CXCL14在卵巢癌腹腔转移中的生物学功能及分子机制研究

Ovarian cancer is one of the most common gynecological malignancies, whose primary metastatic site is peritoneal cavity. However, the underlying molecular mechanisms remain far from elucidated. Thus, it is of great importance to screen for key mediators responsible for peritoneal metastasis of ovarian cancer, which could potentially serve as novel diagnostic biomarkers as well as therapeutic targets of ovarian cancer. We previously found that the expression level of CXCL14 in the metastatic site of ovarian cancer was significantly higher than that in the primary site, which was also correlated with clinical outcome of ovarian cancer patients. Moreover, in vitro studies demonstrated that CXCL14 overexpression could remarkably enhance the metastatic capacity of ovarian cancer cells. This project aims to use peritoneal metastatic ovarian cancer as experimental model to systematically analyze the biological functions of CXCL14 in ovarian cancer peritoneal metastasis by molecular and cellular biological techniques on both in vivo and in vitro levels. More importantly, we attempt to explore the underlying molecular mechanisms to elucidate the importance of CXCL14 in ovarian cancer metastasis as well as to clarify the potential application values of CXCL14 as a novel early diagnostic biomarker and therapeutic target for ovarian cancer, which might lay theoretical foundations for the development of new diagnosis and treatment strategies of ovarian cancer.

卵巢癌是临床最常见的妇科恶性肿瘤之一，其主要转移途径为腹腔转移，但其中所涉及的机制及相关分子机理目前尚未完全阐明。因此，筛选和鉴定介导卵巢癌腹腔转移关键分子并探索相关分子机理有助于发现卵巢癌新型早期诊断标志物及靶向治疗新策略。我们前期研究发现，CXCL14在人卵巢癌腹腔转移灶中的表达显著高于原位灶，其表达水平与卵巢癌患者临床预后密切关联，体外研究发现CXCL14能显著增强卵巢癌细胞的转移能力。本项目拟在此基础上以卵巢癌腹腔转移模型为研究对象，采用分子细胞学方法从体内外水平系统研究CXCL14在卵巢癌腹腔转移中的生物学功能，阐明其影响卵巢癌转移的相关分子机制，明确CXCL14作为卵巢癌早期诊断标志物或药物靶标的潜在应用价值，为发展新的卵巢癌诊断治疗策略提供理论依据。

在青年科学基金的资助下，我们开展了筛选和鉴定介导卵巢癌腹腔转移关键分子并探索相关分子机理的系统研究：我们以卵巢癌转移体内外模型为研究工具，综合应用分子细胞生物学、组织病理学、生物信息学等技术手段，同时结合完备的临床信息，分析了CXCL14在人卵巢癌转移灶及原位灶中的表达量及细胞定位，进行了体内外实验验证，初步验证了CXCL14在人卵巢癌转移灶肿瘤相关成纤维细胞中的高表达及其介导的下游卵巢癌相关分子事件，探索了其在卵巢癌患者中的临床意义。. 结果显示：CXCL14在人卵巢癌转移灶肿瘤相关成纤维细胞中的表达显著高于卵巢癌原位灶中的肿瘤相关成纤维细胞中的表达，其表达水平与卵巢癌患者临床预后密切关联。在本研究计划中，我们研究发现高表达CXCL14的肿瘤相关成纤维细胞与卵巢癌细胞共培养能够导致卵巢癌细胞发生EMT，并进而增强卵巢癌细胞侵袭能力，其机理在于其能够能够刺激卵巢癌细胞中非编码RNA Lnc00092的表达上调，高表达的Lnc00092通过结合果糖-2,6-双磷酸酶（PFKFB2），进而促进卵巢癌细胞中的Warburg效应并增强其转移能力。因此，本项目系统地阐明了CXCL14在卵巢癌发生发展，侵袭与转移过程中的生物学功能，从实验水平验证了本项目在立项时提出的CXCL14分子可能在卵巢癌发生发展过程中发挥重要作用的科学设想。本项目的研究，有望为后续以CXCL14作为切入点研发卵巢癌早期诊断标记物或药物靶标的潜在应用价值提供新思路和新方法，对建立卵巢癌早期诊断的预警体系、提高卵巢患者的生存率和改善患者的生存质量具有重大战略意义。. 在本项目研究经费的资助下，已经在等本领域主流SCI期刊上以第一作者或者通讯作者发表了论文8篇，参加了国内学术会议3次。