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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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Hypoxia regulates choline kinase expression through hypoxia-inducible factor-1 alpha signaling in a human prostate cancer model.

Project description:The intensity of the total choline (tCho) signal in spectroscopic images of tumors is spatially heterogeneous. The likewise heterogeneous physiologic tumor microenvironment may contribute to this heterogeneity. We therefore investigated the relationship between hypoxia, choline metabolites, and choline kinase (Chk) in a human prostate cancer model. Human PC-3 prostate cancer cells were engineered to express enhanced green fluorescent protein (EGFP) under hypoxic conditions. These PC-3-5HRE-EGFP cells were characterized in culture and as tumors transplanted in mice using (1)H magnetic resonance spectroscopy (MRS) and MRS imaging (MRSI) combined with EGFP fluorescence microscopy and imaging. Hypoxic EGFP-fluorescing tumor regions colocalized with regions of high tCho in combined MRSI and optical imaging studies. Cellular phosphocholine (PC) and tCho concentrations as well as Chk expression levels significantly increased following exposure of PC-3 cells to hypoxia. A putative promoter region located 5' of the translation start site of the human chk-alpha gene was cloned and luciferase (Luc)-based reporter vector constructs were generated. Luc reporter assays provided evidence that some of the putative hypoxia response elements (HRE) within this putative chk-alpha promoter region functioned in vitro. Chromatin immunoprecipitation assays using an antibody against hypoxia-inducible factor (HIF)-1 alpha showed that HIF-1 can directly bind this region of the endogenous chk-alpha promoter in hypoxic PC-3-5HRE-EGFP cells. These data suggest that HIF-1 activation of HREs within the putative chk-alpha promoter region can increase Chk-alpha expression within hypoxic environments, consequently increasing cellular PC and tCho levels within these environments.

| S-EPMC5606139 | biostudies-literature

Vorinostat suppresses hypoxia signaling by modulating nuclear translocation of hypoxia inducible factor 1 alpha.

Project description:Histone deacetylase inhibitors (HDACis) are a potent class of tumor-suppressive agents traditionally believed to exert their effects through loosening tightly-wound chromatin resulting in de-inhibition of various tumor suppressive genes. Recent literature however has shown altered intratumoral hypoxia signaling with HDACi administration not attributable to changes in chromatin structure. We sought to determine the precise mechanism of HDACi-mediated hypoxia signaling attenuation using vorinostat (SAHA), an FDA-approved class I/IIb/IV HDACi. Through an in-vitro and in-vivo approach utilizing cell lines for hepatocellular carcinoma (HCC), osteosarcoma (OS), and glioblastoma (GBM), we demonstrate that SAHA potently inhibits HIF-a nuclear translocation via direct acetylation of its associated chaperone, heat shock protein 90 (Hsp90). In the presence of SAHA we found elevated levels of acetyl-Hsp90, decreased interaction between acetyl-Hsp90 and HIF-a, decreased nuclear/cytoplasmic HIF-α expression, absent HIF-α association with its nuclear karyopharyin Importin, and markedly decreased HIF-a transcriptional activity. These changes were associated with downregulation of downstream hypoxia molecules such as endothelin 1, erythropoietin, glucose transporter 1, and vascular endothelial growth factor. Findings were replicated in an in-vivo Hep3B HRE-Luc expressing xenograft, and were associated with significant decreases in xenograft tumor size. Altogether, this study highlights a novel mechanism of action of an important class of chemotherapeutic.

| S-EPMC5593548 | biostudies-literature

LOXL2 upregulates hypoxia?inducible factor?1? signaling through Snail?FBP1 axis in hepatocellular carcinoma cells.

Project description:Lysyl oxidase?like 2 (LOXL2), a member of the lysyl oxidase gene family, is involved in the progression of hepatocellular carcinoma progression and metastasis. Increased expression of LOXL2 has been identified in several types of cancer, including hepatocellular carcinoma. Recently, LOXL2 has been reported to promote epithelial?mesenchymal transition by reducing E?cadherin expression via the upregulation of Snail expression. The present study provided evidence demonstrating that LOXL2 inhibited the expression of fructose?1, 6?biphosphatase (FBP1) and enhanced the glycolysis of Huh7 and Hep3B hepatocellular carcinoma cell lines in a Snail?dependent manner. Overexpression of the point?mutated form of LOXL2 [LOXL2(Y689F)], which lacks enzymatic activity, does not affect the expression of Snail1 or FBP1. Notably, targeting extracellular LOXL2 of Huh7 cells with a therapeutic antibody was unable to abolish its regulation on the expression of Snail and FBP1. Knockdown of LOXL2 also interrupted the angiogenesis of Huh7 and Hep3B cells, and this effect could be rescued by the overexpression of Snail. Furthermore, upregulation of hypoxia?inducible factor 1? (HIF?1?) and vascular endothelial growth factor (VEGF) expression was observed in Huh7 and Hep3B cells expressing wild?type LOXL2. Notably, the selective LOXL2 inhibitor LOXL2?IN?1 could upregulate the expression of FBP1 and inhibit the expression of Snail, HIF?1? and VEGF in HCC cells, but not in FBP1?knockdown cells. The results of the present study indicated that the intracellular activity of LOXL2 upregulated HIF?1?/VEGF signaling pathways via the Snail?FBP1 axis, and this phenomenon could be inhibited by LOXL2 inhibition. Collectively, these findings further support that LOXL2 exhibits an important role in the progression of hepatocellular carcinoma and implicates LOXL2 as a potential therapeutic agent for the treatment of this disease.

| S-EPMC7107812 | biostudies-literature

BTB/POZ domain-containing protein 7/hypoxia-inducible factor 1 alpha signalling axis modulates hepatocellular carcinoma metastasis.

Project description: Not available

| S-EPMC8506631 | biostudies-literature

Hypoxia-inducible factor-1 mediates pancreatic β-cell dysfunction by intermittent hypoxia.

Project description:The role of hypoxia-inducible factor (HIF)-1 in pancreatic β-cell response to intermittent hypoxia (IH) was examined. Studies were performed on adult wild-type (WT), HIF-1α heterozygous (HET), β-cell-specific HIF-1-/- mice and mouse insulinoma (MIN6) cells exposed to IH patterned after blood O2 profiles during obstructive sleep apnea. WT mice treated with IH showed insulin resistance, and pancreatic β-cell dysfunction manifested as augmented basal insulin secretion, and impaired glucose-stimulated insulin secretion and these effects were absent in HIF-1α HET mice. IH increased HIF-1α expression and elevated reactive oxygen species (ROS) levels in β-cells of WT mice. The elevated ROS levels were due to transcriptional upregulation of NADPH oxidase (NOX)-4 mRNA, protein and enzymatic activity, and these responses were absent in HIF-1α HET mice as well as in β-HIF-1-/- mice. IH-evoked β-cell responses were absent in adult WT mice treated with digoxin, an inhibitor of HIF-1α. MIN6 cells treated with in vitro IH showed enhanced basal insulin release and elevated HIF-1α protein expression, and these effects were abolished with genetic silencing of HIF-1α. IH increased NOX4 mRNA, protein, and enzyme activity in MIN6 cells and disruption of NOX4 function by siRNA or scavenging H2O2 with polyethylene glycol catalase blocked IH-evoked enhanced basal insulin secretion. These results demonstrate that HIF-1-mediated transcriptional activation of NOX4 and the ensuing increase in H2O2 contribute to IH-induced pancreatic β-cell dysfunction.

| S-EPMC7789966 | biostudies-literature

Hypoxia-inducible factor-1 alpha maintains mouse articular cartilage through suppression of NF-κB signaling.

Project description:HIF-1α, an essential transcription factor under hypoxic condition, is indispensable for chondrocytes during skeletal development but its expression and roles in articular chondrocytes are yet to be revealed. We examined HIF-1α protein expression and the hypoxic condition during mouse osteoarthritis (OA) development using state of the art hypoxic probes and found that its expression decreased as OA progressed, coinciding with the change in hypoxic conditions in articular cartilage. Gain- and loss-of-function of HIF-1α in cell culture experiments showed that HIF-1α suppressed catabolic genes such as Mmp13 and Hif2a. We confirmed these anticatabolic effects by measuring glycosaminoglycan release from wild type and conditional knock-out mice femoral heads cultured ex vivo. We went on to surgically induce OA in mice with chondrocyte-specific deletion of Hif1a and found that the development of OA was exacerbated. Increased expression of catabolic factors and activation of NF-κB signalling was clearly evident in the knock-out mice. By microarray analysis, C1qtnf3 was identified as a downstream molecule of HIF-1α, and experiments showed it exerted anti-catabolic effects through suppression of NF-κB. We conclude that HIF-1α has an anti-catabolic function in the maintenance of articular cartilage through suppression of NF-κB signalling.

| S-EPMC7096515 | biostudies-literature

Hypoxia-Inducible Factor 2 Alpha (HIF2α) Inhibitors: Targeting Genetically Driven Tumor Hypoxia.

Project description:Tumors driven by deficiency of the VHL gene product, which is involved in degradation of the hypoxia-inducible factor subunit 2 alpha (HIF2α), are natural candidates for targeted inhibition of this pathway. Belzutifan, a highly specific and well-tolerated HIF2α inhibitor, recently received FDA approval for the treatment of nonmetastatic renal cell carcinomas, pancreatic neuroendocrine tumors, and central nervous system hemangioblastomas from patients with von Hippel-Lindau disease, who carry VHL germline mutations. Such approval is a milestone in oncology; however, the full potential, and limitations, of HIF2α inhibition in the clinic are just starting to be explored. Here we briefly recapitulate the molecular rationale for HIF2α blockade in tumors and review available preclinical and clinical data, elaborating on mutations that might be particularly sensitive to this approach. We also outline some emerging mechanisms of intrinsic and acquired resistance to HIF2α inhibitors, including acquired mutations of the gatekeeper pocket of HIF2α and its interacting partner ARNT. Lastly, we propose that the high efficacy of belzutifan observed in tumors with genetically driven hypoxia caused by VHL mutations suggests that a focus on other mutations that similarly lead to HIF2α stabilization, such as those occurring in neuroendocrine tumors with disruptions in the tricarboxylic acid cycle (SDHA/B/C/D, FH, MDH2, IDH2), HIF hydroxylases (EGLN/PHDs), and the HIF2α-encoding gene, EPAS1, are warranted.

| S-EPMC10216878 | biostudies-literature

Conditional Knockout of Hypoxia-Inducible Factor 1-Alpha in Tumor-Infiltrating Neutrophils Protects against Pancreatic Ductal Adenocarcinoma.

Project description:Large numbers of neutrophils infiltrate tumors and comprise a notable component of the inflammatory tumor microenvironment. While it is established that tumor cells exhibit the Warburg effect for energy production, the contribution of the neutrophil metabolic state to tumorigenesis is unknown. Here, we investigated whether neutrophil infiltration and metabolic status promotes tumor progression in an orthotopic mouse model of pancreatic ductal adenocarcinoma (PDAC). We observed a large increase in the proportion of neutrophils in the blood and tumor upon orthotopic transplantation. Intriguingly, these tumor-infiltrating neutrophils up-regulated glycolytic factors and hypoxia-inducible factor 1-alpha (HIF-1α) expression compared to neutrophils from the bone marrow and blood of the same mouse. This enhanced glycolytic signature was also observed in human PDAC tissue samples. Strikingly, neutrophil-specific deletion of HIF-1α (HIF-1αΔNφ) significantly reduced tumor burden and improved overall survival in orthotopic transplanted mice, by converting the pro-tumorigenic neutrophil phenotype to an anti-tumorigenic phenotype. This outcome was associated with elevated reactive oxygen species production and activated natural killer cells and CD8+ cytotoxic T cells compared to littermate control mice. These data suggest a role for HIF-1α in neutrophil metabolism, which could be exploited as a target for metabolic modulation in cancer.

| S-EPMC9821271 | biostudies-literature

Lack of hypoxia-inducible factor-1 alpha impairs midbrain neural precursor cells involving vascular endothelial growth factor signaling.

Project description:Oxygen tension is critical for proliferation of human and murine midbrain-derived neural precursor cells (mNPCs). Here, we conditionally inactivated the hypoxia-responsive transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha) in murine NPCs to determine its role in proliferation, survival, and dopaminergic differentiation in vitro as well as survival of murine dopaminergic neurons in vivo. HIF-1alpha conditional knock-out (HIF-1alpha CKO) mNPCs showed midbrain-specific impairment of survival and proliferation. Dopaminergic differentiation of HIF-1alpha CKO mNPCs in vitro was markedly reduced. Expression of vascular endothelial growth factor (VEGF) mRNA was reduced in HIF-1alpha CKO mNPCs, whereas erythropoietin signaling was not affected. Treatment of HIF-1alpha CKO mNPCs with 50 ng/ml VEGF partially recovered proliferation and dopaminergic differentiation in vitro. In substantia nigra (SN) of adult HIF-1alpha CKO mice, protein levels of dopaminergic marker molecules such as tyrosine hydroxylase (TH) and aldehyde dehydrogenase were reduced by 41 and 61%, respectively. The cell survival marker Bcl-2 was reduced by 58% while caspase-3 was activated. Nonbiased stereological cell counts of TH-positive neurons in SN of young adult HIF-1alpha CKO mice revealed a reduction of 31% compared with cre/wt mice (in which the wild-type Hif1a allele is expressed in parallel with the Cre recombinase allele). However, we found no impairment of striatal dopamine concentrations or locomotor behavior. In conclusion, HIF-1alpha seems to be a transcription factor relevant to the development and survival of substantia nigra dopaminergic neurons involving VEGF signaling.

| S-EPMC6672078 | biostudies-literature

Expression significance and potential mechanism of hypoxia-inducible factor 1 alpha in patients with myelodysplastic syndromes.

Project description:OBJECTIVE:To investigate the expression level and potential mechanism of hypoxia-inducible factor 1 alpha (HIF-1?) in patients with myelodysplastic syndromes (MDS). METHODS:Immunohistochemistry (IHC) techniques were used to examine the protein expression of HIF-1? in paraffin-embedded myeloid tissues from 82 patients with MDS and 33 controls (patients with lymphoma that is not invading myeloid tissues). In addition, the associations between the protein expression of HIF-1? and clinical parameters were examined. To further investigate the significance of HIF-1? expression in MDS patients, the researchers not only extracted the data about HIF-1? expression from MDS-related microarrays but also analyzed the correlation between the level of HIF-1? expression and MDS. The microRNA (miRNA) targeting HIF-1? was predicted and verified with a dual luciferase experiment. RESULTS:Immunohistochemistry revealed that the positive expression rate of HIF-1? in the bone marrow of patients with MDS was 90.24%. This rate was remarkably higher than that of the controls (72.73%) and was statistically significant (P < .05), which indicated that HIF-1? was upregulated in the myeloid tissues of MDS patients. For the GSE2779, GSE18366, GSE41130, and GSE61853 microarrays, the average expression of HIF-1? in MDS patients was higher than in the controls. Particularly for the GSE18366 microarray, HIF-1? expression was considerably higher in MDS patients than in the controls (P < .05). It was predicted that miR-93-5p had a site for binding with HIF-1?, and a dual luciferase experiment confirmed that miR-93-5p could bind with HIF-1?. CONCLUSION:The upregulated expression of HIF-1? was examined in the myeloid tissues of MDS patients. The presence of HIF-1? (+) suggested an unsatisfactory prognosis for patients, which could assist in the diagnosis of MDS. In addition, miR-93-5p could bind to HIF-1? by targeting, showing its potential to be the target of HIF-1? in MDS.

| S-EPMC6792495 | biostudies-literature

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