A potential signaling axis between RON kinase receptor and hypoxia‐inducible factor‐1 alpha in pancreatic cancer

The Cancer Genome Atlas (TCGA) of a pancreatic cancer cohort identified high MST1R (RON tyrosine kinase receptor) expression correlated with poor prognosis in human pancreatic cancer. RON expression is null/minimal in normal pancreas but elevates from pan‐in lesions through invasive carcinomas. We report using multiple approaches RON directly regulates HIF‐1α, a critical driver of genes involved in cancer cell invasion and metastasis. RON and HIF‐1α are highly co‐expressed in the 101 human PDAC tumors analyzed and RON expression correlated with HIF‐1α expression in a subset of PDAC cell lines. knockdown of RON expression in RON positive cells blocked HIF‐1α expression, whereas ectopic RON expression in RON null cells induced HIF‐1α expression suggesting the direct regulation of HIF‐1α by RON kinase receptor. RON regulates HIF‐1α through an unreported transcriptional mechanism involving PI3 kinase‐mediated AKT phosphorylation and Sp1‐dependent HIF‐1α promoter activity leading to increased HIF‐1α mRNA expression. RON/HIF‐1α modulation altered the invasive behavior of PDAC cells. A small‐molecule RON kinase inhibitor decreased RON ligand, MSP‐induced HIF‐1α expression, and invasion of PDAC cells. Immunohistochemical analysis on RON knockdown orthotopic PDAC tumor xenograft confirmed that RON inhibition significantly blocked HIF‐1α expression. RON/HIF‐1α co‐expression also exists in triple‐negative breast cancer cells, a tumor type that also lacks molecular therapeutic targets. This is the first report describing RON/HIF‐1α axis in any tumor type and is a potential novel therapeutic target.