TACSTD2在卵巢高级别浆液性癌发生发展中的作用及分子机制研究

Ovarian cancer is the most lethal cause of cancer death among women. Recent studies have suggested that fallopian tube is the likely source of ovarian high-grade serous cancer which is considered as the most common histotype of ovarian carcinoma. Until now, there are mainly morphological and evidences, but few genetic findings. Based on our previous study, ILLUMINA Beadarray was used to find the homology in the aspect of gene expression profile between ovarian serous carcinoma and fallopian tube, and select candidate marker TACSTD2. We speculate that TACSTD2 could drive the expression of NF-κB、Cyclin D1 through the activation of ERK/MAPK pathway and then play role in the carcinogenesis and development of high-grade ovarian serous carcinoma. Next step the experiments in vivo and vitro will be performed, to clarify the molecular mechanism of TACSTD2. The expression TACSTD2 in tissue blocks will be tested, to evaluate its prospect in clinic. Our study will supply genetic evidences for tubal origin of high grade ovarian serous carcinoma and potential candidate marker for tumor diagnosis and treatment.

卵巢癌在女性生殖系统肿瘤中致死率居于首位，其中约75%为高级别浆液性癌，发病机制一直存在争议。近年来输卵管起源假说为卵巢癌的发病机制提供了新的研究视角。我们的前期工作表明：相对于卵巢上皮，卵巢高级别浆液性癌和输卵管上皮具有更高的基因表达谱相似性，支持输卵管起源模型。基于基因谱分析及参考相关文献，我们筛选出上调基因TACSTD2。本项目拟阐明TACSTD2对卵巢高级别浆液性癌发生发展的影响，并揭示其是否通过激活ERK/MAPK通路发挥作用。首先将扩大样本量以验证TACSTD2与卵巢高级别浆液性癌的相关性；然后通过功能研究及动物实验明确其对肿瘤生物学行为的影响；分析TACSTD2与ERK/MAPK通路的作用机制并筛选上下游基因；最后检测其在蜡块标本中的表达，评估其在临床诊断预后方面的应用前景。本研究将从TACSTD2这个新视点为揭示卵巢高级别浆液性癌的发病机制及临床诊断预后提供新的思路。

卵巢癌是妇科恶性肿瘤中致死率最高的疾病，缺乏预防和早期诊断的方法。卵巢高级别浆液性癌占卵巢癌的75%，其输卵管起源学说受到越来越多的证据支持。课题组通过免疫组化和芯片分析发现：相比较卵巢上皮，卵巢高级别浆液性癌和输卵管上皮具有更多的免疫学表型和基因表达谱相似性，支持输卵管起源。由此筛选出差异表达基因TACSTD2，并深入分析其对卵巢癌的影响。构建TACSTD2的shRNA慢病毒表达载体,包装shRNA慢病毒颗粒，转染SKOV3细胞并筛选出稳定细胞株，通过划痕实验、Transwell实验和CCK8实验显示沉默TACSTD2后，卵巢癌细胞增殖、浸润能力显著降低，细胞迁移能力无显著改变。建立裸鼠的皮下成瘤动物模型，显示沉默TACSTD2后，卵巢癌细胞的成瘤能力下降。收集临床卵巢高级别浆液性癌患者及其对照组的组织标本和血清标本，分别检测TACSTD2的表达，显示TACSTD2在卵巢癌组织和血清中高表达，敏感度和特异度高，并与不良预后相关。明确了TACSTD2在卵巢高级别浆液性癌中的高表达以及其对卵巢癌的影响，有望能为临床诊断和预后指标。