Sp17作为卵巢癌预后分子标志物及其介导化疗耐药机制研究

Biomarkers for predicting chemosensitivity are urgently needed to guide individualized treatment due to the high rate of chemoresistance in ovarian cancer. Sperm protein 17 (Sp17) is a cancer/testicular antigen that is highly expressed in ovarian cancer and low expressed in normal tissues.There are few studies on the role and mechanism of Sp17 in ovarian cancer. Previously, our group found that the high expression of Sp17 was closely related to chemotherapy resistance of ovarian cancer. In order to reveal the role and mechanism of Sp17 in ovarian cancer chemotherapeutic resistance, the project intends to suty the correlation between Sp17 levels in serum and tissue and chemotherapy resistance of ovarian cancer, to explore the feasibility of Sp17 as a marker for predicting chemotherapy sensitivity of ovarian cancer; establish ovarian cancer cell models with overexpression and knockout of Sp17, to analyze the effect of Sp17 on ovarian cancer chemotherapeutic sensitivity; and then analyze the effect of Sp17 on STAT3 signaling pathway and PD-L1 expression of ovarian cancer cells, to clarify the molecular mechanism of Sp17 enhancing ovarian cancer chemotherapeutic resistance; Further analyze the therapeutic effect of Sp17 vaccine combined with chemotherapy on ovarian cancer treatment. This study would not only help to reveal the role and mechanism of Sp17 in ovarian cancer chemosensitivity, but also provide targets for predicting chemosensitivity and individualized treatment of ovarian cancer.

卵巢癌化疗抵抗普遍，亟需新的预测化疗敏感性标志物以便指导个体化治疗。精子蛋白17（Sp17）是在卵巢癌中高表达而在正常组织中无或低表达的癌症/睾丸抗原。目前关于Sp17在卵巢癌中作用和机制研究很少。本课题组前期发现Sp17高表达与卵巢癌化疗抵抗密切相关。为揭示Sp17在卵巢癌化疗抵抗中作用及其机制，项目拟分析血清和组织中Sp17水平与卵巢癌化疗抵抗的关系，探讨Sp17作为预测卵巢癌化疗敏感性标志物的可行性；建立Sp17过表达和敲除的卵巢癌细胞系，分析Sp17对卵巢癌化疗敏感性的影响；然后分析Sp17对卵巢癌细胞STAT3信号通路和PD-L1表达的影响，明确Sp17增强卵巢癌化疗抵抗的分子机制；同时分析化疗联合Sp17疫苗对卵巢癌治疗作用。项目研究不仅有助于揭示Sp17在卵巢癌化疗抵抗中的作用及其机制，而且能为卵巢癌的化疗敏感性预测以及个体化治疗提供靶标。

Sp17是一个在卵巢癌等多种肿瘤中高表达的癌胚抗原，在多种肿瘤中有报道其可增加肿瘤的进展，可作为肿瘤疫苗抗原。但是Sp17在黑素瘤中表达及功能还未见报道，本项目研究了Sp17在黑素瘤中作用及对免疫微环境的影响，发现了Sp17促进黑素瘤的进展，对黑素瘤的免疫微环境的调控，免疫检查点的表达，基于Sp17的肿瘤疫苗对黑素瘤的治疗作用还有待进一步优化。本项目发现黑素瘤进展的潜在新机制和新靶点。肿瘤免疫治疗已经改变了肿瘤的治疗范式。如何准确预测其疗效是免疫治疗的挑战，然而基于治疗前检测肿瘤突变负荷、PD-L1蛋白表达等传统手段并不能对所有患者的疗效进行有效预测。本项目阐明了肿瘤患者在治疗前后的免疫动态平衡过程，包括免疫检测点的表达和免疫细胞的浸润正向相关，提示免疫系统的激活可以用于预测患者疗效。在2个治疗周期内，基于血浆中白细胞介素动态变化构建免疫治疗激活预测模型，能很好地预测患者免疫治疗的长期结局，相关工作已经发表在The Innovation杂志。同时本项目发现了肿瘤免疫治疗应答组和无应答组中环状RNA的特征区别，基于环状RNA的ICBcircSig作为预后生物标志物的构建，并在独立临床队列验证，环状RNA可以作为稳定的生物标志物，探讨了其对免疫治疗的影响及作为预测免疫治疗疗效的可行性，相关工作已经在nature communications杂志小修。关节炎型银屑病危害重，大多是由寻常型银屑病进展而来，对于关节炎型银屑病早期预测标志物的发现具有重要临床意义，本项目基于临床多组学数据利用机器学习构建关节炎型银屑病预测模型，对银屑病诊疗具有重要意义，相关工作已经发表在NPJ Digital Med杂志。