HPV诱导的宫颈癌的发病机制，卵巢癌顺铂耐药的机制研究

The pathogenesis of HPV-induced cervical cancer;

The mechanism of cisplatin resistance in ovarian cancer

中国医师协会妇产科医师分会手术加速康复学组委员、上海市医学会妇产科分会青年副主委、上海市医学会妇科肿瘤分会宫颈癌学组副会长、上海市第一妇婴保健院宫颈科科主任

从事妇科肿瘤的临床、科研、教学工作18年。近5年申请人主要致力于探索宫颈癌的发病机制和改善疗效的研究，并取得一些有创新意义的进展和成果，在Clin Cancer Res，Lab Invest等学术期刊上以第一作者或者通讯作者发表相关SCI论文30余篇，并多次受邀在国际会议上交流。近5年主持国家级课题1项，省部级课题2项，厅局级课题7项。申请人已取得的主要研究成果如下：

1. 放化疗耐药是影响妇科恶性肿瘤预后的主要原因。申请人一直致力于改善化疗疗效的研究，多视角地研究肿瘤耐药的机制和增敏方法。申请人前期采用生物信息学方法发现卵巢癌中TGF-β1及其信号通路是受化疗调控的关键信号通路，并在宫颈癌患者组织中验证了化疗可激活宫颈癌组织中TGFβ信号通路。随后在国际上率先解析了TGF-β1调控化疗反应的机制，提出常用化疗药物通过刺激宫颈癌和卵巢癌细胞中TGFβ1的产生和分泌，活化TGFβ信号，促进上皮间质转化和肿瘤干性特征，从而降低化疗敏感性。之后，在动物模型中，验证了本团队自主研发的新型TGF-β抑制剂RER，可有效阻断化疗药物活化的TGFβ信号，从而增强顺铂抗肿瘤的疗效，相关研究发表在“Clin Cancer Res”。相关成果被美国癌症研究学会2016年AACR肿瘤大会邀请交流，获得高度关注。

2. HPV感染诱导宫颈上皮细胞恶性转化的具体机制尚不明确。申请人前期研究发现RAGE、GLI2/3等基因均参与了HPV诱导的宫颈癌的发生发展，初步揭示了HPV诱导的宫颈癌的致病机制，为靶向性对宫颈癌的发生发展进行分子阻遏提供实验依据。

Engaged in clinical, scientific research and teaching of gynecological tumors for 18 years. In the past 5 years, I have mainly devoted myself to exploring the pathogenesis of cervical cancer and improving the efficacy of research, and have made some innovative progress and results. I have published relevant articles in academic journals such as Clin Cancer Res and Lab Invest as the first author or corresponding author. There are more than 30 SCI papers and have been invited to exchange at international conferences many times. Currently presides over and participates in 2 national-level projects, and presides over 7 provincial and ministerial-level and department-level projects. The main research results obtained by the applicant are as follows:

1.Radiotherapy and chemotherapy resistances are the main reason that affects the prognosis of gynecological malignant tumors. I have been committed to improving the efficacy of chemotherapy, studying the mechanisms of tumor resistance and sensitization methods from multiple perspectives. I used bioinformatics methods to find that TGF-β1 and its signaling pathway in ovarian cancer are the key signaling pathways regulated by chemotherapy, and verified that chemotherapy can activate the TGFβ signaling pathway in cervical cancer tissues. Subsequently, I was the first to analyze the mechanism of TGF-β1 regulating chemotherapy response in the world, and proposed that commonly used chemotherapy drugs stimulate the production and secretion of TGFβ1 in cervical cancer and ovarian cancer cells, activate TGFβ signals, promote epithelial-mesenchymal transition and tumor stemness characteristics in order to reduce chemotherapy sensitivity. Later, in animal models, it was verified that the new TGF-β inhibitor RER independently developed by our team can effectively block the TGFβ signal activated by chemotherapeutic drugs, thereby enhancing the anti-tumor efficacy of cisplatin. Related research was published in "Clin Cancer Res ". The relevant results were invited to exchange at the 2016 AACR Oncology Conference of the American Society for Cancer Research and received high attention.

2.The specific mechanism of HPV infection-induced malignant transformation of cervical epithelial cells is still unclear. My previous research found that genes such as RAGE and GLI2/3 are involved in the occurrence and development of HPV-induced cervical cancer, and initially revealed the pathogenic mechanism of HPV-induced cervical cancer, providing targeted molecular suppression of the occurrence and development of cervical cancer Experimental basis.