The Role Of GSK3β-regulated TRAF6 Expression In Colorectal Cancer Metastasis

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.