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Hypoxia-inducible factor-1α–mediated upregulation of CD99 promotes the proliferation of placental mesenchymal stem cells by regulating ERK1/2 被引量:1
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作者 Xu-Dong Feng Jia-Qi Zhu +7 位作者 Jia-Hang Zhou Fei-Yan Lin Bing Feng Xiao-Wei Shi Qiao-Ling Pan Jiong Yu Lan-Juan Li Hong-Cui Cao 《World Journal of Stem Cells》 SCIE 2021年第4期317-330,共14页
BACKGROUND As human placenta-derived mesenchymal stem cells(hP-MSCs)exist in a physiologically hypoxic microenvironment,various studies have focused on the influence of hypoxia.However,the underlying mechanisms remain... BACKGROUND As human placenta-derived mesenchymal stem cells(hP-MSCs)exist in a physiologically hypoxic microenvironment,various studies have focused on the influence of hypoxia.However,the underlying mechanisms remain to be further explored.AIM The aim was to reveal the possible mechanisms by which hypoxia enhances the proliferation of hP-MSCs.METHODS A hypoxic cell incubator(2.5%O2)was used to mimic a hypoxic microenvironment.Cell counting kit-8 and 5-ethynyl-20-deoxyuridine incorporation assays were used to assay the proliferation of hP-MSCs.The cell cycle was profiled by flow cytometry.Transcriptome profiling of hP-MSCs under hypoxia was performed by RNA sequencing.CD99 mRNA expression was assayed by reverse transcription-polymerase chain reaction.Small interfering RNA-mediated hypoxia-inducible factor 1α(HIF-1α)or CD99 knockdown of hP-MSCs,luciferase reporter assays,and the ERK1/2 signaling inhibitor PD98059 were used in the mechanistic analysis.Protein expression was assayed by western blotting;immunofluorescence assays were conducted to evaluate changes in expression levels.RESULTS Hypoxia enhanced hP-MSC proliferation,increased the expression of cyclin E1,cyclin-dependent kinase 2,and cyclin A2,and decreased the expression of p21.Under hypoxia,CD99 expression was increased by HIF-1α.CD99-specific small interfering RNA or the ERK1/2 signaling inhibitor PD98059 abrogated the hypoxia-induced increase in cell proliferation.CONCLUSION Hypoxia promoted hP-MSCs proliferation in a manner dependent on CD99 regulation of the MAPK/ERK signaling pathway in vitro. 展开更多
关键词 hypoxia-inducible factor hypoxia Mesenchymal stem cells proliferation CD99 RNA sequencing assay MAPK/ERK signaling pathway
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Effects of hypoxia-inducible factor-1α silencing on the proliferation of CBRH-7919 hepatoma cells 被引量:19
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作者 Lin-Feng Xu Jia-Yan Ni +2 位作者 Hong-Liang Sun Yao-Ting Chen Yu-Dan Wu 《World Journal of Gastroenterology》 SCIE CAS 2013年第11期1749-1759,共11页
AIM:To study the effects of hypoxia-inducible factor1α(HIF-1α) silencing on the proliferation of hypoxic CBRH-7919 rat hepatoma cells.METHODS:The CBRH-7919 rat hepatoma cell line was used in this study and the hypox... AIM:To study the effects of hypoxia-inducible factor1α(HIF-1α) silencing on the proliferation of hypoxic CBRH-7919 rat hepatoma cells.METHODS:The CBRH-7919 rat hepatoma cell line was used in this study and the hypoxic model was constructed using CoCl2.The HIF-1α-specific RNAi sequences were designed according to the gene coding sequence of rat HIF-1α obtained from GeneBank.The secondary structure of the HIF-1α gene sequence was analyzed using RNA draw software.The small interfering RNA(siRNA) transfection mixture was produced by mixing the siRNA and Lipofectamine2000TM,and transfected into the hypoxic hepatoma cells.Real time reverse transcription-polymerase chain reaction(RTPCR) and Western blotting assay were used to detect the expression levels of mRNA and protein.HIF-1α and vascular endothelial growth factor(VEGF) mRNA was determined using real time RT-PCR;the protein expression levels of AKT,p-AKT,p21 and cyclinD1 were determined using Western blotting.The proliferation of hepatoma cells was observed using the methyl thiazolyl tetrazolium(MTT) assay and the bromodeoxyuridine(BrdU) incorporation cell proliferation assay.RESULTS:Under induced hypoxia,the viability of the hepatoma cells reached a minimum at 800 μmol/L CoCl2;the viability of the cells was relatively high at CoCl2 concentrations between 100 μmol/L and 200 μmol/L.Under hypoxia,the mRNA and protein expression levels of HIF-1α and VEGF were significantly higher than that of hepatoma cells that were cultured in normaxia.HIF-1α-specific RNAi sequences were successfully transfected into hepatoma cells.The transfection of specific siRNAs significantly inhibited the mRNA and protein expression levels of HIF-1α and VEGF,along with the protein expression levels of p-AKT and cyclinD1;the protein expression of p21 was significantly increased,and there was no significant difference in the expression of AKT.The MTT assay showed that the amount of hepatoma cells in S phase in the siRNA transfection group was obviously smaller than that in the control group;in the siRNA transfection group,the amount of hepatoma cells in G1 phase was more than that in the control group.The BrdU incorporation assay showed that the number of BrdU positive hepatoma cells in the siRNA transfection group was less than that in the control group.The data of the MTT assay and BrdU incorporation assay suggested that HIF-1α silencing using siRNAs significantly inhibited the proliferation of hepatoma cells.CONCLUSION:Hypoxia increases the expression of HIF-1α,and HIF-1α silencing significantly inhibits the proliferation of hypoxic CBRH-7919 rat hepatoma cells. 展开更多
关键词 RNA interference hypoxia-inducible factor Vascular ENDOTHELIAL growth factor Protein KINASE B CBRH-7919 HEPATOMA cells
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Cerebral dopamine neurotrophic factor promotes the proliferation and differentiation of neural stem cells in hypoxic environments 被引量:2
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作者 Chao-Qun Lin Lu-Kui Chen 《Neural Regeneration Research》 SCIE CAS CSCD 2020年第11期2057-2062,共6页
Previous research found that cerebral dopamine neurotrophic factor(CDNF)has a protective effect on brain dopaminergic neurons,and CDNF is regarded as a promising therapeutic agent for neurodegenerative diseases.Howeve... Previous research found that cerebral dopamine neurotrophic factor(CDNF)has a protective effect on brain dopaminergic neurons,and CDNF is regarded as a promising therapeutic agent for neurodegenerative diseases.However,the effects of CDNF on the proliferation,differentiation,and apoptosis of neural stem cells(NSCs),which are very sensitive to hypoxic environments,remain unknown.In this study,NSCs were extracted from the hippocampi of fetal rats and cultured with different concentrations of CDNF.The results showed that 200 nM CDNF was the optimal concentration for significantly increasing the viability of NSCs under non-hypoxic environmental conditions.Then,the cells were cultured with 200 nM CDNF under the hypoxic conditions of 90%N_2,5%CO_2,and 5%air for 6 hours.The results showed that CDNF significantly improved the viability of hypoxic NSCs and reduced apoptosis among hypoxic NSCs.The detection of markers showed that CDNF increased the differentiation of hypoxic NSCs into neurons and astrocytes.CDNF also reduced the expression level of Lin28 protein and increased the expression of Let-7 mRNA in NSCs,under hypoxic conditions.In conclusion,we determined that CDNF was able to reverse the adverse proliferation,differentiation,and apoptosis effects that normally affect NSCs in a hypoxic environment.Furthermore,the Lin28/Let-7 pathway may be involved in this regulated function of CDNF.The present study was approved by the Laboratory Animal Centre of Southeast University,China(approval No.20180924006)on September 24,2018. 展开更多
关键词 apoptosis ASTROCYTE CEREBRAL DOPAMINE NEUROTROPHIC factor differentiation hypoxia LET-7 Lin28 neural stem cells neuron proliferation
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Effects of biological clock gene BMAL1 and hypoxia-inducible factor HIF-1αon proliferation,migration and radiotherapy sensitivity of nasopharyngeal carcinoma cells HONE1
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作者 Yaxue Tang Yuanyuan Li +5 位作者 Chaofen Zhao Lina Liu Qianyong He Yuxin Li Dingan Zhou Feng Jin 《Holistic Integrative Oncology》 2023年第1期256-269,共14页
Objective To understand the effects of clock gene BMAL1 and HIF-1α(Hypoxia inducible factor-1α)on proliferation,migration and sensitivity to radiotherapy of nasopharyngeal carcinoma cells HONE1.At the same time,whet... Objective To understand the effects of clock gene BMAL1 and HIF-1α(Hypoxia inducible factor-1α)on proliferation,migration and sensitivity to radiotherapy of nasopharyngeal carcinoma cells HONE1.At the same time,whether the biological clock gene BMAL1 can affect the expression of HIF-1αprotein was investigated.It will lay the foundation for further study on the correlation between clock gene BMAL1 and HIF pathway.Methods BMAL1 gene overexpression and interference lentivirus and HIF-1αgene interference lentivirus were constructed respectively,and were transfected into nasopharyngeal carcinoma cells HONE1.Western blot was used to verify the establishment of overexpressed and knockdown BMAL1 cell lines and HIF-1αgene knockdown cell line,and to investigate the expression of HIF-1αprotein in overexpressed and knockdown BMAL1 cell lines.CCK-8 cell proliferation test and scratch test were used to analyze the proliferation and migration ability of cells.Cell apoptosis after radiotherapy was analyzed by flow cytometry.The effects of BMAL1 and HIF-1αon the sensitivity of HONE1 radiotherapy in nasopharyngeal carcinoma cells after X-ray irradiation at different doses(0Gy,2Gy,4Gy,6Gy)were detected by clone formation assay.Results The overexpression of BMAL1 gene and lentivirus interference were constructed to effectively up regulate and down regulate the expression of BMAL1 protein in nasopharyngeal carcinoma cells HONE1.Meanwhile,HIF-1αgene interference lentivirus was constructed to effectively down-regulate the expression of HIF-1αprotein in nasopharyngeal carcinoma cell line HONE1,and successfully screen out stable nasopharyngeal carcinoma cell lines.Western blot results showed that overexpression of BMAL1 gene could inhibit the expression of HIF-1αprotein in HONE1 of nasopharyngeal carcinoma cells,while knockdown of BMAL1 gene promoted the expression of HIF-1αprotein in HONE1 of nasopharyngeal carcinoma cells(P<0.05).CCK-8 cell proliferation and scratch test showed that overexpression of BMAL1 gene or knockdown of HIF-1αgene could inhibit the proliferation and migration of HONE1 cells(P<0.05).Flow cytometry results showed that after 8Gy irradiation for 72 h,the apoptosis rate of BMALl gene overexpression group was higher than that of the overexpression control group,similarly,the apoptosis rate of HIF-1αgene knockdown group was higher than that of the knockdown control group(P<0.05).After X-ray irradiation at different doses(0Gy,2Gy,4Gy,6Gy),clon-formation experiment showed that the clon-formation rate and cell survival fraction of BMALl overexpression group or HIF-1αknockdown group were lower than those of negative control group(P<0.05).Sigmaplot analysis showed that the D0,Dq and SF2 of the BMAL1 overexpression group or HIF-1αknockdown group were lower than those of the negative control group,and the radiosensitization ratios were 1.381 and 1.063,respectively.Conclusion Overexpression of BMAL1 gene can inhibit the proliferation and migration of nasopharyngeal carcinoma cell line HONE1,increase apoptosis after radiotherapy and improve radiosensitivity.Knock down HIF-1αGene can inhibit the proliferation and migration of nasopharyngeal carcinoma cell line HONE1,increase apoptosis after radiotherapy and improve radiosensitivity.In nasopharyngeal carcinoma cells HONE1,overexpression of BMAL1 gene can inhibit the expression of HIF-1αprotein while knockdown of BMAL1 gene can promote the expression of HIF-1αprotein. 展开更多
关键词 Circadian clock gene BMAL1 hypoxia inducible factor HIF-1α Nasopharyngeal carcinoma Cell proliferation Cell migration Radiotherapy sensitivity
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DI-3-n-butylphthalide exerts neuroprotective effects by modulating hypoxia-inducible factor 1-alpha ubiquitination to attenuate oxidative stress-induced apoptosis 被引量:9
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作者 Shuai Li Jingyuan Zhao +4 位作者 Yan Xi Jiaqi Ren Yanna Zhu Yan Lu Deshi Dong 《Neural Regeneration Research》 SCIE CAS CSCD 2023年第11期2424-2428,共5页
DI-3-n-butylphthalide is used to treat mild and moderate acute ischemic stroke.However,the precise underlying mechanism requires further investigation.In this study,we investigated the molecular mechanism of DI-3-n-bu... DI-3-n-butylphthalide is used to treat mild and moderate acute ischemic stroke.However,the precise underlying mechanism requires further investigation.In this study,we investigated the molecular mechanism of DI-3-n-butylphthalide action by various means.We used hydrogen peroxide to induce injury to PC12cells and RAW264.7 cells to mimic neuronal oxidative stress injury in stroke in vitro and examined the effects of DI-3-n-butylphthalide.We found that DI-3-nbutylphthalide pretreatment markedly inhibited the reduction in viability and reactive oxygen species production in PC12 cells caused by hydrogen peroxide and inhibited cell apoptosis.Furthermore,DI-3-n-butylphthalide pretreatment inhibited the expression of the pro-apoptotic genes Bax and Bnip3.DI-3-nbutylphthalide also promoted ubiquitination and degradation of hypoxia inducible factor 1α,the key transcription factor that regulates Bax and Bnip3 genes.These findings suggest that DI-3-n-butylphthalide exhibits a neuroprotective effect on stroke by promoting hypoxia inducible factor-1α ubiquitination and degradation and inhibiting cell apoptosis. 展开更多
关键词 blood-brain barrier Dl-3-n-butylphthalide hypoxia inducible factor MITOCHONDRIA NEUROPROTECTION oxidative stress reactive oxygen species stroke transcription factor UBIQUITINATION
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Royal Jelly Extract Accelerates Keratinocyte Proliferation, and Upregulates Laminin α3 and Integrin β1 mRNA Expression, via Akt/mTOR/HIF-1α Pathway 被引量:2
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作者 Akihiro Aioi 《Journal of Cosmetics, Dermatological Sciences and Applications》 2022年第2期83-94,共12页
Background: In the previous decade, various benefits and biological activities of royal jelly, applied in alternative and modern medicine, and cosmetics, have been reported. However, the effects of royal jelly extract... Background: In the previous decade, various benefits and biological activities of royal jelly, applied in alternative and modern medicine, and cosmetics, have been reported. However, the effects of royal jelly extract (RJ) on keratinocytes have not been fully elucidated. Objective: The primary objectives of this study were to reveal the effects of RJ on keratinocytes and explore the underlying mechanism. Methods: HaCaT cells, an immortal human epidermis-derived keratinocyte cell line, were used in this study. Laminin α3 (LAMA3), integrin β1 (ITGB1), and hypoxia-inducible factor-1α (HIF-1α) mRNA expression levels were determined using real-time PCR. Cell proliferation rate was measured using a bromodeoxyuridine uptake assay. Results: RJ treatment upregulated LAMA3, ITGB1 and HIF-1α mRNA expression, and accelerated HaCaT cell proliferation. Akt and mTOR inhibitors suppressed the RJ-induced HIF-1α expression and cell proliferation. HIF-1α silencing abrogated RJ-induced LAMA3 and ITGB1 mRNA expression and cell proliferation, whereas LAMA3 silencing and antibody-mediated ITGB1 blockade did not affect the effects of RJ. Conclusion: RJ upregulates LAMA3 and ITGB1 mRNA expression levels by HIF-1α expression enhancement. In addition, RJ accelerates keratinocyte proliferation via Akt/mTOR/HIF-1α/NF-κB signaling pathway. These suggest that RJ is beneficial for anti-aging, as a skin care product ingredient. 展开更多
关键词 Royal Jelly KERATINOCYTE proliferation Epidermal Basement Membrane hypoxia-inducible factor-1
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The impact of hypoxic-ischemic brain injury on stem cell mobilization,migration,adhesion,and proliferation 被引量:5
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作者 Stephanie M.Parry Eric S.Peeples 《Neural Regeneration Research》 SCIE CAS CSCD 2018年第7期1125-1135,共11页
Neonatal hypoxic-ischemic encephalopathy continues to be a significant cause of death or neurodevelopmental delays despite standard use of therapeutic hypothermia.The use of stem cell transplantation has recently emer... Neonatal hypoxic-ischemic encephalopathy continues to be a significant cause of death or neurodevelopmental delays despite standard use of therapeutic hypothermia.The use of stem cell transplantation has recently emerged as a promising supplemental therapy to further improve the outcomes of infants with hypoxic-ischemic encephalopathy.After the injury,the brain releases several chemical mediators,many of which communicate directly with stem cells to encourage mobilization,migration,cell adhesion and differentiation.This manuscript reviews the biomarkers that are released from the injured brain and their interactions with stem cells,providing insight regarding how their upregulation could improve stem cell therapy by maximizing cell delivery to the injured tissue. 展开更多
关键词 brain-derived neurotrophic hypoxia inducible erythropoietin factor matrix metalloproteinase neonatal stromal cell-derived vascular endothelial growth
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Desferoxamine preconditioning protects against cerebral ischemia in rats by inducing expressions of hypoxia inducible factor 1α and erythropoietin 被引量:1
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作者 李云霞 丁素菊 +2 位作者 肖林 郭卫 詹青 《Neuroscience Bulletin》 SCIE CAS CSCD 2008年第2期89-95,共7页
Objective To investigate whether desferoxamine (DFO) preconditioning can induce tolerance against cerebral ischemia and its effect on the expression of hypoxia inducible factor 1 α (HIF- 1α) and erythropoietin ... Objective To investigate whether desferoxamine (DFO) preconditioning can induce tolerance against cerebral ischemia and its effect on the expression of hypoxia inducible factor 1 α (HIF- 1α) and erythropoietin (EPO) in vivo and in vitro. Methods Rat model of cerebral ischemia was established by middle cerebral artery occlusion with or without DFO administration. Infarct size was examined by TTC staining, and the neurological severity score was evaluated according to published method. Cortical neurons were cultured under ischemia stress which was mimicked by oxygen-glucose deprivation (OGD), and the neuron damage was assessed by MTT assay. Immunofluorescent staining was employed to detect the expressions of HIF-1 and EPO. Results The protective effect induced by DFO (decreasing the infarction volume and ameliorating the neurological function) appeared at 2 d after administration ofDFO (post-DFO), lasted until 7 d and disappeared at 14 d (P 〈 0.05); the most effective action was observed at 3 d post-DFO. DFO induced tolerance of cultured neurons against OGD: neuronal viability was increased 23%, 34%, 40%, 48% and 56% at 8 h, 12 h, 24 h, 36 h, and 48 h, respectively, post-DFO (P 〈 0.05). Immunofluorescent staining found that HIF-1 α and EPO were upregulated in the neurons of rat brain at 3 d and 7 d post-DFO; increase of HIF-1 α and EPO appeared in cultured cortex neurons at 36 h and 48 h post-DFO. Conclusion DFO induced tolerance against focal cerebral ischemia in rats, and exerted protective effect on OGD cultured cortical neurons. DFO significant induced the expression of HIF- 1 α and EPO both in vivo and in vitro. DFO preconditioning can protect against cerebral ischemia, which may be associated with the synthesis of HIF- 1 α and EPO. 展开更多
关键词 desferoxamine ischemia preconditioning hypoxia inducible factor 1 α ERYTHROPOIETIN
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Hypoxia upregulates hypoxia inducible factor(HIF)-3α expression in lung epithelial cells: characterization and comparison with HIF-1α 被引量:16
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作者 Qi Fang Li Xiang Rui Wang Yue Wu Yang Han Lin 《Cell Research》 SCIE CAS CSCD 2006年第6期548-558,共11页
The role of the hypoxia-inducible factor(HIF)subunits 1α and 2α in response to hypoxia is well established in lungepithelial cells,whereas little is known about HIF-3α with respect to transcriptional and translatio... The role of the hypoxia-inducible factor(HIF)subunits 1α and 2α in response to hypoxia is well established in lungepithelial cells,whereas little is known about HIF-3α with respect to transcriptional and translational regulation by hy-poxia.HIF-3α and HIF-1α are two similar but distinct basic helix-loop-helix-PAS proteins,which have been postulatedto activate hypoxia responsive genes in response to hypoxia.Here,we used quantitative real time RT-PCR and immu-noblotting to determine the activation of HIF-3α vs.HIF-1α by hypoxia.HIF-3α was strongly induced by hypoxia(1%O_2)both at the level of protein and mRNA due to an increase in protein stability and transcriptional activation,whereasHIF-1α protein and mRNA levels enhanced transiently and then decreased because of a reduction in its mRNA stabilityin A549 cells,as measured on mRNA and protein levels.Interestingly,HIF-3α and HIF-1α exhibited strikingly similarresponses to a variety of activating or inhibitory pharmacological agents.These results demonstrate that HIF-3α is ex-pressed abundantly in lung epithelial cells,and that the transcriptional induction of HIF-3α plays an important role in theresponse to hypoxia in vitro.Our findings suggest that HIF-3α,as a member of the HIF system,is complementary ratherthan redundant to HIF-1α induction in protection against hypoxic damage in alveolar epithelial cells. 展开更多
关键词 hypoxia inducible factor alveolar epithelial type cells hypoxia gene expression in vitro
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Expression of Nerve Growth Factor and Hypoxia Inducible Factor-1α and Its Correlation with Angiogenesis in Non-Small Cell Lung Cancer 被引量:8
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作者 逯青丽 刘建 +1 位作者 朱晓莉 徐文佳 《Journal of Huazhong University of Science and Technology(Medical Sciences)》 SCIE CAS 2014年第3期359-362,共4页
Summary: In order to investigate the expression of nerve growth factor (NGF) and hypoxia inducible factor-1α (HIF-1α) and its correlation with angiogenesis in non-small cell lung cancer (NSCLC), paraffin-embe... Summary: In order to investigate the expression of nerve growth factor (NGF) and hypoxia inducible factor-1α (HIF-1α) and its correlation with angiogenesis in non-small cell lung cancer (NSCLC), paraffin-embedded tissue blocks from 20 patients with NSCLC were examined. Twenty corresponding para-cancerous lung tissue specimens were obtained to serve as a control. The expression of NGF, HIF-1α, and vascular endothelial growth factor (VEGF) in the NSCLC tissues was detected by using immunohistochemistry. The microvascular density (MVD) was determined by CD31 staining. The resuits showed that the expression levels ofNGF, HIF-1α and VEGF in the NSCLC tissues were remarkably higher than those in the para-cancerous lung tissues (P〈0.05). There was significant difference in the MVD between the NSCLC tissues (9.19±1.43) and para-cancerous lung tissues (2.23±1.19) (P〈0.05). There were positive correlations between NGF and VEGF, between HIF-1α and VEGF, and between NGF and HIF-1α in NSCLC tissues, with the spearman correlation coefficient being 0.588, 0.519 and 0.588, respectively. In NSCLC tissues, the MVD had a positive correlation with the three factors (P〈0.05). Theses results suggest that NGF and HIF-1α are synergically involved in the angiogenesis of NSCLC. 展开更多
关键词 non-small cell lung cancer IMMUNOHISTOCHEMISTRY nerve growth factor hypoxia inducible factor-1α vascular endothelial growth factor CD31 microvascular density
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Hypoxia inducible factor in hepatocellular carcinoma:A therapeutic target 被引量:23
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作者 Daniel Lin Jennifer Wu 《World Journal of Gastroenterology》 SCIE CAS 2015年第42期12171-12178,共8页
Hepatocellular carcinoma(HCC) is one of the most commonly diagnosed and deadly cancers worldwide; its incidence has been rising in the United States due to the increase in hepatitis C associated cirrhosis and the grow... Hepatocellular carcinoma(HCC) is one of the most commonly diagnosed and deadly cancers worldwide; its incidence has been rising in the United States due to the increase in hepatitis C associated cirrhosis and the growing epidemic of obesity. There have been no effective therapeutic options in the advanced disease setting beyond sorafenib, a multi-targeted tyrosine kinase inhibitor that showed significant survival benefit. Because of this, there is an urgent need to search for novel pathways in sorafenib experienced patients. This review will focus on the role of hypoxia and hypoxiainducible factor alpha(HIF-1α) in cancer development, specifically in HCC. We will discuss the biology of HIF-1α, the pathways with which it interacts, and the function of HIF-1α in HCC. Furthermore, we will review studies highlighting the relevance of HIF-1α in the clinical setting, as well as the pre-clinical data supporting its further investigation. Finally, we will conclude with a discussion of the potential role of a HIF-1α m RNA antagonist for the treatment of HCC, and hypothesize the ways in which such an inhibitor may be best utilized in the management of advanced HCC. Hypoxia plays a significant role in the development of HCC. HIF-1α is a key transcription factor involved in the hypoxic response of cancer cells. It activates transcription of genes responsible for angiogenesis, glucose metabolism, proliferation, invasion and metastasis in HCC. Its involvement in multiple, essential tumor pathways makes it an attractive potential therapeutic target in HCC. 展开更多
关键词 hypoxia hypoxia-inducible factor ALPHA Hepatocellu
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Antisense Oligonucleotide of Hypoxia-inducible Factor-1alpha Suppresses Growth and Tumorigenicity of Lung Cancer Cells A549 被引量:2
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作者 张万广 张惠兰 邢丽华 《Journal of Huazhong University of Science and Technology(Medical Sciences)》 SCIE CAS 2006年第4期448-450,共3页
Summary: To study the role and mechanisms of hypoxia-inducible factor-lalpha (HIF-1α on the growth and tumorigenicity of lung cancer cells A549, the antisense oligonucleotide of HIF-1α was transfected to A549 cell... Summary: To study the role and mechanisms of hypoxia-inducible factor-lalpha (HIF-1α on the growth and tumorigenicity of lung cancer cells A549, the antisense oligonucleotide of HIF-1α was transfected to A549 cells. The effect of the antisense oligonucleotide on tumor growth in vitro and in vivo was evaluated by the growth rate suppression of A549 cells and subcutaneous implanted tumor in nude mice, and the effect on tumorigenicity was evaluated by the expression inhibition of angiogenic factors, the microvessel density (MVD)and vascular endothelial growth factor (VEGF) protein expression which were detected by immohistochemistry and western blot respectively. This study revealed that in vitro the growth rate of antisense oligonucleotide group was significantly decreased as compared with that of control group, sense oligonucleotide group and false-sense oligonucleotide group; in vivo the weight of implanted tumors in nude mice of antisense oligonucleotide group was 1.51±0.40 g, which was significantly lower than that of control group (2.79±0.33 g), sense oligonucleotide group (2.81±0.45g) and false-sense oligonucleotide group (2.89±0.39 g) and the inhibitory rate was 47 %. Both MVD and VEGF protein expression were significantly inhibited in antisense oligonucleotide group compared with those in other groups. These results indicated that antisense oligonucleotide of HIF-1α could inhibit lung cancer cells A549 growth in vitro and in vivo, and the mechanism may be due to the inhibition of vascular growth and VEGF protein expression. 展开更多
关键词 hypoxia inducible factor-lalpha antisense oligonucleotide vascular endothelial growth factor
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Expression of caspase-3 and hypoxia inducible factor 1αin hepatocellular carcinoma complicated by hemorrhage and necrosis 被引量:3
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作者 Hui Liang Jian-Guo Wu +4 位作者 Fei Wang Bo-Xuan Chen Shi-Tian Zou Cong Wang Shuai-Wu Luo 《World Journal of Clinical Cases》 SCIE 2021年第23期6725-6733,共9页
BACKGROUND Hepatocellular carcinoma(HCC)is a malignant tumor that occurs in the liver.Its onset is latent,and it shows high heterogeneity and can readily experience intrahepatic metastasis or systemic metastasis,which... BACKGROUND Hepatocellular carcinoma(HCC)is a malignant tumor that occurs in the liver.Its onset is latent,and it shows high heterogeneity and can readily experience intrahepatic metastasis or systemic metastasis,which seriously affects patients’quality of life.Numerous studies have shown that hypoxia inducible factor1α(HIF-1α)plays a significant role in the occurrence and development of tumors,as it promotes the formation of intratumoral vessels and plays a key role in their metastasis and invasion.Some studies have reported that caspase-3,which is induced by various factors,is involved in the apoptosis of tumor cells.AIM To investigate the expression of caspase-3 and HIF-1αand their relationship to the prognosis of patients with primary HCC complicated by pathological changes of hemorrhage and necrosis.METHODS A total of 88 patients with HCC complicated by pathological changes of hemorrhage and necrosis who were treated at our hospital from January 2017 to December 2019 were selected.The expression of caspase-3 and HIF-1αin HCC and paracancerous tissues from these patients was assessed.RESULTS The positive expression rate of caspase-3 in HCC tissues was 27.27%,which was significantly lower than that in the paracancerous tissues(P<0.05),while the positive expression rate of HIF-1αwas 72.73%,which was significantly higher than that in the paracancerous tissues(P<0.05).The positive expression rates for caspase-3 in tumor node metastasis(TNM)stage III and lymph node metastasis tissues were 2.78%and 2.50%,respectively,which were significantly lower than those in TNM stage I-II and non-lymph node metastasis tissues(P<0.05).The positive expression rates of HIF-1αin TNM stage III,lymph node metastasis,and portal vein tumor thrombus tissues were 86.11%,87.50%,and 88.00%,respectively,and these values were significantly higher than those in TNM stage I-II,non-lymph node metastasis,and portal vein tumor thrombus tissues(P<0.05).The expression of caspase-3 and HIF-1αin HCC tissues were negatively correlated(rs=−0.426,P<0.05).The median overall survival time of HCC patients was 18.90 mo(95%CI:17.20–19.91).The results of the Cox proportional risk regression model analysis showed that TNM stage,portal vein tumor thrombus,lymph node metastasis,caspase-3 expression,and HIF-1αexpression were the factors influencing patient prognosis(P<0.05).CONCLUSION The expression of caspase-3 decreases and HIF-1αincreases in HCC tissues complicated by pathological changes of hemorrhage and necrosis,and these are related to clinicopathological features and prognosis. 展开更多
关键词 Hepatocellular carcinoma CASPASE-3 hypoxia inducible factor HEMORRHAGE NECROSIS PROGNOSIS
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Expression and clinical significance of CD73 and hypoxia-inducible factor-1α in gastric carcinoma 被引量:14
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作者 Xiao-Xia Lu Yi-Tian Chen +3 位作者 Bing Feng Xiao-Bei Mao Bo Yu Xiao-Yuan Chu 《World Journal of Gastroenterology》 SCIE CAS 2013年第12期1912-1918,共7页
AIM: To investigate the expression of CD73 and hypoxia-inducible factor-1α (HIF-1α) in human gastric carcinoma, and explore their clinical significance and prognostic value. METHODS: CD73 and HIF-1α expressions wer... AIM: To investigate the expression of CD73 and hypoxia-inducible factor-1α (HIF-1α) in human gastric carcinoma, and explore their clinical significance and prognostic value. METHODS: CD73 and HIF-1α expressions were detected by immunohistochemistry in consecutive sections of tissue samples from 68 gastric carcinoma patients. The peritumor tissues 2 cm away from the tumor were obtained and served as controls. The presence of CD73 and HIF-1α was analyzed by immunohis-tochemistry using the Envision technique. RESULTS: CD73 and HIF-1α expressions in gastric carcinoma were significantly higher than those in gastric mucosal tissues as control (P < 0.001) and showed a close correlation (Spearman r = 0.390, P = 0.001). Overexpression of CD73 was positively correlated with differentiation of tumor (P = 0.000), histopathology (P = 0.041), depth of invasion (P < 0.001), nodal status (P = 0.003), metastasis (P = 0.013), and the American Joint Committee on Cancer (AJCC) stage (P < 0.001). High expression of HIF-1α was positively correlated with tumor diameter (P = 0.031), depth of invasion (P = 0.022), and AJCC stage (P = 0.035). The overall survival rate was low in the patients with high expression of CD73 (P < 0.001). Moreover, CD73+/HIF-1α+ patients had the worst prognosis (P < 0.001). CD73 expression was proven to be an independent predictor for patients with gastric carcinoma by both multivariate Cox regression analysis (P = 0.021) and receiver operating characteristic curves (P = 0.001).CONCLUSION: CD73 expression correlates closely with HIF-1α expression in gastric carcinoma. CD73 could be an independent prognostic indicator for gastric carcinoma. 展开更多
关键词 CD73 hypoxia-inducible factor-1α Gastric carcinoma IMMUNOHISTOCHEMISTRY Prognosis
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Wortmannin influences hypoxia-inducible factor-1 alpha expression and glycolysis in esophageal carcinoma cells 被引量:7
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作者 Ling Zeng Hai-Yun Zhou +5 位作者 Na-Na Tang Wei-Feng Zhang Gui-Jun He Bo Hao Ya-Dong Feng Hong Zhu 《World Journal of Gastroenterology》 SCIE CAS 2016年第20期4868-4880,共13页
AIM: To investigate the influence of phosphatidylinositol-3-kinase protein kinase B(PI3K/AKT)-HIF-1α signaling pathway on glycolysis in esophageal carcinoma cells under hypoxia. METHODS: Esophageal carcinoma cell lin... AIM: To investigate the influence of phosphatidylinositol-3-kinase protein kinase B(PI3K/AKT)-HIF-1α signaling pathway on glycolysis in esophageal carcinoma cells under hypoxia. METHODS: Esophageal carcinoma cell lines Eca109 and TE13 were cultured under hypoxia environment, and the protein, m RNA and activity levels of hypoxia inducible factor-1 alpha(HIF-1α), glucose transporter 1, hexokinase-Ⅱ, phosphofructokinase 2 and lactate dehydrogenase-A were determined. Supernatant lactic acid concentrations were also detected. The PI3K/AKT signaling pathway was then inhibited with wortmannin, and the effects of hypoxia on the expression or activities of HIF-1α, associated glycolytic enzymes and lactic acid concentrations were observed. Esophageal carcinoma cells were then transfected with interference plasmid with HIF-1α-targeting si RNA to assess impact of the high expression of HIF-1α on glycolysis.RESULTS: HIF-1α is highly expressed in the esophageal carcinoma cell lines tested, and with decreasing levels of oxygen, the expression of HIF-1α and the associated glycolytic enzymes and the extracellular lactic acid concentration were enhanced in the esophageal carcinoma cell lines Eca109 and TE13. In both normoxia and hypoxic conditions, the level of glycolytic enzymesand the secretion of lactic acid were both reduced by wortmannin. The expression and activities of glycolytic enzymes and the lactic acid concentration in cells were reduced by inhibiting HIF-1α, especially the decreasing level of glycolysis was significant under hypoxic conditions.CONCLUSION: The PI3K/AKT pathway and HIF-1α are both involved in the process of glycolysis in esophageal cancer cells. 展开更多
关键词 hypoxia-inducible factor-1 ALPHA hypoxia GLYCOLYSIS ESOPHAGEAL neoplasms Cell metabolism
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Quantitative analysis of hepatic hypoxia-inducible factor-1α and its abnormal gene expression during the formation of hepatocellular carcinoma 被引量:28
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作者 Deng-Fu Yao,Hua Jiang,Min Yao,Yue-Ming Li,Wen-Jing Gu,Yu-Cheng Shen, Li-Wei Qiu,Wei Wu,Xin-Hua Wu and Wen-Li Sai Research Center of Clinical Molecular Biology,Department of Laboratory Science,and Department of Oncology,Affiliated Hospital of Nantong University,Nantong 226001, China Third Department of Medicine,Jiaonan People’s Hospital,Jiaonan 266400,China 《Hepatobiliary & Pancreatic Diseases International》 SCIE CAS 2009年第4期407-413,共7页
BACKGROUND:Hepatic hypoxia-inducible factor-1(HIF-1) is activated in the progression of hepatocellular carcinoma (HCC).This study aimed to investigate the dynamic alterations of HIF-1αand its gene expression so as to... BACKGROUND:Hepatic hypoxia-inducible factor-1(HIF-1) is activated in the progression of hepatocellular carcinoma (HCC).This study aimed to investigate the dynamic alterations of HIF-1αand its gene expression so as to explore the relationship between HIF-1αexpression and hepatocarcinogenesis at the early stage of HCC. METHODS:A hepatoma model was made with 2-fluorenyl- acetamide(2-FAA)in male Sprague-Dawley rats.Morphological changes of rat hepatocytes were assessed pathologically (HE staining).The dynamic expression of hepatic and circulating HIF-1αwas quantitatively analyzed by ELISA. The gene fragments of hepatic HIF-1αmRNA were amplified by RT-PCR and confirmed by sequencing.The cellular distribution of hepatic HIF-1αexpression was confirmed by immunohistochemistry. RESULTS:Histological examination confirmed granulelike degeneration to atypical hyperplasia and HCC development in rat hepatocytes and progressive increases in the levels of hepatic and circulating HIF-1αand its gene expression during the course.The levels of HIF-1α expression in the liver and blood of rats with hepatoma were significantly higher than those in normal ratsand those with degeneration.Immunohistochemical analysis confirmed the positive expression and hepatocyte distribution of HIF-1αin the development of rat hepatoma. A positive relationship was found between HIF-1α expression in the liver and blood(P<0.01). CONCLUSIONS:The above observations support the hypothesis that the overexpression of HIF-1αand its gene are closely associated with the malignant transformation of hepatocytes and play an important role at the stage of hepatocarcinogenesis. 展开更多
关键词 hepatocellular carcinoma hypoxia inducible factor-1α early expression dynamic alteration
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Activation of hypoxia-inducible factor 1 attenuates periapical inflammation and bone loss 被引量:22
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作者 Kimito Hirai Hisako Furusho +1 位作者 Kiichi Hirota Hajime Sasaki 《International Journal of Oral Science》 SCIE CAS CSCD 2018年第2期92-101,共10页
Hypoxia(low oxygen level) is an important feature during infections and affects the host defence mechanisms. The host has evolved specific responses to address hypoxia, which are strongly dependent on the activation... Hypoxia(low oxygen level) is an important feature during infections and affects the host defence mechanisms. The host has evolved specific responses to address hypoxia, which are strongly dependent on the activation of hypoxia-inducible factor 1(HIF-1).Hypoxia interferes degradation of HIF-1 alpha subunit(HIF-1α), leading to stabilisation of HIF-1α, heterodimerization with HIF-1 beta subunit(HIF-1β) and subsequent activation of HIF-1 pathway. Apical periodontitis(periapical lesion) is a consequence of endodontic infection and ultimately results in destruction of tooth-supporting tissue, including alveolar bone. Thus far, the role of HIF-1 in periapical lesions has not been systematically examined. In the present study, we determined the role of HIF-1 in a wellcharacterised mouse periapical lesion model using two HIF-1α-activating strategies, dimethyloxalylglycine(DMOG) and adenovirusinduced constitutively active HIF-1α(CA-HIF1 A). Both DMOG and CA-HIF1 A attenuated periapical inflammation and tissue destruction. The attenuation in vivo was associated with downregulation of nuclear factor-κappa B(NF-κB) and osteoclastic gene expressions. These two agents also suppressed NF-κB activation and subsequent production of proinflammatory cytokines by macrophages. Furthermore, activation of HIF-1α by DMOG specifically suppressed lipopolysaccharide-stimulated macrophage differentiation into M1 cells, increasing the ratio of M2 macrophages against M1 cells. Taken together, our data indicated that activation of HIF-1 plays a protective role in the development of apical periodontitis via downregulation of NF-κB, proinflammatory cytokines, M1 macrophages and osteoclastogenesis. 展开更多
关键词 CA Activation hypoxia-inducible factor attenuates periapical inflammation bone loss HIF
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The Regulation and Interactions of the Hypoxia Inducible Factor Pathway in Carcinogenesis and Potential Cancer Therapeutic Strategies 被引量:2
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作者 Niraj Shenoy Makardhwaj Shrivastava +2 位作者 Vineeth Sukrithan Dimitra Papaspyridi Karine Darbinyan 《Journal of Cancer Therapy》 2015年第6期511-521,共11页
The Hypoxia Inducible factor (HIF) pathway is known to be constitutionally active in various cancers and is the dominant pathway in some cancers such as VHL mutant clear cell Renal cell carcinoma. HIF-1α and HIF-2α ... The Hypoxia Inducible factor (HIF) pathway is known to be constitutionally active in various cancers and is the dominant pathway in some cancers such as VHL mutant clear cell Renal cell carcinoma. HIF-1α and HIF-2α overexpression is known to be important for tumor cell proliferation, maintenance of stemness and angiogenesis. There has been growing interest in therapeutic strategies targeting the HIF pathway over the last decade. We review in this section the role of hypoxia inducible factor pathway in carcinogenesis, its crosstalk with other pathways and potential cancer therapeutic strategies targeting the HIF pathway, its upstream regulators and downstream signaling. 展开更多
关键词 hypoxia inducible factor (HIF) CANCER Therapy
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Metabolic shift in liver: Correlation between perfusion temperature and hypoxia inducible factor-1α 被引量:5
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作者 Andrea Ferrigno Laura Giuseppina Di Pasqua +2 位作者 Alberto Bianchi Plinio Richelmi Mariapia VairettiAndrea Ferrigno 《World Journal of Gastroenterology》 SCIE CAS 2015年第4期1108-1116,共9页
AIM: To study at what temperature the oxygen carried by the perfusate meets liver requirements in a model of organ perfusion. METHODS: in this study, we correlated hypoxia induciblefactor(Hi F)-1α expression to the p... AIM: To study at what temperature the oxygen carried by the perfusate meets liver requirements in a model of organ perfusion. METHODS: in this study, we correlated hypoxia induciblefactor(Hi F)-1α expression to the perfusion temperature and the hepatic oxygen uptake in a model of isolated perfused rat liver. Livers from Wistar rats were perfused for 6 h with an oxygenated medium at 10, 20, 30 and 37 ℃. Oxygen uptake was measured by an oxygen probe; lactate dehydrogenase activity, lactate release and glycogen were measured spectrophotometrically; bile flow was gravitationally determined; p H of the perfusate was also evaluated; Hi F-1α m RNA and protein expression were analyzed by real time-polymerase chain reaction and ELi SA, respectively. RESULTS: Livers perfused at 10 and 20 ℃ showed no difference in lactate dehydrogenase release after 6 h of perfusion(0.96 ± 0.23 vs 0.93 ± 0.09 m U/min per g) and had lower hepatic damage as compared to 30 and 37 ℃(5.63 ± 0.76 vs 527.69 ± 45.27 m U/min per g, respectively, P s < 0.01). After 6 h, tissue ATP was significantly higher in livers perfused at 10 and 20 ℃than in livers perfused at 30 and 37 ℃(0.89 ± 0.06 and 1.16 ± 0.05 vs 0.57 ± 0.09 and 0.33 ± 0.08 nmol/mg, respectively, P s < 0.01). No sign of hypoxia was observed at 10 and 20 ℃, as highlighted by low lactate release respect to livers perfused at 30 and 37 ℃(121.4 ± 12.6 and 146.3 ± 7.3 vs 281.8 ± 45.3 and 1094.5 ± 71.7 nmol/m L, respectively, P s < 0.02), and low relative Hi F-1α m RNA(0.40 ± 0.08 and 0.20 ± 0.03 vs 0.60 ± 0.20 and 1.47 ± 0.30, respectively, P s < 0.05) and protein(3.72 ± 0.16 and 3.65 ± 0.06 vs 4.43 ± 0.41 and 6.44 ± 0.82, respectively, P s < 0.05) expression.CONCLUSION: Livers perfused at 10 and 20 ℃ show no sign of liver injury or anaerobiosis, in contrast to livers perfused at 30 and 37 ℃. 展开更多
关键词 ANAEROBIOSIS hypoxia inducible factor-1 α ISCHEMIA
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Lysyl oxidase and hypoxia-inducible factor 1α: biomarkers of gastric cancer 被引量:7
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作者 Ya-Lin Han Li Chen +3 位作者 Rui Qin Guan-Qing Wang Xiao-Hua Lin Guang-Hai Dai 《World Journal of Gastroenterology》 SCIE CAS 2019年第15期1828-1839,共12页
BACKGROUND Gastric cancer(GC) is one of the main causes of cancer mortality worldwide.Recent studies on tumor microenvironments have shown that tumor metabolism exerts a vital role in cancer progression.AIM To investi... BACKGROUND Gastric cancer(GC) is one of the main causes of cancer mortality worldwide.Recent studies on tumor microenvironments have shown that tumor metabolism exerts a vital role in cancer progression.AIM To investigate whether lysyl oxidase(LOX) and hypoxia-inducible factor 1α(HIF1α) are prognostic and predictive biomarkers in GC.METHODS A total of 80 tissue and blood samples were collected from 140 patients admitted to our hospital between August 2008 and March 2012. Immunohistochemical staining was performed to measure the expression of LOX and HIF1α in tumor and adjacent tissues collected from patients with GC. Real-time quantitative reverse transcription polymerase chain reaction(qRT-PCR) analysis was used to detect the mRNA expression levels of LOX and HIF1α in patients with GC. In addition, single-factor analysis was applied to analyze the relationship between LOX, HIF1α and prognosis of GC.RESULTS Immunohistochemical staining suggested that the expression levels of LOX and HIF1α increased in tumor tissues from patients with GC. QRT-PCR analysis indicated that mRNA expression of LOX and HIF1α was also upregulated in tumor tissues, which was in accordance with the above results. We also detected expression of these two genes in blood samples. The expression level of LOX and HIF1α was higher in patients with GC than in healthy controls. Additional analysis showed that the expression level of LOX and HIF1α was related to the clinicopathological characteristics of GC. Expression of LOX and HIF1α increased with the number of lymph node metastases, deeper infiltration depth and later tumor–node–metastasis stages. Single-factor analysis showed that high expression of LOX and HIF1α led to poor prognosis of patients with GC.CONCLUSION LOX and HIF1α can be used as prognostic and predictive biomarkers for GC. 展开更多
关键词 Lysyl OXIDASE hypoxia-inducible factor GASTRIC cancer BIOMARKER Prognosis
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