【作者】 杨天宇；

【导师】 李建明； 吴华；

【作者基本信息】 苏州大学 ， 病理学与病理生理学， 2019， 硕士

【摘要】 结直肠癌是消化道最常见的恶性肿瘤之一,在我国其位列全国恶性肿瘤发病第三位,仅次于肺癌和胃癌。近年来,我国结直肠癌发病率和死亡人数不断增加,结直肠癌居全国恶性肿瘤死亡人数的第五位。因而,结直肠癌的防治是非常重要的公共卫生问题之一。而结直肠癌细胞的转移作为结直肠癌发展进程中的关键事件,直接影响临床结直肠癌患者的治疗和预后。因此,深入研究结直肠癌转移的相关机制,找出调控结直肠癌转移的关键分子,并阐明其调控机制对预防和治疗结直肠癌具有极其重要的意义。Wnt/β3-catenin信号通路是调控结直肠癌发生和转移的重要通路。有趣的是,前期我们发现TRAF6可通过调控自噬选择性的β-catenin降解新机制抑制结直肠癌细胞的侵袭和转移。在本研究中,我们进一步发现糖原合成激酶3β(GSK3β3)可参与调控这一重要分子事件。我们发现G SK3β与TRAF6的表达在绝大多数临床结直肠癌组织标本中存在显著的负相关性,且其表达与结直肠癌病人的预后紧密相关。机制的研究揭示GSK3β可通过与TRAF6的相互作用诱发其266位苏氨酸发生磷酸化,这一重要的蛋白质翻译后修饰可极大地促进TRAF6发生K48连接的多聚泛素化修饰并启动其发生蛋白酶体途径的降解,进而抑制TRAF6介导的自噬选择性的β-catenin降解途径,最终促进结直肠癌细胞的发生侵袭和转移。应用一种特异靶向GSK3β的抑制剂tideglusib,可有效地稳定TRAF6的蛋白表达,促进β-catenin的降解以及抑制结直肠癌细胞的侵袭转移。因此,靶向GSK3β/TRAF6/Autoβhagy/β-catenin信号转导新途径极有可能作为治疗中晚期结直肠癌的潜在靶点。更多还原

【Abstract】 Colorectal cancer is one of the most common digestive malignant tumors,it ranks the third place in the incidence of malignant tumors in China and its only lower than lung carcinoma and gastric cancer.In recent years,the incidence of colorectal cancer and the number of deaths have been increasing in China,and colorectal cancer ranks the fifth in the number of malignant tumor deaths in China.Therefore,the prevention and treatment of colorectal cancer is one of the most important public health issues.As a key event in the development of colorectal cancer,metastasis of colorectal cancer cells directly affects the treatment and prognosis of clinical colorectal cancer.Therefore,deEPly understanding the molecular mechanism of tumor metastasis and recurrence is of great significance for the treatment and prognosis of colorectal cancer.Wnt/β-catenin signal pathway is an important pathway to regulate the occurrence and metastasis of colorectal cancer.Interestingly,we found that GSK3β-mediated TRAF6/autophagy/β-catenin axis inhibit edEPithelial-mesenchymal transformation(EMT)and colorectal cancer metastasis.In this study,we further found that glycogen synthetic kinase 3β(GSK3β)is involved in the regulation of this molecular process,We found that the expression of GSK3β and TRAF6 were significantly negatively correlated in most clinical colorectal cancer tissue specimens,and its expression was closely related to the prognosis of colorectal cancer patients.Studies have shown that GSK3β can induce phosphorylation of its 266 threonine through interaction with TRAF6.This important post-translational modification of the protein can greatly promote the occurrence of k48-bound polyubiquitination of TRAF6 and initiate its proteasomal degradation,it inhibits the TRAF6-mediated autophagy selective-catenin degradation pathway,and ultimately promotes the invasion and metastasis of colorectal cancer cells.Pharmacological inhibition of GSK3β activity stabilized the TRAF6 protein,promoted β-catenin degradation,and effectively suppressed EMT and CRC metastasis Thus,targeting TRAF6 and its pathway may be meaningful for treating advanced CRC.更多还原