肿瘤抗原OVA66致瘤机制和临床应用前景

OVA66, a novel tumor-associated antigen, was obtained from a human ovarian cancer cDNA library utilizing the approach of SEREX analysis in our lab, which is mainly located in cytoplasm and characteristically highly-expressed in tumor cells and tissues. We have demonstrated that the tumor antigen OVA66 was able to promote the proliferation, metastasis and inhibit the apoptosis of cancer cells, which is closely correlated with the tumorigenesis and tumor metastasis, validated by both in vivo and in vitro experiments. This project is extensively studying in three aspects: Firstly, we are focusing on OVA66 interacting protein and its signal transduction pathway, analyzing the expression change of OVA66-related molecules in both gene and protein level both in vivo and vitro, discovering the OVA66 interacting protein, attempting to reveal the biological function of the tumor antigen OVA66 and its mechanism in the process of tumorigenesis and tumor development. Secondly, referring to the analysis of the B cell antigenic epitopes, we are concentrating on investigating the level and feature of the distribution of the OVA66 antibody or antigen in the tumor patients of different types and stages to develop novel testing kit for the detection of tumor marker. Thirdly, we are attempting to use immunne, bio-reagents or medicines targeted to OVA66 interacting proteins or related signaling molecules to realize interventional therapy for tumors. We indicat that the accomplishment of this project is of great theoretical significance and good prospect of application, which is probably a new breakthrough of the field.

肿瘤相关抗原OVA66是本实验是应用SEREX法筛选自行构建的人卵巢癌cDNA表达文库获得一种新的蛋白，主要位于胞浆，在肿瘤细胞（组织）中呈特征性高表达。体内、外实验证实OVA66蛋白具有促进细胞增殖、迁移和抑制细胞凋亡作用，与肿瘤发生和转移密切相关。本项目主要从三方面深入研究：1）着重探讨OVA66相互作用蛋白和信号途径，从体内、外分析基因和蛋白水平相关分子表达变化，发现OVA66相互作用的相关蛋白，试图揭示OVA66蛋白生物学功能及在肿瘤发生、发展中作用机制；2）结合B细胞抗原表位分析，着力探讨不同类型/分期肿瘤病人OVA66抗体或抗原分布水平/特征，为肿瘤标志物开发新的检测试剂；3）对OVA66相互作用蛋白或相关信号分子尝试免疫、生物试剂或药物干预性肿瘤靶点治疗。该项目的研究具有重要的理论价值和良好的应用前景，有可能成为肿瘤免疫领域新的突破点。

肿瘤抗原OVA66是本实验利用人卵巢癌重组cDNA表达文库通过SEREX方法筛选并鉴定的一个新cancer/testis(C/T)抗原。本实验室前期研究表明，在多数肿瘤组织标本OVA66基因/蛋白呈特征性高表达；OVA66抗原能激化机体产生相应抗体，并且正常人和不同肿瘤患者血清OVA66抗体水平有显著性差异(P<0.001)；OVA66具有促进HeLa肿瘤细胞增殖、迁移和抑制凋亡等作用。本项目深入研究肿瘤抗原OVA66在肿瘤发生、发展过程中的生物学功能和致瘤机制。通过shRNA干扰及基因转染技术，体内、外实验结果证实OVA66在肿瘤细胞株如SK-OV-3，HO8910等的干扰或过表达显著抑制或促进肿瘤细胞的增殖、侵袭及抗凋亡能力；应用高通量的信号通路相关蛋白磷酸化抗体芯片、Western Blot法等技术在多个肿瘤细胞株中发现OVA66表达水平对于IGF-1R-ERK1/2-HSP27信号通路的活化程度具有重要影响；并利用IGF-1R信号通路的特异抑制剂Linsitinib或特异小分子干扰RNA(siRNA)，阻断该信号通路的活化，显示特异阻断IGF-1R信号通路明显抑制OVA66蛋白促进肿瘤细胞增殖、侵袭及抗凋亡能力的生物学功能。为揭示肿瘤抗原OVA66与肿瘤发生、发展的相互关系提供理论依据，并对发展新的肿瘤诊断方法，研发新的化学药物、免疫及生物制剂等药物靶向性肿瘤治疗手段奠定可靠的实验基础。