Apigenin Targets MicroRNA-155, Enhances SHIP-1 Expression, and Augments Anti-Tumor Responses in Pancreatic Cancer

SIMPLE SUMMARY: Pancreatic Cancer (PC) is one of the most lethal cancers. PC promotes the expansion of immunosuppressive Myeloid-Derived Suppressor Cells (MDSC) and Tumor Associated Macrophages (TAM) that dampen anti-tumor immunity and renders immunotherapies ineffective. We have identified Src Homology-2 (SH2) domain-containing Inositol 5′-Phosphatase-1 (SHIP-1) as a potential new molecular target that controls myeloid associated immunosuppression. We previously demonstrated that apigenin (API) (bioflavonoid) increases SHIP-1 expression and promotes the development of monocytic-MDSC (M-MDSC) into M1 TAM (Tumoricidal) in the pancreatic tumor microenvironment (TME), which corresponded with an increase in anti-tumor immunity (tumor regression) mice harboring PC. In the present study, we demonstrate that API suppresses PC-induced micro-RNA (miR-155), a negative transcriptional regulator of SHIP-1 expression, something which corresponds with the augmented SHIP-1 expression that itself corresponds with an increase in the proportion of M1 macrophages in the bone marrow (BM) of mice with PC. This work supports the idea of enhancing SHIP-1 as a potential new therapeutic target for treatment of pancreatic cancer. ABSTRACT: Pancreatic cancer (PC) is a deadly disease with a grim prognosis. Pancreatic tumor derived factors (TDF) contribute to the induction of an immunosuppressive tumor microenvironment (TME) that impedes the effectiveness of immunotherapy. PC-induced microRNA-155 (miRNA-155) represses expression of Src homology 2 (SH2) domain-containing Inositol 5′-phosphatase-1 (SHIP-1), a regulator of myeloid cell development and function, thus impacting anti-tumor immunity. We recently reported that the bioflavonoid apigenin (API) increased SHIP-1 expression which correlated with the expansion of tumoricidal macrophages (TAM) and improved anti-tumor immune responses in the TME of mice with PC. We now show that API transcriptionally regulates SHIP-1 expression via the suppression of miRNA-155, impacting anti-tumor immune responses in the bone marrow (BM) and TME of mice with PC. We discovered that API reduced miRNA-155 in the PC milieu, which induced SHIP-1 expression. This promoted the restoration of myelopoiesis and increased anti-tumor immune responses in the TME of heterotopic, orthotopic and transgenic SHIP-1 knockout preclinical mouse models of PC. Our results suggest that manipulating SHIP-1 through miR-155 may assist in augmenting anti-tumor immune responses and aid in the therapeutic intervention of PC.