Studies on Pathogenesis of Cervical Carcinoma Based on the Analysis of Growth and Differentiation Mechanism of Cervical Squamous Epithelium

基于宫颈鳞状上皮生长和分化机制分析的宫颈癌发病机制研究

• 批准号: 02454381
• 负责人: FUJII Shingo
• 金额: $ 4.48万
• 依托单位: Shinshu University (1991-1992)Kyoto University (1990)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1990
• 资助国家: 日本
• 起止时间: 1990 至 1992
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-02454381/
• 关键词: Cervical Squamous Neoplasia; Human Papillomavirus; Estrogen Receptor; Progesterone Receptor; Epidermal Growth Factor Receptor; C-erbB-2 Protein; ADF; Thioredoxin; Immunogloblin; HPV DNA; replication; Progesterone; EGFR; CーerbBー2 Protein; ADF

The analysis of Langerhans cell in the cervical squamous epithelium, and IgG and IgA in the cervical mucus revealed that the cervix possesses a local defense mechanism in the follicular phase of the menstrual cycle. Analysis of a cell proliferation antigen Ki-67 in normal cervix revealed that parabasel cells enter the cell cycle more frequently in the luteal phase than in the follicular phase. Basal and reserve cells are usually resting, but a few cells enter the cell cycle during the luteal phase and during pregnancy. Since cycling cells are more susceptible to viral infection, the basal and/or reserve cells during the luteal phase and pregnancy are suggested to be under the risk of human papillomavirus (HPV) infection. As factors regulationg growth and differentiation of normal cervical squamous epithelium, sex steroids through the expression of estrogen receptors(ER) and progesterone receptors (PR), epidermal growth factor receptor (EGFR), and C-erbB-2 protein were suggested. Howeve … More r, the squamous epithelium infected by HPV showed down-expression of ER and up-expression of PR which were the characteristics of receptor status of normal cervical squamous proliferation. Moreover, transfection of HPV 16 DNA into the ER-positive mammary cancer cell line (ZR-75-1) resulted in its down-expression of ER. This suggested that HPV DNA directly affects the expression of ER. Moreover, up-expression of PR in the HPV-infected squamous neoplasia suggested that, through the glucocorticoid responsive element of HPV, progesterone promotes the proliferation of HPV-infected squamous epithelium. In addition, up-expression of EGFR and down-expression of C-erbB-2protein were observed in the HPV-infected squamous epithelium. Since C-erbB-2 protein expression was closely associated with the differentiation of normal cervical epithelium, these results suggest that HPV-infection affects the differentiation of cervical squamous cells. And co- expression of ADF/thioredoxin and HPV DAN in the neoplastic cervical squamous epithelium suggest that ADF-expression is closely associated with HPV DNA replication. In summary, a human sexual behavior irrespective of the menstrual cycle may be an inherent risk for HPV-infection. HPV infection possibly induces down-expression of ER and up- expression of PR which are the receptor status of squamous proliferation, and up-expression of EGFR and down expression of C-erbB-2 protein, and abnormal ADF-expression. These results suggest that HPV infection is deeply involved in the neoplastic transformation of cervical squamous cells. Less

宫颈鳞状上皮中朗格汉斯细胞及宫颈黏液中IgG和IgA的检测表明，在月经周期卵泡期，宫颈具有局部防御机制。对正常宫颈细胞增殖抗原Ki-67的分析显示，旁基底细胞在黄体期比在卵泡期更频繁地进入细胞周期。基础细胞和储备细胞通常处于静止状态，但少数细胞在黄体期和怀孕期间进入细胞周期。由于循环细胞更容易受到病毒感染，黄体期和妊娠期的基础细胞和/或储备细胞被认为有感染人乳头瘤病毒（HPV）的风险。正常宫颈鳞状上皮的生长分化调节因子包括雌激素受体（ER）、孕激素受体（PR）、表皮生长因子受体（EGFR）、C-erbB-2蛋白等。更重要的是，HPV感染的鳞状上皮表现为ER的低表达和PR的高表达，这是正常宫颈鳞状上皮增生受体状态的特征。此外，将HPV 16 DNA转染到ER阳性的乳腺癌细胞系（ZR-75-1）中，导致其ER表达下调。提示HPV DNA直接影响ER的表达。此外，在HPV感染的鳞状瘤变中PR的上调表达表明，孕激素通过HPV的糖皮质激素反应元件促进HPV感染的鳞状上皮的增殖。此外，在hpv感染的鳞状上皮中，EGFR呈上升表达，c - erbb -2蛋白呈下降表达。由于C-erbB-2蛋白的表达与正常宫颈上皮的分化密切相关，这些结果表明hpv感染影响宫颈鳞状细胞的分化。ADF/硫氧还蛋白和HPV DAN在宫颈鳞状上皮肿瘤中的共同表达提示ADF的表达与HPV DNA复制密切相关。总之，无论月经周期如何，人类的性行为都可能是hpv感染的固有风险。HPV感染可能诱导鳞状细胞增殖的受体状态ER下调、PR上调、EGFR上调、C-erbB-2蛋白下调、adf表达异常。这些结果提示HPV感染深入参与宫颈鳞状细胞的肿瘤转化。少

项目成果

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