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.

Vav1‐dependent Rac1 activation mediates hypoxia‐induced gemcitabine resistance in pancreatic ductal adenocarcinoma cells through upregulation of HIF‐1α expression

“…We next explored the potential downstream effector of Rac1 in mediating hypoxia‐induced GEM resistance. HIF‐1α is the key signaling molecule regulating the adaptation of cancer cells to hypoxic environments (Kato et al, 2021; Zhuang et al, 2021). HIF‐1α has been demonstrated to be involved GEM resistance in PDAC cells (Nagaraju et al, 2019; Zhao et al, 2020).…”

Interaction and Collaboration of SP1, HIF-1, and MYC in Regulating the Expression of Cancer-Related Genes to Further Enhance Anticancer Drug Development

“…In the latter example, the suppression of PRMT1, which prevents the recruitment of SP1/SP3 to the HIF1A gene promoter, allows SP1/SP3 to activate the transcription of HIF1A (Figure 2C). In both cases, SP1 directly induces transcriptional activity of the HIF1A gene via its binding to SP1 consensus sequences in the HIF1A gene promoter (Figure 1) and upregulates expression of the HIF1A gene [77][78][79][80][81][82][83][84][85][86][87][88][89]. Meanwhile, SP1 can indirectly regulate HIF1A expression by modulating the gene expression of histone deacetylase 4 (HDAC4) in rat cardiomyocytes (Figure 2D) [95].…”

“…For example, SP1, HIF-1, and MYC can interact and modulate the activities of each other. Figure 1 shows the promoters of human SP1, HIF1A, and MYC genes [85][86][87][88][89][90][91][92]. 'SP1 and 'HRE' in the figure indicate the locations of SP1 and the HRE consensus sequences, respectively.…”

“…There are numerous SP1 consensus sequences in the HIF1A gene promoter, which suggests that SP1 can induce HIF1A gene expression (Figure 1) [88,89]; however, no definitely active HRE has been found in the HIF1A promoter to date (Figure 1) [88,89]. These data confirm that the HRE in the SP1 gene promoter contributes to the induction of SP1 gene transcription by HIF1A, and SP1 consensus sequences in the HIF1A gene promoter contribute to the induction of HIF1A gene transcription by SP1 [85][86][87][88][89]. Thus, there may be a positive activation feedback loop of HIF-1 and SP1, and hypoxia-mediated induction of HIF-1 may trigger the activation of both SP1 and HIF-1 until normoxia deactivates HIF-1.…”

“…contribute to the induction of HIF1A gene transcription by SP1 [85][86][87][88][89]. Thus, there may be a positive activation feedback loop of HIF-1 and SP1, and hypoxia-mediated induction of HIF-1 may trigger the activation of both SP1 and HIF-1 until normoxia deactivates HIF-1.…”