【作者】 于静；

【导师】 林晨；

【作者基本信息】 中国协和医科大学 ， 细胞生物学， 2007， 博士

【摘要】 宫颈癌是常见妇科恶性肿瘤之一，发病率和死亡率在女性恶性肿瘤中居第二位。每年用于宫颈癌筛查和治疗的医疗费用非常巨大。宫颈癌病变的演进与高危型人乳头瘤状病毒HPV的持续感染有非常紧密的联系。HPV持续感染宫颈后，通过其基因产物干扰正常的细胞周期调节，导致细胞的连续增殖与恶性转化。因此，阻断HPV对宫颈的感染及感染后的恶性转化是预防宫颈癌发生的根本途径。由于从癌前病变-宫颈上皮内瘤样变（cervical intraepithelial neoplasia，CIN）发展到宫颈癌大约需要十年的时间，所以充分利用好病变发展演进的这段时间，在病变进入高速发展的不可逆期以前进行有效干预，可使宫颈癌成为可预防和可治愈的疾病。一种满意的治疗宫颈癌的药物，除了能纠正肿瘤细胞中的缺陷基因的表达，还应该能够清除HPV病毒。As₂O₃是传统中药砒霜的有效成分，近年来它被证明是一种广谱的抗癌药物，对治疗急性早幼粒白血病有显著疗效。本论文探讨了As₂O₃对宫颈癌的治疗、预防作用，并研究了其作用的可能机制。通过As₂O₃对培养的人宫颈癌细胞及动物模型的实验结果进行分析，我们首次提出，As₂O₃是通过线粒体途径和激活JNK／p38／GADD45以及p53信号通路诱导宫颈癌细胞凋亡；并且通过影响细胞的胞外基质粘附、迁移能力抑制宫颈癌细胞侵袭转移。我们用促有丝分裂剂——佛波脂（TPA）化学诱导的人宫颈上皮细胞转化模型，在体内、外研究了As₂O₃对宫颈细胞恶性转化的影响，发现As₂O₃显著抑制TPA诱导的HPV阳性的宫颈上皮永生化细胞的恶性转化，表明As₂O₃具有良好的宫颈癌化学预防及治疗作用，为其更好的应用于抗肿瘤临床应用提供了基础。更多还原

【Abstract】 Carcinoma of the cervix is one of the most common malignancies in women,second most common malignancy in both incidence and mortality. There is a bigfinancial and laborious burden for cervical cancer screening and treatment everyyear. Highly pathogenic human papillomavirus （HPV） is closely associated withprogression of cervical cancer. Continous infection of HPV interfering with cellulargrowth regulatory proteins contributes to malignant transformation of cells. Ittakes almost ten years for cervical epithelium to develop from HPV infection tocervical intraepithelial neoplasia and ultimate cervical cancer. Cervical cancer canbe treated and prevented if we can take full use of the period during theprogression of cervical cancer. A satisfying therapeutic reagent for cervicalcancers should elinimate the continuous effects of HPV, as well as correcting thedefect gene expression in cancer cells.As₂O₃ has been indicated as a broad-spectrum anticancer medicine andsuccessfully employed in the treatment of acute promyelocytic leukemia （APL）.Here we aim to show the promising future of As₂O₃ as a satisfying therapeuticreagent in cervical cancer treatment and the understanding of the mechanisms ofAs₂O₃ action. Study of cell features and tumor mouse model by As₂O₃demonstrates that As₂O₃ has a therapeutic effect on cervical cancer in vitro and invivo. In the present study, we show that As₂O₃ can induce cervical cancer cellsapoptosis through the mitochondrial pathway by downregulating expression ofHPV E6/E7 and activating JNK/p38/GADD45 and p53 signal pathways; As₂O₃ can also inhibit attachment of tumor cells to Fibronectin and Matrigel, reduce cellmotility and inhibit tumor invasion potential. In our exeriment, we also designedto evaluate the potential of As₂O₃ to inhibit the induction of malignanttransformation of TPA-immortalized and HPV-positive cervical epithelial cells invitro and in vivo （TPA is a potent tumor-promoting compound.）. In our study, As₂O₃appears to decrease the risk of developing pre-invasive and invasivemalignancies in cervical epithelial cells. Our studies enlarged the range of As₂O₃usage in cervical cancer treatment and prevention, suggesting a potential clinicalapplication in cervical cancer therapies.更多还原