Gene Summary

Gene:HIF1A; hypoxia inducible factor 1 subunit alpha
Aliases: HIF1, MOP1, PASD8, HIF-1A, bHLHe78, HIF-1alpha, HIF1-ALPHA, HIF-1-alpha
Summary:This gene encodes the alpha subunit of transcription factor hypoxia-inducible factor-1 (HIF-1), which is a heterodimer composed of an alpha and a beta subunit. HIF-1 functions as a master regulator of cellular and systemic homeostatic response to hypoxia by activating transcription of many genes, including those involved in energy metabolism, angiogenesis, apoptosis, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia. HIF-1 thus plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jul 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:hypoxia-inducible factor 1-alpha
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: HIF1A (cancer-related)

Itoh M, Okuhashi Y, Takahashi Y, et al.
Hypoxia Up-regulates HIF Expression While Suppressing Cell Growth and NOTCH Activity in Leukaemia Cells.
Anticancer Res. 2019; 39(8):4165-4170 [PubMed] Related Publications
AIM: To examine the influence of hypoxia on the in vitro growth of leukaemia cells and the activity of signalling proteins to better understand the pathophysiology of leukaemia cells in human bone marrow.
MATERIALS AND METHODS: Six human leukaemia cell lines were cultured under normoxic or hypoxic conditions. Cell growth, recovery of clonogenic cells, and the expression and activation of various signalling proteins were examined.
RESULTS: Hypoxia suppressed cell growth and the recovery of clonogenic cells. Moreover, hypoxia up-regulated hypoxia-inducible factor (HIF) 1α and HIF2α expression while suppressing the expression and activation of NOTCH1, mechanistic target of rapamycin kinase (mTOR) activation, and nuclear factor-kappa B (NF-κB) phosphorylation.
CONCLUSION: We found that hypoxia up-regulated HIF expression while it suppressed the self-renewal capacity of leukaemia cells, NOTCH activity, and expression of its down-stream signalling molecules, which differs from previous reports mentioning that HIF activates NOTCH signalling. Our findings serve to further elucidate the in vivo pathophysiology of leukaemia cells.

Li Y, Xu Q, Yang W, et al.
Oleanolic acid reduces aerobic glycolysis-associated proliferation by inhibiting yes-associated protein in gastric cancer cells.
Gene. 2019; 712:143956 [PubMed] Related Publications
Gastric cancer represents a common malignancy of digestive tract with high incidence and mortality. Increasing evidence suggests that the growth of gastric tumor cells relies largely on aerobic glycolysis. Currently, many potential anti-cancer candidates are derived from natural products. Here, we evaluated the effects of oleanolic acid (OA), a triterpenoid component widely found in the plants of Oleaceae family, on aerobic glycolysis and proliferation in human MKN-45 and SGC-7901 gastric cancer cells. Our results demonstrated that OA reduced the viability and proliferation of gastric cancer cells and inhibited the expression of cyclin A and cyclin-dependent kinase 2. OA blocked glycolysis in these cells evidenced by decreases in the uptake and consumption of glucose, intracellular lactate levels and extracellular acidification rate. Glycolysis inhibitor 2-deoxy-d-glucose, similar to OA, suppressed gastric cancer cell proliferation. OA also decreased the expression and intracellular activities of glycolysis rate-limiting enzymes hexokinase 2 (HK2) and phosphofructokinase 1 (PFK1). Moreover, OA downregulated the expression of hypoxia inducible factor-1α (HIF-1α) and decreased its nuclear abundance. Upregulation of HIF-1α by deferoxamine rescued OA-inhibited HK2 and PFK1. Furthermore, OA reduced the nuclear abundance of yes-associated protein (YAP) in gastric tumor cells. YAP inhibitor verteporfin, similar to OA, downregulated the expression of HIF-1α and glycolytic enzymes in gastric cancer cells; whereas overexpression of YAP abrogated all these effects of OA. Collectively, inhibition of YAP was responsible for OA blockade of HIF-1α-mediated aerobic glycolysis and proliferation in human gastric tumor cells. OA could be developed as a promising candidate for gastric cancer treatment.

Penolazzi L, Bonaccorsi G, Gafà R, et al.
SLUG/HIF1-α/miR-221 regulatory circuit in endometrial cancer.
Gene. 2019; 711:143938 [PubMed] Related Publications
BACKGROUND AND PURPOSE: The pathogenesis of endometrial cancer (EC) involves many regulatory pathways including transcriptional regulatory networks supported by transcription factors and microRNAs only in part known. The aim of this retrospective study was to explore the possible correlation in the EC microenvironment between master regulators of complex phenomena such as steroid responsiveness through estrogen receptor alpha (ERα) and progesterone receptor (PR), epithelial-to-mesenchymal transition (supported by SLUG transcription factor), hypoxia (with hypoxia inducible factor-1 alpha, HIF-1α), and obesity that has been recognized as a EC risk factor.
METHODS: Formalin-Fixed Paraffin-Embedded (FFPE) blocks from University of Ferrara Pathology Archive were used and allocated into 2 groups according to their immunohistochemical positivity to ERα and PR, distinguishing the samples with a more benign prognosis (ERα
RESULTS: We showed a comparable percentage of HIF1-α and SLUG positive samples in the ERα
CONCLUSIONS: A molecular circuit of mutual regulation between ERα, PR, HIF1-α, SLUG and miR-221 is feasible in the EC and was firstly suggested by our research. In this interplay miR-221 seems to be in a nodal point of the regulatory system that is particularly strengthened by the metabolic changes in obesity.

Zang W, Bian H, Huang X, et al.
Traditional Chinese Medicine (TCM)
Anticancer Res. 2019; 39(6):2739-2747 [PubMed] Related Publications
BACKGROUND/AIM: The aim of the present study was to investigate the vascular normalization effect of traditional Chinese medicine Astragalus membranaceus (AM) and Curcuma wenyujin (CW) on tumor-derived endothelial cells (TECs).
MATERIALS AND METHODS: TECs were isolated from the xenografted HCC cell line HepG2 expressing red fluorescent protein (RFP). The effect of AM and CW on TECs proliferation was measured using the CCK8 assay. The vascular normalization potential of AM and CW was assessed using a tube formation assay. Immunocytochemistry was performed to assess the effect of AM and CW on the expression of angiogenic maker CD34 and hypoxia-inducible factor HIF1a.
RESULTS: The isolated TECs and endothelioma (EOMA) cells did not differ with regard to the expression levels of endothelial markers CD34, VEGFR-1, VEGFR-2, PDGFR-α and PDGFR-β. All AM, CW, AM+CW and Nintedanib (Nin) showed a dose-dependent increasing inhibition effect on either TECs or EOMA cells. AM, CW and AM+CW significantly reduced HIF1a expression, increased CD34 expression and enhanced endothelial network formation in TECs or EOMA cells compared to the control.
CONCLUSION: AM and CW promoted vascular normalization in tumor-derived endothelial cells of HCC, through increased expression of CD34 and reduced expression of HIF1a.

Mai L, Luo M, Wu JJ, et al.
The combination therapy of HIF1α inhibitor LW6 and cisplatin plays an effective role on anti-tumor function in A549 cells.
Neoplasma. 2019; 2019 [PubMed] Related Publications
Hypoxia-inducible factor 1α (HIF1α) has been demonstrated to be involved in the resistance of various human cancer cells to chemotherapies. However, the correlation between HIF1α and the sensitivity of human non-small cell lung cancer (NSCLC) cells to cisplatin has not been illuminated. The aim of the present study was to investigate the effects of HIF1α on drug resistance in NSCLC cells. A549 cells were incubated in 21% or 0.5% O2 followed by the assessment of the level of HIF1α with qRT-PCR and western blot and ROS level by DCFH-DA assays. Effects of hypoxia or HIF1α inhibitor LW6 on the proliferation and apoptosis of A549 cells were evaluated via CCK-8 and flow cytometry assays. IC50 of A549 cells to cisplatin was determined by MTT assay. The mitochondrial membrane potential (MMP) was measured via JC-1 staining. Moreover, the expression of apoptosis related protein (Bcl-2, Bax) and drug resistance related proteins (MDR1, MRP1) were measured by western blotting. Exposure of A549 cells to 1% O2 significantly up-regulated HIF1α expression, maintained cell viability to cisplatin but decreased the ROS level, which promoted chemoresistance to cisplatin. LW6-treated A549 cells showed an increase in ROS level that blocked the hypoxia induced resistance to cisplatin and in addition, decreased expression of MDR1 and MRP1 in cisplatin-treated cells. This study revealed that hypoxia-improved cisplatin chemoresistance of NSCLC cells by regulated MDR1 and MRP1 expression via HIF1α/ROS pathway is reversed by LW6, suggesting that LW6 may act as effective sensitizer in chemotherapy for NSCLC.

Dabral S, Muecke C, Valasarajan C, et al.
A RASSF1A-HIF1α loop drives Warburg effect in cancer and pulmonary hypertension.
Nat Commun. 2019; 10(1):2130 [PubMed] Free Access to Full Article Related Publications
Hypoxia signaling plays a major role in non-malignant and malignant hyperproliferative diseases. Pulmonary hypertension (PH), a hypoxia-driven vascular disease, is characterized by a glycolytic switch similar to the Warburg effect in cancer. Ras association domain family 1A (RASSF1A) is a scaffold protein that acts as a tumour suppressor. Here we show that hypoxia promotes stabilization of RASSF1A through NOX-1- and protein kinase C- dependent phosphorylation. In parallel, hypoxia inducible factor-1 α (HIF-1α) activates RASSF1A transcription via HIF-binding sites in the RASSF1A promoter region. Vice versa, RASSF1A binds to HIF-1α, blocks its prolyl-hydroxylation and proteasomal degradation, and thus enhances the activation of the glycolytic switch. We find that this mechanism operates in experimental hypoxia-induced PH, which is blocked in RASSF1A knockout mice, in human primary PH vascular cells, and in a subset of human lung cancer cells. We conclude that RASSF1A-HIF-1α forms a feedforward loop driving hypoxia signaling in PH and cancer.

Su H, Zou D, Sun Y, Dai Y
Hypoxia-associated circDENND2A promotes glioma aggressiveness by sponging miR-625-5p.
Cell Mol Biol Lett. 2019; 24:24 [PubMed] Free Access to Full Article Related Publications
Background: As a newfound type of non-coding RNA, circular RNAs (circRNAs) are involved in various physiological and pathological processes via regulation of gene expression. Increasing evidence shows that aberrantly expressed circRNAs play a crucial role in the initiation and progression of many tumors. However, the functions of different circRNAs in gliomas remain elusive.
Methods: The levels of circRNAs, miRNAs, and mRNAs were quantified by qPCR. The interaction between circDENND2A and miR-625-5p was determined by luciferase reporter and pull-down assays. The migratory and invasive capabilities of glioma cells were examined by wound healing and Transwell assays. Immunohistochemistry was performed to analyze the HIF1α level in glioma tissues.
Results: We predicted circDENND2A (has_circ_0002142) to be a hypoxia-responsive circRNA in glioma via a bioinformatic analysis. We found that hypoxia induced the expression of circDENND2A, which promoted migration and invasion of glioma cells. To understand the behaviors of circDENND2A in glioma, we studied the putative miRNAs targeted by circDENND2A and identified circDENND2A as an efficient sponge of miR-625-5p in glioma cells. Phenotype experiments verified that circDENND2A was required for the hypoxia-induced migration and invasion of glioma cells and that this occurred by sponging of miR-625-5p. Notably, glioma tissues overexpressing HIF1α exhibited a high expression of circDENND2A as well as a low expression of miR-625-5p. circDENND2A was negatively correlated with miR-625-5p.
Conclusion: circDENND2A is required for the hypoxia-induced malignancy of glioma cells and functions by sponging miR-625-5p.

Saccà CD, Gorini F, Ambrosio S, et al.
Inhibition of lysine-specific demethylase LSD1 induces senescence in Glioblastoma cells through a HIF-1α-dependent pathway.
Biochim Biophys Acta Gene Regul Mech. 2019; 1862(5):535-546 [PubMed] Related Publications
Senescence is a stress-responsive cellular program that leads to cell cycle arrest. In cancer cells, senescence has profound implications for tumor aggressiveness and clinical outcome, but the molecular events that provoke cancer cells to undergo senescence remain unclear. Herein, we provide evidence that the histone demethylase LSD1/KDM1A supports the growth of Glioblastoma tumor cells and its inhibition triggers senescence response. LSD1 is a histone modifier that participates in key aspects of gene transcription as well as in the regulation of methylation dynamics of non-histone proteins. We found that down-regulation of LSD1 inhibits Glioblastoma cell growth, impairs mTOR pathway and cell migration and induces senescence. At mechanistic level, we found that LSD1 regulates HIF-1α protein stability. Pharmacological inhibition or siRNA-mediated silencing of LSD1 expression effectively reduces HIF-1α protein levels, which suffices for the induction of senescence. Our findings elucidate a mechanism whereby LSD1 controls senescence in Glioblastoma tumor cells through the regulation of HIF-1α, and we propose the novel defined LSD1/HIF-1α axis as a new target for the therapy of Glioblastoma tumors.

Wang HF, Wang SS, Zheng M, et al.
Hypoxia promotes vasculogenic mimicry formation by vascular endothelial growth factor A mediating epithelial-mesenchymal transition in salivary adenoid cystic carcinoma.
Cell Prolif. 2019; 52(3):e12600 [PubMed] Related Publications
OBJECTIVES: To investigate the role of hypoxia in vasculogenic mimicry (VM) of salivary adenoid cystic carcinoma (SACC) and the underlying mechanism involved.
MATERIALS AND METHODS: Firstly, wound healing, transwell invasion, immunofluorescence and tube formation assays were performed to measure the effect of hypoxia on migration, invasion, EMT and VM of SACC cells, respectively. Then, immunofluorescence and RT-PCR were used to detect the effect of hypoxia on VE-cadherin and VEGFA expression. And pro-vasculogenic mimicry effect of VEGFA was investigated by confocal laser scanning microscopy and Western blot. Moreover, the levels of E-cadherin, N-cadherin, Vimentin, CD44 and ALDH1 were determined by Western blot and immunofluorescence in SACC cells treated by exogenous VEGFA or bevacizumab. Finally, CD31/ PAS staining was performed to observe VM and immunohistochemistry was used to determine the levels of VEGFA and HIF-1α in 95 SACC patients. The relationships between VM and clinicopathological variables, VEGFA or HIF-1α level were analysed.
RESULTS: Hypoxia promoted cell migration, invasion, EMT and VM formation, and enhanced VE-cadherin and VEGFA expression in SACC cells. Further, exogenous VEGFA markedly increased the levels of N-cadherin, Vimentin, CD44 and ALDH1, and inhibited the expression of E-cadherin, while the VEGFA inhibitor reversed these changes. In addition, VM channels existed in 25 of 95 SACC samples, and there was a strong positive correlation between VM and clinic stage, distant metastases, VEGFA and HIF-1α expression.
CONCLUSIONS: VEGFA played an important role in hypoxia-induced VM through regulating EMT and stemness, which may eventually fuel the migration and invasion of SACC.

Campbell EJ, Dachs GU, Morrin HR, et al.
Activation of the hypoxia pathway in breast cancer tissue and patient survival are inversely associated with tumor ascorbate levels.
BMC Cancer. 2019; 19(1):307 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The transcription factor hypoxia inducible factor (HIF) -1 drives tumor growth and metastasis and is associated with poor prognosis in breast cancer. Ascorbate can moderate HIF-1 activity in vitro and is associated with HIF pathway activation in a number of cancer types, but whether tissue ascorbate levels influence the HIF pathway in breast cancer is unknown. In this study we investigated the association between tumor ascorbate levels and HIF-1 activation and patient survival in human breast cancer.
METHODS: In a retrospective analysis of human breast cancer tissue, we analysed primary tumor and adjacent uninvolved tissue from 52 women with invasive ductal carcinoma. We measured HIF-1α, HIF-1 gene targets CAIX, BNIP-3 and VEGF, and ascorbate content. Patient clinical outcomes were evaluated against these parameters.
RESULTS: HIF-1 pathway proteins were upregulated in tumor tissue and increased HIF-1 activation was associated with higher tumor grade and stage, with increased vascular invasion and necrosis, and with decreased disease-free and disease-specific survival. Grade 1 tumors had higher ascorbate levels than did grade 2 or 3 tumors. Higher ascorbate levels were associated with less tumor necrosis, with lower HIF-1 pathway activity and with increased disease-free and disease-specific survival.
CONCLUSIONS: Our findings indicate that there is a direct correlation between intracellular ascorbate levels, activation of the HIF-1 pathway and patient survival in breast cancer. This is consistent with the known capacity of ascorbate to stimulate the activity of the regulatory HIF hydroxylases and suggests that optimisation of tumor ascorbate could have clinical benefit via modulation of the hypoxic response.

Chen F, Chen J, Yang L, et al.
Extracellular vesicle-packaged HIF-1α-stabilizing lncRNA from tumour-associated macrophages regulates aerobic glycolysis of breast cancer cells.
Nat Cell Biol. 2019; 21(4):498-510 [PubMed] Related Publications
Metabolic reprogramming is a hallmark of cancer. Here, we demonstrate that tumour-associated macrophages (TAMs) enhance the aerobic glycolysis and apoptotic resistance of breast cancer cells via the extracellular vesicle (EV) transmission of a myeloid-specific lncRNA, HIF-1α-stabilizing long noncoding RNA (HISLA). Mechanistically, HISLA blocks the interaction of PHD2 and HIF-1α to inhibit the hydroxylation and degradation of HIF-1α. Reciprocally, lactate released from glycolytic tumour cells upregulates HISLA in macrophages, constituting a feed-forward loop between TAMs and tumour cells. Blocking EV-transmitted HISLA inhibits the glycolysis and chemoresistance of breast cancer in vivo. Clinically, HISLA expression in TAMs is associated with glycolysis, poor chemotherapeutic response and shorter survival of patients with breast cancer. Our study highlights the potential of lncRNAs as signal transducers that are transmitted between immune and tumour cells via EVs to promote cancer aerobic glycolysis.

Mukund V, Saddala MS, Farran B, et al.
Molecular docking studies of angiogenesis target protein HIF-1α and genistein in breast cancer.
Gene. 2019; 701:169-172 [PubMed] Related Publications
Therapeutic inhibition of hypoxia inducible factor-1α (HIF-1α) action has emerged as a potential approach for managing several diseases including breast cancer (BC). Genistein has been found to exert anti-malignant activity. However, its mechanisms of action remain unknown. Studies indicate that it could act by downregulating HIF-1α. Based on these findings, we investigated whether genistein could reduce HIF-1α in BC cell lines. Furthermore, we performed molecular docking studies to characterize the sites of interaction between genistein and HIF-1α. In the present investigation, we prove, for the first time, that genistein downregulates HIF-1α in BC cells. Molecular docking analysis also revealed that genistein binds to the FIH-1 binding site of HIF-1α protein. These findings thus indicate that genistein and/or HIF-1α antagonists could be a potential treatment for BC.

Ezzeddini R, Taghikhani M, Somi MH, et al.
Clinical importance of FASN in relation to HIF-1α and SREBP-1c in gastric adenocarcinoma.
Life Sci. 2019; 224:169-176 [PubMed] Related Publications
AIMS: Identifying alterations in lipid metabolism along gastric adenocarcinoma (GA) tumorigenesis pathways could lead to a new approach for potential diagnosis, efficient prediction and promising therapeutic strategies. This study aimed to identify the possible effect of HIF-1α on FASN and SREBP-1c regulation in GA.
MAIN METHODS: AGS cell line was cultured in normoxic and hypoxic conditions, and HIF-1α, FASN and SREBP-1c gene expression were analyzed by qRT-PCR and Western blot. Serum HIF-1α, FASN and insulin concentration were measured in 112 GA patients and 156 control cases by ELISA, and immunohistochemical method was employed to analyze SREBP-1c expression. Tissue mRNA expression of SREBP-1c, FASN and HIF-1α were determined by qRT-PCR.
KEY FINDINGS: In vitro findings indicate upregulation of HIF-1α, FASN and SREBP-1c gene and protein expression in the hypoxic culture of AGS cells. High circulating levels of HIF-1α and FASN were significantly observed in GA patients compared to the controls. HIF-1α, SREBP-1c and FASN gene expression were higher in GA vs. controls. In addition, SREBP-1c protein level was enhanced in GA tissues compared to controls. Furthermore, elevated serum levels of HIF-1α and FASN and expression of HIF-1α, SREBP-1c and FASN genes were associated with unfavorable clinicopathological features such as diffuse type tumor and poor survival.
SIGNIFICANCE: The results by correlating increased levels of FASN to those of HIF-1α and SREBP-1c are consistent with a possible up-regulation of FASN upon induction of HIF-1α through SREBP-1c.

Liao Y, Luo H, He Z, et al.
A Combination of UTMD-Mediated HIF-1
Biomed Res Int. 2019; 2019:1937460 [PubMed] Free Access to Full Article Related Publications
To explore the antitumor effect of hypoxia-inducible factor-1

Jabari M, Allahbakhshian Farsani M, Salari S, et al.
Hypoxia-Inducible Factor1-Α (HIF1α) and Vascular Endothelial Growth Factor-A (VEGF-A) Expression in De Novo AML Patients
Asian Pac J Cancer Prev. 2019; 20(3):705-710 [PubMed] Related Publications
Background: Bone marrow hypoxia can promote leukemia progression in human cases of acute myeloid leukemia (AML). In addition, low oxygen tension is able to regulate the expression of different genes involved in malignancy. In this study, we hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF-A) genes were assessed as principal regulators of hypoxia in do novo AML patients. Methods: Peripheral blood and bone marrow samples were collected from 57 AML patients and 17 normal control subjects with informed consent. Expression of HIF1α and VEGF-A was then evaluated using quantitative real-time PCR (Q-Real time PCR) and data were analyzed with SPSS 16. Result: HIF1α and VEGF-A showed overexpression in AML patients compared to normal controls (P <0.0001 and P<0.005, respectively). The expression level of HIF1α was significantly higher in AML-M3 cases versus AML-non M3 cases. Furthermore, there was a positive correlation between HIF1α and VEGF-A ( P <0.0001 and r = 0.497). Conclusion: Adding to the many studies on the role of hypoxia in solid tumors, our data indicate that HIF1a and VEGF-A overexpression also occurs in AML patients. We consider that this is possibly involved in leukemic cell growth and therefore could be a promising target for clinical control.

Cardoso CM, de Jesus SF, de Souza MG, et al.
Is HIF1-a deregulated in malignant salivary neoplasms?
Gene. 2019; 701:41-45 [PubMed] Related Publications
BACKGROUND: There is significant controversy in the literature regarding the relationship between hypoxia and salivary gland neoplasms (SGNs).
OBJECTIVE: The current study aims to investigate levels of hypoxia markers in both benign and malignant salivary neoplasms.
PATIENTS AND METHODS: The current study sample is comprised of a total of 62 samples. HIF-1α expression was evaluated by immunohistochemistry. Additionally, HIF-1α mRNA and miR-210 levels were assessed using qRT-PCR.
RESULTS: No differences in HIF-1α expression were observed among the control group, benign and malignant SGNs. Similarly, HIF-1α mRNA levels were similar between benign and malignant SGNs. Also, there was no difference in miR-210 expression between case and control groups.
CONCLUSION: The angiogenic markers, miR-210 and HIF-1α, do not appear to distinguish malignancy in salivary glands.

Guo R, Li Y, Wang Z, et al.
Hypoxia-inducible factor-1α and nuclear factor-κB play important roles in regulating programmed cell death ligand 1 expression by epidermal growth factor receptor mutants in non-small-cell lung cancer cells.
Cancer Sci. 2019; 110(5):1665-1675 [PubMed] Free Access to Full Article Related Publications
Some driver gene mutations, including epidermal growth factor receptor (EGFR), have been reported to be involved in expression regulation of the immunosuppressive checkpoint protein programmed cell death ligand 1 (PD-L1), but the underlying mechanism remains obscure. We investigated the potential role and precise mechanism of EGFR mutants in PD-L1 expression regulation in non-small-cell lung cancer (NSCLC) cells. Examination of pivotal EGFR signaling effectors in 8 NSCLC cell lines indicated apparent associations between PD-L1 overexpression and phosphorylation of AKT and ERK, especially with increased protein levels of phospho-IκBα (p-IκBα) and hypoxia-inducible factor-1α (HIF-1α). Flow cytometry results showed stronger membrane co-expression of EGFR and PD-L1 in NSCLC cells with EGFR mutants compared with cells carrying WT EGFR. Additionally, ectopic expression or depletion of EGFR mutants and treatment with EGFR pathway inhibitors targeting MEK/ERK, PI3K/AKT, mTOR/S6, IκBα, and HIF-1α indicated strong accordance among protein levels of PD-L1, p-IκBα, and HIF-1α in NSCLC cells. Further treatment with pathway inhibitors significantly inhibited xenograft tumor growth and p-IκBα, HIF-1α, and PD-L1 expression of NSCLC cells carrying EGFR mutant in nude mice. Moreover, immunohistochemical analysis revealed obviously increased protein levels of p-IκBα, HIF-1α, and PD-L1 in NSCLC tissues with EGFR mutants compared with tissues carrying WT EGFR. Non-small-cell lung cancer tissues with either p-IκBα or HIF-1α positive staining were more likely to possess elevated PD-L1 expression compared with tissues scored negative for both p-IκBα and HIF-1α. Our findings showed important roles of phosphorylation activation of AKT and ERK and potential interplay and cooperation between NF-κB and HIF-1α in PD-L1 expression regulation by EGFR mutants in NSCLC.

Hayashi Y, Yokota A, Harada H, Huang G
Hypoxia/pseudohypoxia-mediated activation of hypoxia-inducible factor-1α in cancer.
Cancer Sci. 2019; 110(5):1510-1517 [PubMed] Free Access to Full Article Related Publications
Since the first identification of hypoxic cells in sections of carcinomas in the 1950s, hypoxia has been known as a central hallmark of cancer cells and their microenvironment. Indeed, hypoxia benefits cancer cells in their growth, survival, and metastasis. The historical discovery of hypoxia-inducible factor-1α (HIF1A) in the early 1990s had a great influence on the field as many phenomena in hypoxia could be explained by HIF1A. However, not all regions or types of tumors are necessarily hypoxic. Thus, it is difficult to explain whole cancer pathobiology by hypoxia, especially in the early stage of cancer. Upregulation of glucose metabolism in cancer cells has been well known. Oxygen-independent glycolysis is activated in cancer cells even in the normoxia condition, which is known as the Warburg effect. Accumulating evidence and recent advances in cancer metabolism research suggest that hypoxia-independent mechanisms for HIF signaling activation is a hallmark for cancer. There are various mechanisms that generate pseudohypoxic conditions, even in normoxia. Given the importance of HIF1A for cancer pathobiology, the pseudohypoxia concept could shed light on the longstanding mystery of the Warburg effect and accelerate better understanding of the diverse phenomena seen in a variety of cancers.

Li X, Chen C, Dai Y, et al.
Cinobufagin suppresses colorectal cancer angiogenesis by disrupting the endothelial mammalian target of rapamycin/hypoxia-inducible factor 1α axis.
Cancer Sci. 2019; 110(5):1724-1734 [PubMed] Free Access to Full Article Related Publications
Inducing angiogenesis is a hallmark of cancers that sustains tumor growth and metastasis. Neovascularization is a surprisingly early event during the multistage progression of cancer. Cinobufagin, an important bufadienolide originating from Chan Su, has been clinically used to treat cancer in China since the Tang dynasty. Here, we show that cinobufagin suppresses colorectal cancer (CRC) growth in vivo by downregulating angiogenesis. The hierarchized neovasculature is significantly decreased and the vascular network formation is disrupted in HUVEC by cinobufagin in a dose-dependent way. Endothelial apoptosis is observed by inducing reactive oxygen species (ROS) accumulation and mitochondrial dysfunction which can be neutralized by N-acetyl-l-cysteine (NAC). Expression of hypoxia-inducible factor 1α (HIF-1α) is reduced and phosphorylation of mTOR at Ser2481 and Akt at Ser473 is downregulated in HUVEC. Endothelial apoptosis is triggered by cinobufagin by stimulation of Bax and cascade activation of caspase 9 and caspase 3. Increased endothelial apoptosis rate and alterations in the HIF-1α/mTOR pathway are recapitulated in tumor-bearing mice in vivo. Further, the anti-angiogenesis function of cinobufagin is consolidated based on its pro-apoptotic effects on an EOMA-derived hemangioendothelioma model. In conclusion, cinobufagin suppresses tumor neovascularization by disrupting the endothelial mTOR/HIF-1α pathway to trigger ROS-mediated vascular endothelial cell apoptosis. Cinobufagin is a promising natural anti-angiogenetic drug that has clinical translation potential and practical application value.

Liu W, Chen X, He Y, et al.
TNF‑α inhibits xenograft tumor formation by A549 lung cancer cells in nude mice via the HIF‑1α/VASP signaling pathway.
Oncol Rep. 2019; 41(4):2418-2430 [PubMed] Related Publications
Lung cancer is the leading cause of cancer‑associated mortality worldwide. Tumor necrosis factor α (TNF‑α) is an important cytokine in the tumor microenvironment that serves a function in the balance of cell survival and cell death pathways. Our previous studies indicated that hypoxia‑inducible factor 1α (HIF‑1α) acts downstream of TNF‑α in MCF‑7 luminal breast cancer cells. However, whether vasodilator‑stimulated phosphoprotein (VASP) is implicated in the direct regulation of HIF‑1α in response to TNF‑α in lung cancer remains unknown. In vitro studies were performed using A549 and H226 lung carcinoma cells and in vivo studies of tumor xenograft models were performed to investigate the effects of TNF‑α. The results demonstrated that TNF‑α decreased VASP expression by upregulating the expression of HIF‑1α to inhibit A549 cell proliferation and adhesion. Inhibition of transplanted tumor growth was associated with downregulation of VASP expression in nude mice. Bioinformatics analysis indicated that expression levels of VASP or HIF‑1α lead to differential outcomes of overall survival in lung carcinoma. These results suggest that the HIF‑1α/VASP signaling pathway serves an important function in the regulation of TNF‑α‑induced suppression of A549 cell proliferation and xenograft growth. This may improve our understanding of the antitumor effect of TNF‑α.

Cimmino F, Avitabile M, Lasorsa VA, et al.
HIF-1 transcription activity: HIF1A driven response in normoxia and in hypoxia.
BMC Med Genet. 2019; 20(1):37 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: HIF1A (Hypoxia-Inducible-Factor 1A) expression in solid tumors is relevant to establish resistance to therapeutic approaches. The use of compounds direct against hypoxia signaling and HIF1A does not show clinical efficiency because of changeable oxygen concentrations in solid tumor areas. The identification of HIF1A targets expressed in both normoxia and hypoxia and of HIF1A/hypoxia signatures might meliorate the prognostic stratification and therapeutic successes in patients with high-risk solid tumors.
METHODS: In this study, we conducted a combined analysis of RNA expression and DNA methylation of neuroblastoma cells silenced or unsilenced for HIF1A expression, grown in normoxia and hypoxia conditions.
RESULTS: The analysis of pathways highlights HIF-1 (heterodimeric transcription factor 1) activity in normoxia in metabolic process and HIF-1 activity in hypoxia in neuronal differentiation process. HIF1A driven transcriptional response in hypoxia depends on epigenetic control at DNA methylation status of gene regulatory regions. Furthermore, low oxygen levels generate HIF1A-dependent or HIF1A-independent signatures, able to stratify patients according to risk categories.
CONCLUSIONS: These findings may help to understand the molecular mechanisms by which low oxygen levels reshape gene signatures and provide new direction for hypoxia targeting in solid tumor.

Lu Y, Li Y, Wang Z, et al.
Downregulation of RGMA by HIF-1A/miR-210-3p axis promotes cell proliferation in oral squamous cell carcinoma.
Biomed Pharmacother. 2019; 112:108608 [PubMed] Related Publications
Repulsive guidance molecules comprise a group of proteins that play an important role in carcinogenesis through interactions with their receptors, but their function in oral squamous cell carcinoma (OSCC) is unclear. Here, we investigated the potential role of the RGM family members in oral cancer pathogenesis. Our study showed that only RGMA was significantly downregulated in the OSCC tissues analyzed by TCGA and validated this finding in OSCC cells. The decreased expression of RGMA was strongly associated with the T stage and with poor prognosis. The ectopic expression of RGMA significantly inhibited the proliferation of OSCC cells both in vitro and in vivo. Moreover, we confirmed that RGMA was a target of miR-210-3p in OSCC and miR-210-3p overexpression contributed to the acceleration of OSCC growth. Further experiments revealed that HIF1A specifically interacted with the promoter of miR-210-3p and enhanced its expression. In summary, our research indicates that RGMA is regulated by the HIF1A/miR-210-3p axis and inhibits OSCC cell proliferation; thus, in the future, the development of therapies that target the HIF1A/miR-210-3p/RGMA axis may aid in the treatment of aggressive cancers.

Kurelac I, Iommarini L, Vatrinet R, et al.
Inducing cancer indolence by targeting mitochondrial Complex I is potentiated by blocking macrophage-mediated adaptive responses.
Nat Commun. 2019; 10(1):903 [PubMed] Free Access to Full Article Related Publications
Converting carcinomas in benign oncocytomas has been suggested as a potential anti-cancer strategy. One of the oncocytoma hallmarks is the lack of respiratory complex I (CI). Here we use genetic ablation of this enzyme to induce indolence in two cancer types, and show this is reversed by allowing the stabilization of Hypoxia Inducible Factor-1 alpha (HIF-1α). We further show that on the long run CI-deficient tumors re-adapt to their inability to respond to hypoxia, concordantly with the persistence of human oncocytomas. We demonstrate that CI-deficient tumors survive and carry out angiogenesis, despite their inability to stabilize HIF-1α. Such adaptive response is mediated by tumor associated macrophages, whose blockage improves the effect of CI ablation. Additionally, the simultaneous pharmacological inhibition of CI function through metformin and macrophage infiltration through PLX-3397 impairs tumor growth in vivo in a synergistic manner, setting the basis for an efficient combinatorial adjuvant therapy in clinical trials.

Luo D, Ren H, Zhang W, et al.
Clinicopathological and prognostic value of hypoxia-inducible factor-1α in patients with bone tumor: a systematic review and meta-analysis.
J Orthop Surg Res. 2019; 14(1):56 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Recently, many studies have shown the role of hypoxia-inducible factor-1α (HIF-1α) expression in the outcome of bone tumor. However, the results remain inconclusive. It is necessary to carry out a meta-analysis of all the current available data to clarify the relationship between HIF-1α and survival or clinicopathological features of bone tumor.
METHODS: PubMed, Cochrane Library, Web of Science, China National Knowledge Internet, and Wanfang databases were used to search the relationship between HIF-1α and bone tumor. Articles investigating clinicopathological and prognostic value of HIF-1α in bone tumor patients were enrolled in this meta-analysis. Overlapping articles, duplicate data, reviews, case reports, and letters without original data were excluded. The pooled risk ratios (RRs) and hazard ratios (HRs) were used to evaluate the clinicopathological and prognostic value of HIF-1α on bone tumor patients, respectively.
RESULTS: A total of 28 studies including 1443 patients were included in this meta-analysis, which were involved in three different types of bone tumor including 3 chondrosarcomas, 2 giant cell tumors of bone, and 23 osteosarcomas. Our results showed that high expression levels of HIF-1α were associated with poorer OS (overall survival) (HR = 2.61, 95% CI 2.11-3.23, P <  0.001) and shorter DFS (disease-free survival) (HR = 2.02, 95% CI 1.41-2.89, P <  0.001) in bone tumor. In addition, this study also analyzed the role of HIF-1α expression in clinicopathological features, which were closely related with the severity of bone tumor, including differentiation, clinical stage, metastasis, and microvessel density. Our results indicated that HIF-1α overexpression was significantly associated with differentiation (RR = 1.56, 95% CI 1.00-2.43, P = 0.049), clinical stage (RR = 1.75, 95% CI 1.25-2.45, P = 0.001), metastasis (RR = 1.78, 95% CI 1.58-2.00, P <  0.001), and microvessel density (SMD = 2.34, 95% CI 1.35-3.34, P <  0.001) of bone tumor.
CONCLUSIONS: HIF-1α overexpression indicated an unfavorable factor for OS and DFS in bone tumor, suggesting that HIF-1α may serve as a potential prognostic marker for bone tumor.

Jia D, Lu M, Jung KH, et al.
Elucidating cancer metabolic plasticity by coupling gene regulation with metabolic pathways.
Proc Natl Acad Sci U S A. 2019; 116(9):3909-3918 [PubMed] Free Access to Full Article Related Publications
Metabolic plasticity enables cancer cells to switch their metabolism phenotypes between glycolysis and oxidative phosphorylation (OXPHOS) during tumorigenesis and metastasis. However, it is still largely unknown how cancer cells orchestrate gene regulation to balance their glycolysis and OXPHOS activities. Previously, by modeling the gene regulation of cancer metabolism we have reported that cancer cells can acquire a stable hybrid metabolic state in which both glycolysis and OXPHOS can be used. Here, to comprehensively characterize cancer metabolic activity, we establish a theoretical framework by coupling gene regulation with metabolic pathways. Our modeling results demonstrate a direct association between the activities of AMPK and HIF-1, master regulators of OXPHOS and glycolysis, respectively, with the activities of three major metabolic pathways: glucose oxidation, glycolysis, and fatty acid oxidation. Our model further characterizes the hybrid metabolic state and a metabolically inactive state where cells have low activity of both glycolysis and OXPHOS. We verify the model prediction using metabolomics and transcriptomics data from paired tumor and adjacent benign tissue samples from a cohort of breast cancer patients and RNA-sequencing data from The Cancer Genome Atlas. We further validate the model prediction by in vitro studies of aggressive triple-negative breast cancer (TNBC) cells. The experimental results confirm that TNBC cells can maintain a hybrid metabolic phenotype and targeting both glycolysis and OXPHOS is necessary to eliminate their metabolic plasticity. In summary, our work serves as a platform to symmetrically study how tuning gene activity modulates metabolic pathway activity, and vice versa.

Safwat El-Deeb O, Abd-Ellatif RN, Othman TS, et al.
The evolving role of protein disulfide isomerase A3 in Egyptian bladder cancer patients.
Gene. 2019; 693:76-83 [PubMed] Related Publications
BACKGROUND: Protein disulfide isomerase A3 (PDIA3), an endoplasmic reticulum protein, is expressed in bladder of BC patients. However, its role in BC has been elusive till now.
OBJECTIVES: This study was conducted to assess whether PDIA3 gene expression was associated with increased odds of BC, in particular muscle-invasive BC (MIBC).
METHODS: Ninety three patients underwent cystoscopy and bladder tumors were biopsied and histologically assessed. Data collected including: patient demographics and clinical characteristics. Biochemical markers: hypoxia inducible factor 1-alpha (HIF-1 α), interleukin 6 (IL-6), advanced oxidation protein products (AOPP), Malondialdehyde (MDA), 8-hydroxy 2-deoxyguanosine (8-OHdG), and reduced glutathione (GSH) and molecular marker PDIA3 gene expression were measured.
RESULTS: According to the tumor grade and stage, 36 patients were found to have MIBC, 27 patients have non MIBC (NMIBC) and 30 patients have no bladder lesions (control group). PDIA3 gene expression level had the largest contribution to a multivariable model for predicting BC, which achieved 89.0% predictive accuracy. The AUC for discriminating MIBC significantly increased from 0.644 to 0.938 when biochemical markers were replaced by molecular PDIA3 marker in the final model.
CONCLUSIONS: Using PDIA3 expression along with prior information of patient's age, bilharzial history with gross hematuria, can help clinicians predict BC, discriminate MIBC and decide consequently the most promising therapeutic management in Egyptian population.

Jarman EJ, Ward C, Turnbull AK, et al.
HER2 regulates HIF-2α and drives an increased hypoxic response in breast cancer.
Breast Cancer Res. 2019; 21(1):10 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Tumour hypoxia is a driver of breast cancer progression associated with worse prognosis and more aggressive disease. The cellular response to hypoxia is mediated by the hypoxia-inducible transcription factors HIF-1 and HIF-2, whose transcriptional activity is canonically regulated through their oxygen-labile HIF-α subunits. These are constitutively degraded in the presence of oxygen; however, HIF-1α can be stabilised, even at high oxygen concentrations, through the activation of HER receptor signalling. Despite this, there is still limited understanding on how HER receptor signalling interacts with HIF activity to contribute to breast cancer progression in the context of tumour hypoxia.
METHODS: 2D and 3D cell line models were used alongside microarray gene expression analysis and meta-analysis of publicly available gene expression datasets to assess the impact of HER2 overexpression on HIF-1α/HIF-2α regulation and to compare the global transcriptomic response to acute and chronic hypoxia in an isogenic cell line model of HER2 overexpression.
RESULTS: HER2 overexpression in MCF7 cells leads to an increase in HIF-2α but not HIF-1α expression in normoxia and an increased upregulation of HIF-2α in hypoxia. Global gene expression analysis showed that HER2 overexpression in these cells promotes an exaggerated transcriptional response to both short-term and long-term hypoxia, with increased expression of numerous hypoxia response genes. HIF-2α expression is frequently higher in HER2-overexpressing tumours and is associated with worse disease-specific survival in HER2-positive breast cancer patients. HER2-overexpressing cell lines demonstrate an increased sensitivity to targeted HIF-2α inhibition through either siRNA or the use of a small molecule inhibitor of HIF-2α translation.
CONCLUSIONS: This study suggests an important interplay between HER2 expression and HIF-2α in breast cancer and highlights the potential for HER2 to drive the expression of numerous hypoxia response genes in normoxia and hypoxia. Overall, these findings show the importance of understanding the regulation of HIF activity in a variety of breast cancer subtypes and points to the potential of targeting HIF-2α as a therapy for HER2-positive breast cancer.

Martinez CA, Kerr B, Jin C, et al.
Obstructive Sleep Apnea Activates HIF-1 in a Hypoxia Dose-Dependent Manner in HCT116 Colorectal Carcinoma Cells.
Int J Mol Sci. 2019; 20(2) [PubMed] Free Access to Full Article Related Publications
Obstructive sleep apnea (OSA) affects a significant proportion of the population and is linked to increased rates of cancer development and a worse cancer outcome. OSA is characterized by nocturnal intermittent hypoxia and animal models of OSA-like intermittent hypoxia show increased tumor growth and metastasis. Advanced tumors typically have regions of chronic hypoxia, activating the transcription factor, HIF-1, which controls the expression of genes involved in cancer progression. Rapid intermittent hypoxia from OSA has been proposed to increase HIF-1 activity and this may occur in tumors. The effect of exposing a developing tumor to OSA-like intermittent hypoxia is largely unknown. We have built a cell-based model of physiological OSA tissue oxygenation in order to study the effects of intermittent hypoxia in HCT116 colorectal cancer cells. We found that HIF-1α increases following intermittent hypoxia and that the expression of HIF-target genes increases, including those involved in glycolysis, the hypoxic pathway and extracellular matrix remodeling. Expression of these genes acts as a 'hypoxic' signature which is associated with a worse prognosis. The total dose of hypoxia determined the magnitude of change in the hypoxic signature rather than the frequency or duration of hypoxia-reoxygenation cycles per se. Finally, transcription of

Guo H, Ci X, Ahmed M, et al.
ONECUT2 is a driver of neuroendocrine prostate cancer.
Nat Commun. 2019; 10(1):278 [PubMed] Free Access to Full Article Related Publications
Neuroendocrine prostate cancer (NEPC), a lethal form of the disease, is characterized by loss of androgen receptor (AR) signaling during neuroendocrine transdifferentiation, which results in resistance to AR-targeted therapy. Clinically, genomically and epigenetically, NEPC resembles other types of poorly differentiated neuroendocrine tumors (NETs). Through pan-NET analyses, we identified ONECUT2 as a candidate master transcriptional regulator of poorly differentiated NETs. ONECUT2 ectopic expression in prostate adenocarcinoma synergizes with hypoxia to suppress androgen signaling and induce neuroendocrine plasticity. ONEUCT2 drives tumor aggressiveness in NEPC, partially through regulating hypoxia signaling and tumor hypoxia. Specifically, ONECUT2 activates SMAD3, which regulates hypoxia signaling through modulating HIF1α chromatin-binding, leading NEPC to exhibit higher degrees of hypoxia compared to prostate adenocarcinomas. Treatment with hypoxia-activated prodrug TH-302 potently reduces NEPC tumor growth. Collectively, these results highlight the synergy between ONECUT2 and hypoxia in driving NEPC, and emphasize the potential of hypoxia-directed therapy for NEPC patients.

Hoseinkhani Z, Rastegari-Pouyani M, Oubari F, et al.
Contribution and prognostic value of TSGA10 gene expression in patients with acute myeloid leukemia (AML).
Pathol Res Pract. 2019; 215(3):506-511 [PubMed] Related Publications
BACKGROUND: Different studies have investigated TSGA10 expression in various cancerous tissues but, so far no study has been conducted on newly diagnosed (ND) AML patients. The association of TSGA10 gene expression with hypoxia inducible factor (HIF) and angiogenic factors has remained to be fully elucidated and is still a controversial issue. The present study was designed to investigate this association in patients newly diagnosed with AML.
METHODS: We evaluated TSGA10, HIF-1α and VEGF mRNA levels in ND AML patients and healthy subjects using real-time PCR technique. Data were analyzed via comparative Livak method.
RESULTS: Based on the results of this study, TSGA10 gene expression was decreased in 28 out of 30 (93.3%) samples while VEGF and HIF-1α expression levels were increased in all ND AML patients compared to healthy controls. Diagnostic evaluation was performed by receiver operating characteristic (ROC) curve and area under the curve (AUC) calculation. Respectively, using cut-off relative quantification of 1.604, 0.0329, and 0.0042, the sensitivity values of TSGA10, VEGF, and HIF-1α gene expression were 86.7%, 90%, and 100%. Also, specificity values were 100%, 100% and 100%, respectively. TSGA10 expression was shown to be reduced in ND AML patients compared with healthy subjects and we found a negative correlation between TSGA10 and VEGF expression.
CONCLUSIONS: Since TSGA10 interacts with HIF-1 and affects its transcriptional activity, in ND AML patients with decreased TSGA10 expression, VEGF expression was high suggesting a TSGA10 mediated regulation of HIF-1 target genes. Altogether, the current study showed that TSGA10 could be considered as a tumor suppressor in AML patients.

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