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

ABSTRACT: 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.

SUBMITTER: Kato A

PROVIDER: S-EPMC9292374 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCircular RNAs (circRNAs) regulate multiple malignant behaviors of various types of cancer. The role of circDNMT1, a newly identified circRNA, remains unknown in gastric cancer (GC). This study aimed to elucidate the underlying mechanisms of circDNMT1 in regulating GC progression.MethodsmicroRNA (miRNA) and circRNA expression was detected by quantitative real-time PCR. Western blotting was performed to measure hypoxia inducible factor-1 alpha (HIF-1α) protein expression. Sanger sequencing, gel electrophoresis and fluorescence in situ hybridization were performed to identify the presence of circDNMT1. The clinicopathological features and overall survival of patients were analyzed based on circDNMT1 expression. The proliferation, migration and invasion of GC cells were determined by cell counting kit-8, 5-ethynyl-2'-deoxyuridine, wound healing and transwell assays. Glycolysis of GC cells was detected based on the levels of glucose uptake, the lactate acid, ATP and pyruvic acid production and the extracellular acidification and oxygen consumption rates. The binding sites between miR-576-3p and circDNMT1 or HIF-1α were predicted by online bioinformatic tools and were validated using RNA pull-down and luciferase reporter assays. Xenograft models were established to determine the effects of the circDNMT1/miR-576-3p/HIF-1α axis on GC growth and metastasis in vivo.ResultscircDNMT1 was successfully identified and shown to be overexpressed in GC tissues and cell lines. The expression levels of circDNMT1 were correlated with pathological T stage, pathological TNM stage and shorter survival time of GC patients. circDNMT1 knockdown inhibited the proliferation, migration, invasion and glycolysis of GC cells. circDNMT1 functioned as an oncogenic factor by sponging miR-576-3p. HIF-1α was negatively regulated by miR-576-3p via binding its mRNA 3' untranslated region. circDNMT1 promoted malignant behaviors and metabolic reprogramming of GC by targeting the miR-576-3p/HIF-1α axis both in vitro and in vivo.ConclusionThese findings demonstrated that circDNMT1 knockdown inhibited GC proliferation, migration, invasion and glycolysis through sponging miR-576-3p/HIF-1α axis. circDNMT1 may be a novel target for GC treatment.

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

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