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-1 alpha, a critical driver of genes involved in cancer cell invasion and metastasis. RON and HIF-1 alpha are highly co-expressed in the 101 human PDAC tumors analyzed and RON expression correlated with HIF-1 alpha expression in a subset of PDAC cell lines. knockdown of RON expression in RON positive cells blocked HIF-1 alpha expression, whereas ectopic RON expression in RON null cells induced HIF-1 alpha expression suggesting the direct regulation of HIF-1 alpha by RON kinase receptor. RON regulates HIF-1 alpha through an unreported transcriptional mechanism involving PI3 kinase-mediated AKT phosphorylation and Sp1-dependent HIF-1 alpha promoter activity leading to increased HIF-1 alpha mRNA expression. RON/HIF-1 alpha modulation altered the invasive behavior of PDAC cells. A small-molecule RON kinase inhibitor decreased RON ligand, MSP-induced HIF-1 alpha expression, and invasion of PDAC cells. Immunohistochemical analysis on RON knockdown orthotopic PDAC tumor xenograft confirmed that RON inhibition significantly blocked HIF-1 alpha expression. RON/HIF-1 alpha 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-1 alpha axis in any tumor type and is a potential novel therapeutic target.