USP33 promotes pancreatic cancer malignant phenotype through the regulation of TGFBR2/TGFβ signaling pathway

Pancreatic cancer (PC) ranked fourth among cancer-related death worldwide with a survival rate less than 5%. The abnormal proliferation and distant metastasis are major obstacles for the diagnosis and treatment of pancreatic cancer, therefore, it is urgent for researchers to uncover the molecular mechanisms underlying the PC proliferation and metastasis. In current study, we found that USP33, a member of deubiquitinating enzyme family, was upregulated among PC samples and cells, meanwhile, the high expression of USP33 correlated with poor prognosis of patients. Function experiments revealed that USP33 overexpression promoted the proliferation, migration and invasion of PC cells while the inhibition of USP33 expression in PC cells exhibited the opposite effect. The mass spectrum and luciferase complementation assay screened TGFBR2 as the potential binding protein of USP33. Mechanistically, USP33 triggered the deubiquitination of TGFBR2 and prevented its degradation by lysosome, therefore promoted TGFBR2 accumulation in cell membrane and eventually contributed to the sustained activation of TGF-beta signaling. Moreover, our results revealed that the activation of TGF-beta targeted gene ZEB1 promoted the transcription of USP33. In conclusion, our study found that USP33 contributed to the proliferation and metastasis of pancreatic cancer through a positive feedback loop with TGF-beta signaling pathway. Moreover, this study suggested that USP33 may serve as a potential prognostic and therapeutic target in PC.

Automated summary

Pancreatic cancer (PC) is the fourth leading cause of cancer-related death worldwide, with a survival rate below 5%. Abnormal proliferation and distant metastasis are major challenges for the diagnosis and treatment of PC, making it crucial for researchers to understand the molecular mechanisms underlying PC proliferation and metastasis. This study found that USP33, a member of the deubiquitinating enzyme family, is upregulated in PC samples and cells, and its high expression is associated with poor prognosis. Functional experiments showed that USP33 overexpression promotes PC cell proliferation, migration, and invasion, while inhibition of USP33 has the opposite effect. The study also identified TGFBR2 as a potential binding protein of USP33 and revealed a positive feedback loop between USP33 and the TGF-beta signaling pathway.