SYVN1 Promotes Treg Production in Dendritic Cells via Ubiquitinating MST1 and Up-Regulating sirt1 to Advance Pancreatic Cancer Progression

Abstract

Objective: This study aimed to clarify the potential role of SYVN1 (synoviolin 1) in pancreatic cancer biology. Methods: Panc-1 and AsPC-1 cells were independently transfected with SYVN1 overexpression or knockdown plasmid, and injected into nude mice to induce tumor formation. Tumor volume was measured 4 weeks after tumor induction. Then, the mRNA expressions of SYVN1 and mammalian Sterile 20-like kinase 1 (MST1) were determined by quantitative real-time PCR (polymerase chain reaction). After the tumor isolation or co-culture of immature dendritic (imDC) cells and CD4+ T cells, the percentage of regulatory T (Treg) cells was detected by flow cytometry, and MST1 and sirtuin 1 (sirt1) protein levels were measured by Western blot. MST1 ubiquitination in imDC cells was assessed by immunoprecipitation. Results: SYVN1 overexpression facilitated tumor growth in mice after 4 weeks, while silencing SYVN1 exerted tumor suppressive effect. Besides, SYVN1 up-regulation promoted Treg cell infiltration and sirt1 protein expression, but suppressed MST1 protein expression in tumorigenic mice. Similarly, overexpressed SYVN1 down-regulated MST1 protein expression, but up-regulated Treg cell percentage and sirt1 protein level in imDC cells after co-culture with CD4+ T cells. SYVN1 was predicted as E3 ubiquitin ligase of MST1, and SYVN1 overexpression was able to promote MST1 ubiquitination in imDC cells. Moreover, MST1 overexpression reversed SYVN1-induced Treg production and decreased sirt protein expression in imDC cells. Conclusions: SYVN1 facilitates Treg production in imDC cells to accelerate pancreatic cancer progression via MST1 ubiquitination degradation and sirt1 up-regulation.