma of cervical carcinoma promotes proliferation of carcinoma cells by paracrine mechanism. Less