Work

IL-37/ STAT3/ HIF-1α negative feedback signaling drives gemcitabine resistance in pancreatic cancer

Year: 2020

Type: article

Abstract: Human interleukin (IL)-37 is a member of the IL-1 family with potent anti-inflammatory and immunosuppressive properties.Previously, it has been reported that IL-37 suppresses tumor growth and progression.However, the roles of IL-37 in pancreatic cancer development and chemo-resistance remain unknown.Methods: Immunohistochemistry was used to analyze the correlation between IL-37 expression and clinicopathological features of pancreatic ductal adenocarcinoma (PDAC).Western-blot and RT-PCR was used to verify the correlation between IL-37 and hypoxia-inducible factor (HIF)-1α.We performed chromatin immunoprecipitation and luciferase assays to validate HIF-1α suppression of IL-37 expression.Moreover, gain-and loss-of-function studies in vitro and in vivo were used to demonstrate the biological function of IL-37 on PDAC development and chemo-resistance.Results: Our results showed that IL-37 expression was remarkably decreased in PDAC tissues when compared to adjacent normal pancreatic tissues.Reduced IL-37 expression in PDACs was associated with increased PDAC histological grade, tumor size, lymph node metastasis and vessel invasion.IL-37 low patients also have remarkably shorter relapse-free and overall survival.Importantly, IL-37 expression was positively correlated with Gemcitabine efficacy.Mechanistically, HIF-1α attenuated IL-37 transcription by binding to the hypoxia response elements (HREs) in IL-37 promoter.Conversely, IL-37 suppressed HIF-1α expression through STAT3 inhibition.Functionally, downregulation of IL-37 in PDAC cells promoted chemo-resistance, migration and progression in vivo and in vitro.Conclusions: Collectively, our data uncovered IL-37/ STAT3/ HIF-1α negative feedback signaling drives Gemcitabine resistance in PDAC.

Source: Theranostics

DOI: 10.7150/thno.42416