Polymorphisms in the Hypoxia Inducible Factor 1-α and the Impact on the Prognosis of Early Stages of Oral Cancer

2009 ◽  
Vol 16 (8) ◽  
pp. 2351-2358 ◽  
Author(s):  
Mario Fernando Muñoz-Guerra ◽  
María Encarnación Fernández-Contreras ◽  
Ana Laura Capote Moreno ◽  
Irene Domínguez Martín ◽  
Belén Herráez ◽  
...  
Keyword(s):  
Oral Cancer ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1 ◽  
Early Stages ◽  
The Impact

scholarly journals Tumor Angiogenic Inhibition Triggered Necrosis (TAITN) in Oral Cancer

2019 ◽  
Author(s):  
Saori Yoshida ◽  
Hotaka Kawai ◽  
Taka Eguchi ◽  
Shintaro Sukegawa ◽  
May Oo ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Cancer ◽  
Tumor Angiogenesis ◽  
Therapeutic Strategy ◽  
Hypoxia Inducible Factor ◽  
Tumor Vasculature ◽  
Clinical Specimens ◽  
Hypoxia Inducible Factor 1 ◽  
Tumor Survival

CXCR4 is a chemokine receptor crucial in tumor progression, although the angiogenic role of CXCR4 in oral squamous cell carcinoma (OSCC) has not been investigated. Here we show that CXCR4 is crucial for tumor angiogenesis thereby supports tumor survival in OSCC. Immunohistochemistry on human clinical specimens revealed that CXCR4 and a tumor vasculature marker CD34 were co-distributed in tumor vessels in human OSCC specimens. To ask the effects of CXCR4 inhibition, we treated the OSCC-xenografted mice with AMD3100, so-called plerixafor, an antagonist of CXCR4. Notably, we found a unique pathophysiological structure defined as Tumor Angiogenic Inhibition Triggered Necrosis (TAITN) induced by the CXCR4 antagonism. Treatment with AMD3100 increased necrotic area with the induction of hypoxia-inducible factor-1α in the xenografted tumors, suggesting that AMD3100-induced TAITN was involved in hypoxia and ischemia. Taken together, we demonstrated that CXCR4 plays a crucial role in tumor angiogenesis required for OSCC progression, whereas TAITN induced by CXCR4 antagonism could be an effective anti-angiogenic therapeutic strategy in OSCC treatment.

scholarly journals Pengaruh ekspresi p53 dan HIF1 terhadap peningkatan laktat jaringan nasofaring pada pasien karsinoma nasofaring

2018 ◽  
Vol 48 (1) ◽  
pp. 74
Author(s):  
Jemmy Kurniawan ◽  
Pudji Rahaju ◽  
Soehartono Soehartono
Keyword(s):  
Blood Lactate ◽  
Lactate Level ◽  
Elevated Level ◽  
Hypoxia Inducible Factor ◽  
Blood Lactate Level ◽  
Cross Sectional ◽  
Hypoxia Inducible Factor 1 ◽  
Nasopharyngeal Tissue ◽  
Lactate Levels ◽  
The Impact

Latar Belakang: Karsinoma nasofaring (KNF) merupakan keganasan tersering pada kepala dan leher. Pilihan terapi KNF adalah radioterapi dan kemoterapi yang berhubungan dengan toksisitas, resistensi obat, dan rekurensi. Intervensi metabolik yang didasarkan pada perubahan metabolisme sel kanker merupakan salah satu strategi terapi kanker pada saat ini. Untuk dapat mengetahuinya perlu dipahami pengaruh ekspresi p53 dan hypoxia-inducible factor 1 (HIF1) terhadap peningkatan kadar laktat jaringan nasofaring pada pasien KNF. Tujuan: Mengetahui pengaruh ekspresi p53 dan HIF1 terhadap peningkatan kadar laktat jaringan nasofaring, dan untuk mengetahui kesesuaian antara kadar laktat darah dengan laktat jaringan nasofaring. Metode: Penelitian cross sectional melibatkan 10 subjek, dilakukan biopsi nasofaring dengan tuntunan nasoendoskopi untuk pemeriksaan histopatologi, ekspresi p53 dan HIF1 dengan imunohistokimia, laktat jaringan nasofaring dengan colorimetric, dan laktat darah. Hasil: Seluruh subjek mengalami peningkatan ekspresi p53 dan HIF1 dengan rerata p53 19,53±7,37 dan HIF1 24,30±12,28. Seluruh subjek penelitian memiliki kadar laktat jaringan meningkat, dengan rerata kadar laktat 0,67±0,39. Kadar laktat darah subjek cenderung meningkat dengan rerata 2,93±0,65. Terdapat pengaruh peningkatan ekspresi p53 terhadap peningkatan kadar laktat jaringan (p=0,002). Terdapat pengaruh peningkatan ekspresi HIF1 terhadap peningkatan kadar laktat jaringan (p=0,042). Tidak terdapat kesesuaian antara kadar laktat darah dengan laktat jaringan nasofaring (p=0,000). Kesimpulan: Peningkatan ekspresi p53 dan HIF1 berpengaruh terhadap peningkatan kadar laktat jaringan nasofaring pada pasien KNF, namun kadar laktat darah tidak menggambarkan kadar laktat jaringan nasofaring. ABSTRACTBackground: Nasopharyngeal carcinoma (NPC) is the most frequent malignancy of the head and neck. The options of NPC therapy are radiotherapy and chemotherapy, associated with toxicity, drug resistance, and recurrence. Metabolic intervention based on changes in cancer cell metabolism is currently one of the strategies of cancer therapy. Aim: To determine the impact of p53 and hypoxia-inducible factor 1 (HIF1) expression on elevated lactate levels of nasopharyngeal tissue, and to determine the compatibility between blood lactate and nasopharyngeal tissue lactate levels in patients with NPC. Method: This cross-sectional study involved 10 subjects who underwent nasopharyngeal biopsy for histopathologic examination, p53 and HIF1 expression using immunohistochemistry, lactate of nasopharyngeal tissue using colorimetric, and blood lactate. Results: All subjects had increased expression of p53 and HIF1 with p53 mean of 19.53±7.37 and HIF1 mean of 24.30±12.28. All subjects had elevated tissue lactate levels, with lactate levels mean of 0.67±0.39. The blood lactate level of the subjects increased, with blood lactate level mean of 2.93±0.65. There was a significant increasing impact of p53 expression on tissue lactate elevated level (p=0.002) and a significant increasing impact of HIF1 expression on tissue lactate elevated level (p=0.042). There was no correlation between lactate levels of blood lactate and nasopharyngeal tissue (p=0.000). Conclusion: Increased expression of p53 and HIF1 had an effect on increased levels of lactate nasopharyngeal tissue in NPC patients, but blood lactate levels did not have a correlation with lactate levels of nasopharyngeal tissue.

scholarly journals GRK6 Depletion Induces HIF Activity in Lung Adenocarcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Sumei Yao ◽  
Ayse Ertay ◽  
Yilu Zhou ◽  
Liudi Yao ◽  
Charlotte Hill ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Hypoxia Inducible Factor ◽  
Lung Epithelial Cells ◽  
Alveolar Epithelial ◽  
Hypoxia Inducible Factor 1 ◽  
Lung Epithelial ◽  
Hif Pathway ◽  
The Impact ◽  
G Protein Coupled

G protein-coupled receptor kinase 6 (GRK6) is expressed in various tissues and is involved in the development of several diseases including lung cancer. We previously reported that GRK6 is down-regulated in lung adenocarcinoma patients, which induces cell invasion and metastasis. However, further understanding of the role of GRK6 in lung adenocarcinoma is required. Here we explored the functional consequence of GRK6 inhibition in lung epithelial cells. Analysis of TCGA data was coupled with RNA sequencing (RNA-seq) in alveolar epithelial type II (ATII) cells following depletion of GRK6 with RNA interference (RNAi). Findings were validated in ATII cells followed by tissue microarray analysis. Pathway analysis suggested that one of the Hallmark pathways enriched upon GRK6 inhibition is ‘Hallmark_Hypoxia’ (FDR = 0.014). We demonstrated that GRK6 depletion induces HIF1α (hypoxia-inducible factor 1 alpha) levels and activity in ATII cells. The findings were further confirmed in lung adenocarcinoma samples, in which GRK6 expression levels negatively and positively correlate with HIF1α expression (P = 0.015) and VHL expression (P < 0.0001), respectively. Mechanistically, we showed the impact of GRK6 on HIF activity could be achieved via regulation of VHL levels. Taken together, targeting the HIF pathway may provide new strategies for therapy in GRK6-depleted lung adenocarcinoma patients.

scholarly journals Activation of hypoxia-inducible factor-1 protects airway epithelium against oxidant-induced barrier dysfunction

2011 ◽  
Vol 301 (6) ◽  
pp. L993-L1002 ◽  
Author(s):  
Nels Olson ◽  
Milena Hristova ◽  
Nicholas H. Heintz ◽  
Karen M. Lounsbury ◽  
Albert van der Vliet
Keyword(s):  
Oxidative Stress ◽  
Barrier Function ◽  
Hypoxia Inducible Factor ◽  
Respiratory Epithelium ◽  
Epithelial Barrier ◽  
Protective Effects ◽  
Hypoxia Inducible Factor 1 ◽  
Junction Protein ◽  
Primary Mouse ◽  
The Impact

The respiratory epithelium forms an important barrier against inhaled pollutants and microorganisms, and its barrier function is often compromised during inflammatory airway diseases. Epithelial activation of hypoxia-inducible factor-1 (HIF-1) represents one feature of airway inflammation, but the functional importance of HIF-1 within the respiratory epithelium is largely unknown. Using primary mouse tracheal epithelial (MTE) cells or immortalized human bronchial epithelial cells (16HBE14o−), we evaluated the impact of HIF-1 activation on loss of epithelial barrier function during oxidative stress. Exposure of either 16HBE14o− or MTE cells to H2O2 resulted in significant loss of transepithelial electrical resistance and increased permeability to fluorescein isothiocyanate-dextran (4 kDa), and this was attenuated significantly after prior activation of HIF-1 by preexposure to hypoxia (2% O2; 6 h) or the hypoxia mimics CoCl2 or dimethyloxalylglycine (DMOG). Oxidative barrier loss was associated with reduced levels of the tight junction protein occludin and with hyperoxidation of the antioxidant enzyme peroxiredoxin (Prx-SO2H), events that were also attenuated by prior activation of HIF-1. Involvement of HIF-1 in these protective effects was confirmed using the pharmacological inhibitor YC-1 and by short-hairpin RNA knockdown of HIF-1α. The protective effects of HIF-1 were associated with induction of sestrin-2, a hypoxia-inducible enzyme known to reduce oxidative stress and minimize Prx hyperoxidation. Together, our results suggest that loss of epithelial barrier integrity by oxidative stress is minimized by activation of HIF-1, in part by induction of sestrin-2.

scholarly journals Aquatic surface respiration improves survival during hypoxia in zebrafish ( Danio rerio ) lacking hypoxia-inducible factor 1-α

2022 ◽  
Vol 289 (1966) ◽  
Author(s):  
Milica Mandic ◽  
Kaitlyn Flear ◽  
Pearl Qiu ◽  
Yihang K. Pan ◽  
Steve F. Perry ◽  
...  
Keyword(s):  
Danio Rerio ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Tolerance ◽  
Wild Type ◽  
Survival Times ◽  
Aquatic Surface Respiration ◽  
Negative Effects ◽  
Hypoxia Inducible Factor 1 ◽  
Impact On Survival ◽  
The Impact

Hypoxia-inducible factor 1-α (Hif-1α), an important transcription factor regulating cellular responses to reductions in O 2 , previously was shown to improve hypoxia tolerance in zebrafish ( Danio rerio ). Here, we examined the contribution of Hif-1α to hypoxic survival, focusing on the benefit of aquatic surface respiration (ASR). Wild-type and Hif-1α knockout lines of adult zebrafish were exposed to two levels (moderate or severe) of intermittent hypoxia. Survival was significantly compromised in Hif-1α knockout zebrafish prevented from accessing the surface during severe (16 mmHg) but not moderate (23 mmHg) hypoxia. When allowed access to the surface in severe hypoxia, survival times did not differ between wild-type and Hif-1α knockouts. Performing ASR mitigated the negative effects of the loss of Hif-1α with the knockouts initiating ASR at a higher P O 2 threshold and performing ASR for longer than wild-types. The loss of Hif-1α had little impact on survival in fish between 1 and 5 days post-fertilization, but as the larvae aged, their reliance on Hif-1α increased. Similar to adult fish, ASR compensated for the loss of Hif-1α on survival. Together, these results demonstrate that age, hypoxia severity and, in particular, the ability to perform ASR significantly modulate the impact of Hif-1α on survival in hypoxic zebrafish.

scholarly journals The Impact of Moderate Chronic Hypoxia and Hyperoxia on the Level of Apoptotic and Autophagic Proteins in Myocardial Tissue

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Alexandra Gyongyosi ◽  
Laura Terraneo ◽  
Paola Bianciardi ◽  
Arpad Tosaki ◽  
Istvan Lekli ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chronic Hypoxia ◽  
Hypoxia Inducible Factor ◽  
Redox Balance ◽  
Heart Tissue ◽  
Protective Mechanism ◽  
Protein Levels ◽  
Hypoxia Inducible Factor 1 ◽  
The Impact ◽  
Hypoxic Group

The redox imbalance and the consequent oxidative stress have been implicated in many pathological conditions, including cardiovascular diseases. The lack or the excess of O2 supply can alter the redox balance. The aim of the present study was to understand the heart responses to prolonged hypoxia or hyperoxia and how such situations may activate survival mechanisms or trigger cell death. Seven-week-old Foxn1 mice were exposed to hypoxia (10% O2), normoxia (21% O2), or hyperoxia (30% O2) for 28 days, then the heart tissue was excised and analyzed. The alterations in redox balance, housekeeping protein levels, and autophagic and apoptotic process regulation were studied. The D-ROM test demonstrated an increased oxidative stress in the hypoxic group compared to the hyperoxic group. The level of hypoxia inducible factor-1 (HIF-1α) was increased by hypoxia while HIF-2α was not affected by treatments. Chronic hypoxia activated the biochemical markers of autophagy, and we observed elevated levels of Beclin-1 while LC3B-II and p62 were constant. Nevertheless, we measured significantly enhanced number of TUNEL-positive cells and higher Bax/Bcl2 ratio in hyperoxia with respect to hypoxia. Surprisingly, our results revealed alterations in the level of housekeeping proteins. The expression of α-tubulin, total-actin, and GAPDH was increased in the hypoxic group while decreased in the hyperoxic group. These findings suggest that autophagy is induced in the heart under hypoxia, which may serve as a protective mechanism in response to enhanced oxidative stress. While prolonged hypoxia-induced autophagy leads to reduced heart apoptosis, low autophagic level in hyperoxia failed to prevent the excessive DNA fragmentation.

scholarly journals HUMMR, a hypoxia- and HIF-1α–inducible protein, alters mitochondrial distribution and transport

2009 ◽  
Vol 185 (6) ◽  
pp. 1065-1081 ◽  
Author(s):  
Yan Li ◽  
Seung Lim ◽  
David Hoffman ◽  
Pontus Aspenstrom ◽  
Howard J. Federoff ◽  
...  
Keyword(s):  
Mitochondrial Protein ◽  
Hypoxia Inducible Factor ◽  
Mitochondrial Transport ◽  
Neuronal Viability ◽  
Hypoxia Inducible Factor 1 ◽  
Mitochondrial Movement ◽  
Mitochondrial Distribution ◽  
Inducible Protein ◽  
And Function ◽  
The Impact

Mitochondrial transport is critical for maintenance of normal neuronal function. Here, we identify a novel mitochondria protein, hypoxia up-regulated mitochondrial movement regulator (HUMMR), which is expressed in neurons and is markedly induced by hypoxia-inducible factor 1 α (HIF-1α). Interestingly, HUMMR interacts with Miro-1 and Miro-2, mitochondrial proteins that are critical for mediating mitochondrial transport. Interestingly, knockdown of HUMMR or HIF-1 function in neurons exposed to hypoxia markedly reduces mitochondrial content in axons. Because mitochondrial transport and distribution are inextricably linked, the impact of reduced HUMMR function on the direction of mitochondrial transport was also explored. Loss of HUMMR function in hypoxia diminished the percentage of motile mitochondria moving in the anterograde direction and enhanced the percentage moving in the retrograde direction. Thus, HUMMR, a novel mitochondrial protein induced by HIF-1 and hypoxia, biases mitochondria transport in the anterograde direction. These findings have broad implications for maintenance of neuronal viability and function during physiological and pathological states.

Vascular adaptations to hypoxia: molecular and cellular mechanisms regulating vascular tone

2007 ◽  
Vol 43 ◽  
pp. 105-120 ◽  
Author(s):  
Michael L. Paffett ◽  
Benjimen R. Walker
Keyword(s):  
Vascular Tone ◽  
Cellular Proliferation ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Hypoxia Inducible Factor ◽  
Systemic Circulation ◽  
Cellular Mechanisms ◽  
Hypoxia Inducible Factor 1 ◽  
Pulmonary Vasoconstriction ◽  
Adaptive Mechanisms ◽  
Adaptive Processes

Several molecular and cellular adaptive mechanisms to hypoxia exist within the vasculature. Many of these processes involve oxygen sensing which is transduced into mediators of vasoconstriction in the pulmonary circulation and vasodilation in the systemic circulation. A variety of oxygen-responsive pathways, such as HIF (hypoxia-inducible factor)-1 and HOs (haem oxygenases), contribute to the overall adaptive process during hypoxia and are currently an area of intense research. Generation of ROS (reactive oxygen species) may also differentially regulate vascular tone in these circulations. Potential candidates underlying the divergent responses between the systemic and pulmonary circulations may include Nox (NADPH oxidase)-derived ROS and mitochondrial-derived ROS. In addition to alterations in ROS production governing vascular tone in the hypoxic setting, other vascular adaptations are likely to be involved. HPV (hypoxic pulmonary vasoconstriction) and CH (chronic hypoxia)-induced alterations in cellular proliferation, ionic conductances and changes in the contractile apparatus sensitivity to calcium, all occur as adaptive processes within the vasculature.

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