Hypoxia-inducible factor 1alpha and vascular endothelial growth factor in Glioblastoma Multiforme:a systematic review going beyond pathologic implications

Glioblastoma multiforme(GBM)is an aggressive primary brain tumor characterized by extensive heterogeneity and vascular proliferation.Hypoxic conditions in the tissue microenvironment are considered a pivotal player leading tumor progression.Specifically,hypoxia is known to activate inducible factors,such as hypoxia-inducible factor 1alpha(HIF-1α),which in turn can stimulate tumor neo-angiogenesis through activation of various downward mediators,such as the vascular endothelial growth factor(VEGF).Here,we aimed to explore the role of HIF-1α/VEGF immunophenotypes alone and in combination with other prognostic markers or clinical and image analysis data,as potential biomarkers of GBM prognosis and treatment efficacy.We performed a systematic review(Medline/Embase,and Pubmed database search was completed by 16th of April 2024 by two independent teams;PRISMA 2020).We evaluated methods of immunoassays,cell viability,or animal or patient survival methods of the retrieved studies to assess unbiased data.We used inclusion criteria,such as the evaluation of GBM prognosis based on HIF-1α/VEGF expression,other biomarkers or clinical and imaging manifestations in GBM related to HIF-1α/VEGF expression,application of immunoassays for protein expression,and evaluation of the effectiveness of GBM therapeutic strategies based on HIF-1α/VEGF expression.We used exclusion criteria,such as data not reporting both HIF-1αand VEGF or prognosis.We included 50 studies investigating in total 1319 GBM human specimens,18 different cell lines or GBM-derived stem cells,and 6 different animal models,to identify the association of HIF-1α/VEGF immunophenotypes,and with other prognostic factors,clinical and macroscopic data in GBM prognosis and therapeutic approaches.We found that increased HIF-1α/VEGF expression in GBM correlates with oncogenic factors,such as miR-210-3p,Oct4,AKT,COX-2,PDGF-C,PLDO3,M2 polarization,or ALK,leading to unfavorable survival.Reduced HIF-1α/VEGF expression correlates with FIH-1,ADNP,or STAT1 upregulation,as well as with clinical manifestations,like epileptogenicity,and a favorable prognosis of GBM.Based on our data,HIF-1αor VEGF immunophenotypes may be a useful tool to clarify MRI-PET imaging data distinguishing between GBM tumor progression and pseudoprogression.Finally,HIF-1α/VEGF immunophenotypes can reflect GBM treatment efficacy,including combined first-line treatment with histone deacetylase inhibitors,thimerosal,or an active metabolite of irinotecan,as well as STAT3 inhibitors alone,and resulting in a favorable tumor prognosis and patient survival.These data were supported by a combination of variable methods used to evaluate HIF-1α/VEGF immunophenotypes.Data limitations may include the use of less sensitive detection methods in some cases.Overall,our data support HIF-1α/VEGF’s role as biomarkers of GBM prognosis and treatment efficacy.

Clinicopathological features of hypoxia-inducible factor-1α and vascular endothelial growth factor expression in patients with lung cancer

Objective The aim of the study was to investigate the clinicopathological characteristics of hypoxiainducible factor-1α(HIF-1α) and vascular endothelial growth factor(VEGF) expression in patients with lung cancer.Methods Cancerous and noncancerous tissues were collected post-operation from 115 patients with lung cancers by the self-control method. Total RNA was extracted from the lung tissues. The status of tissue HIF-1α expression and intercellular distribution was observed by immunochemistry using a tissue microarray. The expression levels of circulating HIF-1α and VEGF were detected by enzyme-linked immunosorbent assay(ELISA).Results The expression of serum HIF-1α [(138.3 ± 28.8) μg/L] in the group of patients with lung cancer was significantly higher(P < 0.01) than that in the group of patients with pneumonia [(58.8 ± 14.5) μg/L] and the control group of patients ((24.1 ± 3.3) μg/L)There was a strong positive correlation of serum HIF-1α levels(r = 0.937, P < 0.01) with serum VEGF levels. The specific concentration of total RNA [(1.52 ± 1.14) μg/mg wet lung tissues] in the cancerous tissues was significantly higher(t = 8.494, P < 0.001) than that in the noncancerous tissues ((0.58 ± 0.33) μg/mg)The clinicopathological features of HIF-1α expression in lung cancer tissues revealed a significant relationship between positive HIF-1α expression and patient sex(χ~2 = 4.494, P = 0.034), tumor size(χ~2 = 4.679, P = 0.031), differentiation degree(χ~2= 8.846, P = 0.012), and presence of lymphatic node metastasis(χ~2= 6.604, P = 0.037).Conclusion Abnormal HIF-1α expression in lung cancer is closely related with nucleic acid metabolism and angiogenesis, and it may be helpful in the diagnosis and identification of lung cancer.

Effect of acetyl L-carnitine on human retinal pigment epithelium-19 cells in hypoxic conditions

AIM:To investigate the effect of acetyl-L-carnitine(ALCAR)on cell viability,morphological integrity,and vascular endothelial growth factor(VEGF)expression in human retinal pigment epithelium(ARPE-19)cells using a hypoxic model.METHODS:In the first set of experiments,the optimal CoCl_(2) dose was determined by exposing ARPE-19 cell cultures to different concentrations.To evaluate the effect of ALCAR on cell viability,five groups of ARPE-19 cell culture were established that included a control group,a sham group(200μM CoCl_(2)),and groups that received 1,10 and 100 mM doses of ALCAR combined with 200μM CoCl_(2),respectively.The cell viability was measured by MTT assay.The morphological characteristics of cells were observed by an inverted phase contrast microscope.The levels of VEGF and HIF-1α secretion by ARPE-19 cells were detected by enzyme linked immunosorbent assay(ELISA)assay.RESULTS:ARPE-19 cells were exposed to different doses of CoCl_(2) in order to create a hypoxia model.Nevertheless,when exposed to a concentration of 200μM CoCl_(2),a notable decrease in viability to 83% was noted.ALCAR was found to increase the cell viability at 1 mM and 10 mM concentrations,while the highest concentration(100 mM)did not have an added effect.The cell viability was found to be significantly higher in the groups treated with a concentration of 1 mM and 10 mM ALCAR compared to the Sham group(P=0.041,P=0.019,respectively).The cell viability and morphology remained unaffected by the greatest dose of ALCAR(100 mM).The administration of 10 mM ALCAR demonstrated a statistically significant reduction in the levels of VEGF and HIF-1α compared with the Sham group(P=0.013,P=0.033,respectively).CONCLUSION:The findings from the current study indicate that ALCAR could represent a viable therapeutic option with the potential to open up novel treatment pathways for retinal diseases,particular relevance for age-related macular degeneration(AMD).However,to fully elucidate ALCAR’s application potential in retinal diseases,additional investigation is necessary to clearly define the exact mechanisms involved.

急性脑出血患者血清HIF-1α与VEGF、Hsp70动态表达情况研究

目的:研究分析急性脑出血患者血清低氧诱导因子(hypoxia-inducible factor-1α,HIF-1α)与血管生长因子(vascular endothelial growth factor,VEGF)、热休克蛋白70(heat shock protein 70,Hsp70)动态表达情况。方法:将2014年3月至2015年4月我院急诊收治的35例急性脑出血患者,根据其出血量分为小量组、中量组、大量组,测定比较各分组人员发病后12 h、1 d、3 d、5 d、7 d的静脉血HIF-1α与VEGF、Hsp70差异,同时研究分析这3者与出血量之间的相关关系。结果:大量组患者不同时间点HIF-1α与VEGF、Hsp70指标均明显高于同时间点其他两组患者,P<0.05;单因素方差分析HIF-1α与VEGF、Hsp70与患者出血量间关系,均成正相关(r=0.563,P<0.05;r=0.771,P<0.05;r=0.602,P<0.05)。结论:HIF-1α、VEGF、Hsp70在急性脑出血患者中表达较高,在脑出血12 h后升高,并随着脑出血的发展呈现动态表达,且与出血量成正相关关系。

HIF-1α signaling: Essential roles in tumorigenesis and implications in targeted therapies

The hypoxic microenvironment is an essential characteristic of most malignant tu-mors.Notably,hypoxia-inducible factor-1 alpha(HIF-1a)is a key regulatory factor of cellular adaptation to hypoxia,and many critical pathways are correlated with the biological activity of organisms via HIF-1a.In the intra-tumoral hypoxic environment,HIF-1αis highly expressed and contributes to the malignant progression of tumors,which in turn results in a poor prog-nosis in patients.Recently,it has been indicated that HiF-1αinvolves in various critical pro-cesses of life events and tumor development via regulating the expression of HiF-1a target genes,such as cell proliferation and apoptosis,angiogenesis,glucose metabolism,immune response,therapeutic resistance,etc.Apart from solid tumors,accumulating evidence has re-vealed that HiF-1αis also closely associated with the development and progression of hemato-logical malignancies,such as leukemia,lymphoma,and multiple myeloma.Targeted inhibition of HiF-1a can facilitate an increased sensitivity of patients with malignancies to relevant ther-apeutic agents.In the review,we elaborated on the basic structure and biological functions of HIF-1a and summarized their current role in various malignancies.It is expected that they will have future potential fortargeted therapy.

Hypoxia-induced ROS aggravate tumor progression through HIF-1α-SERPINE1 signaling in glioblastoma

Hypoxia,as an important hallmark of the tumor microenvironment,is a major cause of oxidative stress and plays a central role in various malignant tumors,including glioblastoma.Elevated reactive oxygen species(ROS)in a hypoxic microenvironment promote glioblastoma progression;however,the underlying mechanism has not been clarified.Herein,we found that hypoxia promoted ROS production,and the proliferation,migration,and invasion of glioblastoma cells,while this promotion was restrained by ROS scavengers N-acetyl-L-cysteine(NAC)and diphenyleneiodonium chloride(DPI).Hypoxia-induced ROS activated hypoxia-inducible factor-1α(HIF-1α)signaling,which enhanced cell migration and invasion by epithelial-mesenchymal transition(EMT).Furthermore,the induction of serine protease inhibitor family E member 1(SERPINE1)was ROS-dependent under hypoxia,and HIF-1αmediated SERPINE1 increase induced by ROS via binding to the SERPINE1 promoter region,thereby facilitating glioblastoma migration and invasion.Taken together,our data revealed that hypoxia-induced ROS reinforce the hypoxic adaptation of glioblastoma by driving the HIF-1α-SERPINE1 signaling pathway,and that targeting ROS may be a promising therapeutic strategy for glioblastoma.

Targeting TRMT5 suppresses hepatocellular carcinoma progression via inhibiting the HIF-1αpathways

Accumulating evidence has confirmed the links between transfer RNA(tRNA)modifications and tumor progression.The present study is the first to explore the role of tRNA methyltransferase 5(TRMT5),which catalyzes the m1G37 modification of mitochondrial tRNAs in hepatocellular carcinoma(HCC)progression.Here,based on bioinformatics and clinical analyses,we identified that TRMT5 expression was upregulated in HCC,which correlated with poor prognosis.Silencing TRMT5 attenuated HCC proliferation and metastasis both in vivo and in vitro,which may be partially explained by declined extracellular acidification rate(ECAR)and oxygen consumption rate(OCR).Mechanistically,we discovered that knockdown of TRMT5 inactivated the hypoxia-inducible factor-1(HIF-1)signaling pathway by preventing HIF-1αstability through the enhancement of cellular oxygen content.Moreover,our data indicated that inhibition of TRMT5 sensitized HCC to doxorubicin by adjusting HIF-1α.In conclusion,our study revealed that targeting TRMT5 could inhibit HCC progression and increase the susceptibility of tumor cells to chemotherapy drugs.Thus,TRMT5 might be a carcinogenesis candidate gene that could serve as a potential target for HCC therapy.

Hypoxia-inducible factor 1 and breast cancer metastasis

Accumulating evidence has shown that the hypoxic microenvironment, which is critical during cancer development, plays a key role in regulating breast cancer progression and metastasis. The effects of hypoxia-inducible factor 1 （HIF-1）, a master regulator of the hypoxic response, have been extensively studied during these processes. In this review, we focus on the roles of HIF-1 in regulating breast cancer cell metastasis, specifically its effects on multiple key steps of metastasis, such as epithelial-mesenchymal transition （EMT）, invasion, extravasation, and metastatic niche formation. We also discuss the roles of HIF-l-regulated non-coding RNAs in breast cancer metastasis, and therapeutic opportunities for breast cancer through targeting the HIF-1 pathway,

Transition of autophagy and apoptosis in fibroblasts depends on dominant expression of HIF-1αor p53

It has been revealed that hypoxia is dynamic in hypertrophic scars;therefore,we considered that it may have different effects on hypoxia-inducible factor-1α(HIF-1α)and p53 expression.Herein,we aimed to confirm the presence of a teeterboard-like conversion between HIF-1αand p53,which is correlated with scar formation and regression.Thus,we obtained samples of normal skin and hypertrophic scars to identify the differences in HIF-1αand autophagy using immunohistochemistry and transmission electron microscopy.In addition,we used moderate hypoxia in vitro to simulate the proliferative scar,and silenced HIF-1αor p53 gene expression or triggered overexpression to investigate the changes of HIF-1αand p53 expression,autophagy,apoptosis,and cell proliferation under this condition.HIF-1α,p53,and autophagy-related proteins were assayed using western blotting and immunofluorescence,whereas apoptosis was detected using flow cytometry analysis,and cell proliferation was detected using cell counting kit-8(CCK-8)and 5-bromo-2′-deoxyuridine(BrdU)staining.Furthermore,immunoprecipitation was performed to verify the binding of HIF-1αand p53 to transcription cofactor p300.Our results demonstrated that,in scar tissue,HIF-1αexpression increased in parallel with autophagosome formation.Under hypoxia,HIF-1αexpression and autophagy were upregulated,whereas p53 expression and apoptosis were downregulated in vitro.HIF-1αknockdown downregulated autophagy,proliferation,and p300-bound HIF-1α,and upregulated p53 expression,apoptosis,and p300-bound p53.Meanwhile,p53 knockdown induced the opposite effects and enhanced HIF-1α,whereas p53 overexpression resulted in the same effects and reduced HIF-1α.Our results suggest a teeterboard-like conversion between HIF-1αand p53,which is linked with scar hyperplasia and regression.

Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting MDR1 through HIF-1α

Objective： To explore the efficacy of ursolic acid in sensitizing colon cancer cells to chemotherapy under hypoxia and its underlying mechanisms. Methods： Three colon cancer cell lines （RKO, LoVo, and SW480） were used as in vitro models. 5-Fluorouracil （5-FU） and oxaliplatin were used as chemotherapeutic drugs. Cell viability and apoptosis were tested to evaluate the sensitivity of colon cancer cells to chemotherapy. The transcription and ex- pression levels of hypoxia-inducible factor-1α （HIF-1α）, multidrug resistance gene 1 （MDR1）, and vascular endothelial growth factors （VEGF） were assessed by quantitative real-time polymerase chain reaction （qRT-PCR） and im- munoblotting. Cycloheximide and MG132 were used to inhibit protein synthesis and degradation, respectively. In vitro tube formation assay was used to evaluate angiogenesis. Results： We demonstrated the chemosensitizing effects of ursolic acid with 5-FU and oxaliplatin in three colon cancer cell lines under hypoxia. This effect was correlated to its inhibition of MDR1 through HIF-la. Moreover, ursolic acid was capable of inhibiting HIF-1α accumulation with little effects on its constitutional expression in normoxia. In addition, ursolic acid also down-regulated VEGF and inhibited tumor angiogenesis. Conclusions： Ursolic acid exerted chemosensitizing effects in colon cancer cells under hypoxia by inhibiting HIF-la accumulation and the subsequent expression of the MDR1 and VEGF.

Electroacupuncture combined with intermittent pneumatic compression therapeutic apparatus for diabetic peripheral neuropathy and the effect on HIF-1α and VEGF levels

Objective： To observe the clinical efficacy of electroacupuncture combined with intermittent pneumatic compression therapeutic apparatus for treatment of diabetic peripheral neuropathy, and the effect on serum VEGF and HIF-lα levels of patients. Methods： Ninety-six patients were randomly divided into electroacupuncture treatment group （EA group）, intermittent pneumatic compression treatment group （IPC group）, electroacupuncture combined with intermittent pneumatic compression treatment group （EA ＋ IPC group） and cobamamide group （CM group）, with 24 cases in each group. Electroacupuncture treatment （once a day）, intermittent pneumatic com pression treatment （twice a day） and intramuscular injection with cobamamide （1 rag, once a day） were carried out in EA group, IPC group and CM group, respectively, and intermittent pneumatic compres- sion treatment （twice a day） was conducted on the basis of electroacupuncture treatment （once a day） in EA＋IPC group. After treatment for 2 consecutive weeks, the differences in subjective symptoms, mo- tor nerve conduction velocity, sensory nerve conduction velocity and serum HIF-lα and VEGF levels of patients in the four groups before and after treatment were observed and compared. Results： After treatment for 2 weeks, the differences in total effective rate between EA group and CM group, IPC group and CM group, as well as EA ＋ IPC group and CM group were all significant （all P 〈 0.05）, and the total effective rate in EA＋ IPC group was significantly higher than that in EA group and IPC group （both P 〈 0.05）. After treatment for 2 weeks, the motor nerve conduction velocity and sensory nerve conduction velocity of median nerve and common peroneal nerve of patients in EA group, 1PC group and EA＋IPC group were all higher than that before treatment （all P 〈 0.05）; the motor nerve conduction velocity of median nerve and the sensory nerve conduction velocity of common peroneal nerve in EA group were all higher than that in CM group （both P 〈 0.05）; the motor nerve conduction velocity and sensory nerve conduction velocity of median nerve in IPC group were also all higher than that in CM group （both P 〈 0.05）; the motor nerve conduction velocity and sensory nerve conduction velocity of median nerve and common peroneal nerve in EA＋IPC group were all higher than that in CM group （both P 〈 0.05）; the sensory nerve conduction velocity of common peroneal nerve in EA ＋ 1PC group was higher than that in EA group and IPC group （both P 〈 0.05）, and the motor nerve conduction velocity of median nerve in EA＋IPC group was higher than that in IPC group （P 〈 0.05）. The serum HIF-1α and VEGF levels of patients in EA group, IPC group and EA ＋ IPC group after treatment significantly reduced （all P 〈 0.05）. and were lower than that in CM group after treatment （all P 〈 0.05）; the serum HIF-lα and VEGF levels of patients in EA ＋ IPC group after treatment were lower than that in EA group and IPC group, and the difference in serum HIF-lα level was statistically significant （both P 〈 0.05）. Conclusion： Electroacupuncture combined with intermittent pneumatic compression therapeutic apparatus can effectively improve the clinical symptoms of patients with diabetic peripheral neuropathy, the efficacy were better than electroacupuncture, intermittent pneumatic compression treatment and cobamamide.

缺氧激活前药evofosfamide(TH-302)在体内和体外对鼻咽癌的疗效

背景与目的肿瘤缺氧被认为是肿瘤转移和疾病复发的重要因素。Evofosfamide是一种缺氧激活前药,可选择性地靶向实体瘤的缺氧区域。由于缺氧诱导因子?1α(hypoxia?inducible factor?1α,HIF?1α)在鼻咽癌(nasopharyngeal carcinoma,NPC)组织中高表达,本研究探讨了evofosfamide在鼻咽癌中的疗效。方法我们评估了evofosfamide作为单药或联合顺铂(DDP)在NPC细胞系CNE?2、HONE?1和HNE?1以及裸鼠异种移植瘤模型中的疗效。结果 Evofosfamide在NPC细胞系中表现出缺氧选择性细胞毒性。在缺氧条件下,对CNE?2、HNE?1和HNE?1细胞的50%抑制浓度(50%inhibition concentration,IC50)分别为8.33±0.75、7.62±0.67和0.31±0.07μmol/L。与常氧对照组相比,在缺氧条件下其增敏率为9–300倍。通过联合指数值评估,evofosfamide联合DDP对NPC细胞的细胞毒性具有协同效应。在缺氧条件下用0.05μmol/L的evofosfamide处理后,细胞周期G2期被阻滞。在缺氧条件下用evofosfamide处理后,组蛋白H2AX磷酸化(Histone H2AXphosphorylation,γH2AX)(DNA损伤的标志之一)表达增强,而HIF?1α表达受到抑制。在HNE?1 NPC异种移植瘤模型中,evofosfamide作为单药或联合DDP显示出抗肿瘤活性。异种移植物组织缺氧区在evofosfamide单药治疗和联合DDP治疗后均明显减少。结论我们的结果为evofosfamide作为单药或联合DDP可选择性靶向鼻咽癌缺氧部分提供了临床前证据,为evofosfamide治疗鼻咽癌的潜在临床应用提供了理论依据。

The impact of ^(60)Co γ-ray on cycles to Hep-2 human laryngeal cancer cell in the condition of hypoxia

Objective： The aim of the study was to investigate the impact of 60Co y-ray on apoptosis, cell cycles and the expression of protein hypoxia-inducible factor-1α （HIF-1α） to Hep-2 cell line in the conditions of normoxia and hypoxia. Methods： Hep-2 cell were divided into 2 groups： group A （normoxia） and group B （hypoxia）. All of the ceils were exposed to y-ray with dosage being 0, 1, 3, 5, 10, 20, and 40 Gy. Flow cytometry was used to measure the protein level of HIF-1α and to detect apoptosis and cell cycles. The protein level of HIF-1α was also determined by immunohistochemistry and Western blotting. Results： The protein level of HIF-1α in group B was significantly higher than that in group A. In group A, low doses （1-5 Gy） of y-ray had caused G0/G1 cell cycle arrest and high doses （10-40 Gy） had caused G2/M cell cycle arrest. In group B, without exposure of y-ray （0 Gy） had caused G0/G1 cell cycle arrest, all of the different dosage of y-ray could cause G2/M cell cycle arrest. The curve of apoptosis rate in group A was a parabola, the apoptotic rate was related to the dosage of y-ray in a dosage dependent manner. The peak was at the point of 5 Gy. The apoptosis rate in group A was significantly higher than that in group B. Conclusion： Different doses of y-ray could cause different cell cycles arrest then make different impact on apoptosis to Hep-2 ceil. The lower apoptosis rate in condition of hypoxia maybe has a relationship with G2/M cell cycle arrest. Up-regulated HIF-1α protein may be one of the reasons for G2/M cell cycle arrest.

The role of hypoxia-induced factor 1α in breast cancer

Breast cancer usually grows very quickly,becoming insensitive to blood flow in nearby veins;because of that,inside solid tumors it's possible to find a hypoxic environment,in other words,an environment where oxygen is less available.Another feature of cancer is its angiogenesis rate,because of the high energy demand,new blood vessels must be produced to take nutrients inside the solid tumor mass.Even with normal blood flow bringing the cancer oxygen and nutrients,its cells favor hypoxia,in an event known as Warburg Effect.According to the Warburg Effect,cells,even with normal oxygen rates,prefer to use fermentation instead of the citric acid cycle to produce ATP.For the cancer to operate normally in hypoxia,a transcription factor family is activated,known as hypoxia-induced factors(HIF),composed of a HIF-1βand a HIF-1αsubunits.As HIF-1αis expressed during hypoxia,it is a great target for treatments and a breast cancer biomarker.Because of the role of HIF-1αin cancer and the high incidence of breast cancer worlwide,this review was performed in order to bring the most recent results concerning the role HIF-1αcan exert in breast cancer development and progression.

Liposome-coated CaO_(2)nanoblockers for enhanced checkpoint blockade therapy by inhibiting PD-L1 de novo biosynthesis

The blocking of the immune checkpoint pathway with antibodies,especially targeting to programmed death-1/programmed death ligand-1(PD-1/PD-L1)pathway,was currently a widely used treatment strategy in clinical practice.However,the shortcomings of PD-L1 antibodies were constantly exposed with the deepening of its research and their therapeutic effect was limited by the translocation and redistribution of intracellular PD-L1.Herein,we proposed to improve immune checkpoint blockade therapy by using liposomes-coated CaO_(2)(CaO_(2)@Lipo)nanoparticles to inhibit the de novo biosynthesis of PD-L1.CaO_(2)@Lipo would produce oxygen and reduce hypoxia-inducible factor-1α(HIF-1α)level,which then downregulated the expression of PD-L1.Our in vitro and in vivo results have confirmed CaO_(2)@Lipo promoted the degradation of HIF-1αand then downregulated the expression of PD-L1 in cancer cells for avoiding immune escape.Furthermore,to mimicking the clinical protocol of anti-PD-L1 antibodies+chemo-drugs,CaO_(2)@Lipo was combined with doxorubicin(DOX)to investigate the tumor inhibition efficiency.We found CaO_(2)@Lipo enhanced DOX-induced immunogenic cell death(ICD)effect,which then promoted the infiltration of T cells,strengthened the blocking effect,thus provided an effective means to overcome the traditional immune checkpoint blockade treatment.

缺氧诱导因子1与头颈部肿瘤

缺氧诱导因子1(hypoxia-induciblefactor1,HIF-1)是机体对缺氧状态适应性反应的一种转录因子,它在恶性肿瘤的发生发展中起重要作用,本文复习近年来相关文献,就HIF-1的结构、调节、相关靶基因及在头颈部肿瘤的研究进展作一简要综述。

Influenza A Virus(H1N1) Infection Induces Glycolysis to Facilitate Viral Replication

Viruses depend on host cellular metabolism to provide the energy and biosynthetic building blocks required for their replication. In this study, we observed that influenza A virus(H1N1), a single-stranded, negative-sense RNA virus with an eight-segmented genome, enhanced glycolysis both in mouse lung tissues and in human lung epithelial(A549) cells. In detail, the expression of hexokinase 2(HK2), the first enzyme in glycolysis, was upregulated in H1N1-infected A549 cells,and the expression of pyruvate kinase M2(PKM2) and pyruvate dehydrogenase kinase 3(PDK3) was upregulated in H1N1-infected mouse lung tissues. Pharmacologically inhibiting the glycolytic pathway or targeting hypoxia-inducible factor 1(HIF-1), the central transcriptional factor critical for glycolysis, significantly reduced H1N1 replication, revealing a requirement for glycolysis during H1N1 infection. In addition, pharmacologically enhancing the glycolytic pathway further promoted H1N1 replication. Furthermore, the change of H1N1 replication upon glycolysis inhibition or enhancement was independent of interferon signaling. Taken together, these findings suggest that influenza A virus induces the glycolytic pathway and thus facilitates efficient viral replication. This study raises the possibility that metabolic inhibitors, such as those that target glycolysis, could be used to treat influenza A virus infection in the future.

Efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in nasopharyngeal carcinoma in vitro and in vivo

Background:Tumor hypoxia is considered an important factor in metastasis and disease relapse.Evofosfamide is a hypoxia-activated prodrug that selectively targets the hypoxic regions of solid tumors.As hypoxia-inducible factor-1α(HIF-1α)is overexpressed in nasopharyngeal carcinoma(NPC)tissues,we performed the present study to evaluate the efficacy profile of evofosfamide in NPC.Methods:We evaluated the efficacy of evofosfamide as a single agent or combined with cisplatin(DDP)in the NPC cell lines CNE-2,HONE-1 and HNE-1,and in nude mouse xenograft tumor models.Results:Evofosfamide exhibited hypoxia-selective cytotoxicity in NPC cell lines,with 50%inhibition concentration(IC50)values of 8.33±0.75,7.62±0.67,and 0.31±0.07μmol/L under hypoxia in CNE-2,HONE-1 and HNE-1 cells,respectively.The sensitization ranged from ninefold to greater than 300-fold under hypoxia compared with normoxia controls.The combination of evofosfamide with DDP had a synergistic effect on cytotoxicity in the NPC cell lines by combination index values assessment.Cell cycle G2 phase was arrested after treated with 0.05μmol/L evofosfamide under hypoxia.Histone H2AX phosphorylation(γH2AX)(a marker of DNA damage)expression increased while HIF-1αexpression suppressed after evofosfamide treatment under hypoxic conditions.In the HNE-1 NPC xenograft models,evofosfamide exhibited antitumor activity both as a single agent and combined with DDP.Hypoxic regions in xeno-graft tissue were reduced after both evofosfamide monotherapy and combined therapy with DDP.Conclusions:Our results present preclinical evidence for targeting the selective hypoxic portion of NPC by evofosfa-mide as a single agent and combined with DDP and provide rationale for the potential clinical application of evofosfa-mide for the treatment of nasopharyngeal carcinoma.