The Functions And Mechanisms Of Ubiquitin Specific Protease11(USP11) In The Progression Of Colorectal Cancer

Objective: Colorectal cancer(CRC)is a common malignant tumor and the improvements in diagnosis and treatment have improved the prognosis of patients with colorectal cancer.However,advanced patients with metastasis have poor prognosis.Moreover,due to the complexity of pathogenesis,the sensitivity to chemotherapy drugs varies greatly in different patients.Therefore,the discovery of novel tumor markers for personalized treatment regimens will help achieve accurate treatment of colorectal cancer.Clinical samples,in vitro and in vivo experiments were used to study the role of USP11 in the progression of CRC.We hope that our study could provide a new theoretical basis for the diagnosis and treatment of colorectal cancer.Methods: 1.Bioinformatics analyses,Western Blot,q PCR and immunohistochemistry experiments were applied for investigating the expression of USP11 in CRC tissues and analyzing the relationship between USP11 and the clinicopathological characteristics of CRC patients.2.The effect of USP11 on the biological behaviors of CRC cells was studied by CCK-8,colony formation,flow cytometry,Transwell assays and in vivo experiments.3.PPP1 CA was identified as the potential interaction molecule by immunoprecipitation combined with LC–MS/MS,and the synergistic mechanism of PPP1 CA and USP11 in CRC progression was studied by Co-IP,ubiquitination assays,Western Blot,IHC,CCK-8,Transwell assays,and in vivo experiments.4.The effect of USP11 on chemotherapy sensitivity of CRC cells and the mechanism were studied by cytotoxicity test,Western Blot and animal experiments.Results: 1.USP11 was overexpressed in CRC tissues and associated with poor prognosis.Overexpression or knockdown of USP11 promoted or inhibited,respectively,the growth and metastasis of CRC cells in vitro and in vivo.2.USP11 stabilized PPP1 CA by deubiquitinating and promoted CRC progression by activating the ERK/MAPK signaling pathway.3.USP11 could activate autophagy through the AMPK/Akt/m TOR pathway,inducing resistance to 5-fluorouracil in CRC cells.Conclusions: 1.USP11 is highly expressed in CRC tissues and is associated with poor prognosis of CRC patients.USP11 could promote tumor growth and metastasis in CRC via the ERK/MAPK pathway by stabilizing PPP1 CA.2.USP11 could activate autophagy to induce resistance to 5-fluorouracil in colorectal cancer cells.