Abstract 1756: The roles of Regnase-1 in pancreatic cancer development and progression

Abstract Background: Regnase-1 is a RNA-degrading enzyme that plays an important role in the regulation of inflammation by degrading mRNA of inflammation-related genes. Although inflammation is known to promote pancreatic carcinogenesis, involvement of Regnase-1 in this process has never been studied. In this study, we thus investigated the role of Regnase-1 in pancreatic cancer development and progression. Methods: We examined the expression levels of Regnase-1 in the pancreas of chronic pancreatitis by repeated administration of caerullein in mice. We sought for a regulator of the Regnase-1 expression in Panc-1 pancreatic cancer cell line. We assessed the biological phenotypes caused by siRNA-mediated Regnase-1 inhibition in multiple pancreatic cancer cell lines, including cell proliferation, migration, apoptosis and cytokine expressions. We generated pancreas-specific Kras-activated and Regnase-1-deficient (PDX1-Cre; Kras G12D KI Regnase-1 fl/fl) mice (PKR mice) and examined these phenotypes. We assessed the relationship between the expression levels of Regnase-1 in pancreatic tumor tissue and prognosis in 39 pancreatic cancer patients who underwent curative surgical resection. Results: The expression levels of Regnase-1 significantly decreased in the murine pancreas of chronic pancreatitis together with the increase in IL-1β. The expression levels of Regnase-1 was downregulated by IL-1β administration in Panc-1 cells. siRNA-mediated Rengase-1 Inhibition significantly promoted cell proliferation, migration and inhibited apoptosis with Bcl-xL upregulation in Panc-1 cells. Rengase-1 Inhibition also upregulated a variety of chemokines involved in the recruitment and activation of myeloid-derived suppressor cells (MDSCs) including CXCL1, CXCL2, CXCL8, CSF2 and CSF3 in Panc1cells. All PKR mice developed pancreatic tumors and became moribund by 3 months of age. We observed massive infiltration of CD11b+Ly6g+Ly6c- PMN-MDSCs and significant upregulation of Arg1, Nos2, Nox2, and S100a8/9 mRNA levels, which are suppressors of anti-tumor immunity known to be secreted from MDSCs. Surgically-resected pancreatic cancer patients with low levels of intra-tumor Regnase-1 expression had significantly shorter recurrence-free and overall survival than those with high levels of Regnase-1. Intratumor Regnase-1 expression levels were negatively correlated with the number of CD11b+ cell infiltration. Conclusion: Inflammation-mediated downregulation of Regnase-1 may contribute to pancreatic cancer development and progression in cell-autonomous and -heteronomous manners. Citation Format: Junya Okabe, Takahiro Kodama, Tetsuo Takehara. The roles of Regnase-1 in pancreatic cancer development and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1756.