PRR11诱导EMT促进胃癌侵袭转移的机制研究

Gastric cancer is one of the common malignant tumor in our country，its incidence and mortality significantly higher than that of western countries, About 60% patients with gastric cancer already exists lymph nodes and/or organ metastases, meanwhile metastasis is an independent prognostic factor for gastric cancer. We found respectively PRR11 and CTHRC1 were related with gastric cancer lymph node metastasis and gastric cancer lymph node metastasis were closely related to the prognosis of patients with gastric cancer, low-expressed PRR11 cause CTHRC1 express lower . Recent literature reports CTHRC1 is linked with Wnt and promotes cancer cell invasion and metastasis. we speculate that PRR11 may acting on the Wnt pathway by CTHRC1, and then promote the invasion and metastasis of gastric cancer. However PRR11 regulating Wnt pathway promote cancer cell invasion and metastasis have not been reported. This study intends to application of tissue microarray, gene transfection, siRNA interference, drug block and related molecular biology technology in histology, cytology and function learning level research the correlation and control way, is to investigate the role of PRR11 in gastric cancer transfer mechanism, to enrich and perfect the Wnt pathway in gastric cancer diagnosis and treatment,down to provide new therapeutic target.

胃癌是我国最常见的消化系统恶性肿瘤之一，其发病率及死亡率居高不下，约60%左右的胃癌患者初诊时已存在淋巴结和/或脏器转移，且转移是影响临床疗效和患者预后的重要因素。我们前期发现PRR11和CTHRC1在胃癌中表达异常，且与淋巴结、远处转移及预后密切相关，敲低PRR11表达，引起CTHRC1表达下降。新近文献报导CTHRC1参与Wnt通路激活，促进肿瘤细胞转移。我们推测PRR11可能通过CTHRC1调控Wnt通路，继而促进胃癌的侵袭及转移。然而，PRR11 调节Wnt通路促进肿瘤转移的文献报道还没有。本研究拟应用组织芯片、基因转染、siRNA干扰、药物阻断以及相关分子生物学技术在组织学、细胞学和功能学水平研究三者的相关性以及调控方式，旨在探讨PRR11在胃癌转移中的作用机制，丰富和完善Wnt通路，为Wnt及其通路在胃癌诊治和转移干预方面提供新的治疗靶点。

背景/目标：胃癌是世界上排名第四的恶性肿瘤。虽然在过去的几十年里胃癌的诊断的治疗取得了重要的进展，但是生存率依然很低。迫切需要新的治疗策略。胃癌是一种含有肿瘤干细胞的高度侵袭性肿瘤，干细胞参与了肿瘤的发生，治疗抵抗和复发。PRR11已被证明在人类癌症中高表达; 然而，它在胃癌干细胞中的作用尚不清楚。我们假设PRR11可能影响胃肿瘤干细胞的致瘤性。因此我们研究了PRR11在胃肿瘤干细胞中的生物学功能和调节作用。.方法：通过实时定量PCR和蛋白质印迹在胃肿瘤干细胞系中评估PRR11的表达。通过使用负载慢病毒载体的shRNA干扰基因表达来检查PRR11对致瘤性的影响。建立NOD/SCID小鼠的异种移植肿瘤模型以检查PRR11在肿瘤发展中的作用。.结果：数据显示PRR11在胃肿瘤干细胞中高表达。PRR11负责维持胃肿瘤干细胞的自我更新和致瘤性，外源性PRR11的超表达可以恢复胃非肿瘤干细胞的自我更新。此外，干扰PRR11改变了多能转录因子的表达。MAPK信号通过增加PRR11蛋白稳定性来控制PRR11表达，以PRR11依赖性方式维持胃肿瘤干细胞的自我更新。.结论：PRR11通过MAPK信号通路调节胃肿瘤干细胞的自我更新和致瘤性，可用作胃癌的治疗靶点。