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

(1)宫颈癌发生途径的鉴别宫颈鳞状细胞癌起源于鳞状-柱状交界处的储备细胞，经轻度、中度和重度异型增生逐步发展。近年来的研究表明，重度不典型增生中的HPV类型与轻度不典型增生不同，这意味着重度不典型增生不一定通过轻度不典型增生发展。在我们目前的研究中，我们阐明了不典型不成熟化生是由恶性类型的HPV感染形成的，并且确实存在从不典型不成熟化生到严重不典型增生的新途径。在腺鳞癌中同时检测到腺癌和鳞状细胞癌部分，然而，仍然不清楚这两个部分是由不同的原始细胞单独形成的，还是由分化为两种细胞类型的单一来源发展而来。我们展示了ade ...更多信息 通过克隆性分析，宫颈非鳞状细胞癌被证明是起源于单个干细胞的组合肿瘤。(2)宫颈癌发生发展调控基因的筛选通过DNA微阵列技术筛选出32个与宫颈癌发生发展相关的基因。其中，Igfbp 5被证明是显着下调，从宫颈癌发生的早期步骤。此外，25%的宫颈癌患者存在PIK 3CA基因的点突变或扩增。RUNX 3基因失活发生在约50%的子宫癌。我们还发现，B4-H7，一个新的基因，负责卵巢癌的发展，在子宫癌中发挥作用。(3)宫颈癌上皮-间质相互作用的分析我们在体内外实验中证实，宫颈癌间质分泌的HB-EGF通过旁分泌机制促进癌细胞的增殖。少

(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