一个新的含Rho-GAP结构域的Rho信号拮抗因子在食管癌中的表观遗传异常及参与癌变的分子机理研究

食管癌是常见的消化道肿瘤，我国是世界上食管癌高发地区之一。食管癌5年存活率很低 (~20％)，伴随淋巴结转移的更低。Rho GTPase在肿瘤细胞的侵袭与转移过程中起着非常重要的作用，表观遗传异常调控的Rho GTPase可导致肿瘤中Rho信号通路的活化，但在食管癌中的报道不多。我们前期利用甲基化转移酶DNMT1和DNMT3A双knock out模型，采用改良的全基因组基于酶切消化的重亚硫酸盐 (dRRBS)测序筛选出新的Rho GAPase-TUSCG2。本项目拟全面阐明TUSCG2在食管癌中的表观遗传调控异常，作为新的抑癌基因的生物学功能、作为Rho信号的拮抗因子抑制肿瘤侵袭与转移的分子机理及其甲基化作为肿瘤早期诊断、预防的分子标志物研究。这将进一步完善定位于Rho GAPase家族成员甲基化修饰的抑癌基因谱，为Rho GAPase在ESCC肿瘤侵袭转移中的生物学功能提供新的实验证据。

Esophageal squamous cell carcinoma (ESCC) is prevalent among Chinese population in mainland China especially the Northern China (Henan) and Shantou areas. ESCC has a very low 5-year survival rate (~13-20%) with frequent metastases, with current therapies only effective to early cancer patients. Thus, molecular studies of ESCC tumorigenesis to develop better biomarkers for its early detection and specific therapy are urgently needed. Rho GTPases play a crucial role in cancer invasion and metastasis by regulating cytoskeletal and cell adhesion dynamics. Epigenetic disruption of Rho GTPases activates Rho signaling, thus contributes tumor progression, while few studies have been reported in ESCC. We previously developed a double restriction enzyme-based RRBS (dRRBS) which significantly improves the analysis coverage and accuracy of CpG. We further analyzed the CpG methylation profile of DNA methyltransferase double knock-out model, and identified a Rho GAP-containing gene, TUSCG2. This proposed proposal aims to investigate epigenetic disruption of TUSCG2 in tumorigenesis of ESCC, its tumor suppressive functions, the mechanism as Rho antagonist inhibiting ESCC metastasis and invasion, as well as its potential as early tumor marker. Through this proposed study, the TSG profile of Rho GTPase will be dispersed, and the understanding of tumor suppressive function of Rho family GTPase will be widened, which will highlight the importance of epigenetic alteration in tumorigenesis and develop potent tumor markers for ESCC early detection.