低氧诱导因子在肾透明细胞癌中作用的研究进展

VHL基因具有调节转录、稳定细胞生长相关基因和调节细胞周期的功能,其突变、缺失、重排和超甲基化与肾细胞癌(RCC)的发生密切相关。VHL基因产物VHL肿瘤抑制蛋白(p VHL)是泛素连接酶的成分,具有调节低氧诱导因子(HIF)稳定性的作用。HIF家族主要包含三种HIFα因子(HIF1α、HIF2α、HIF3α)和两种HIFβ因子(HIF1β、HIF2β)。HIF1α位于14q染色体上,在肾透明细胞癌中该染色体经常缺失,且这种14q的缺失常伴有预后不良。HIF2α的表达异常促进了p VHL缺陷型肾透明细胞癌中的发生。目前,抑制HIF2α及其下游的血管内皮生长因子(VEGF)的药物都处于临床试验的不同阶段,已有四种VEGF抑制剂获准用于肾透明细胞癌的治疗。选择抑制HIF或具有HIF靶基因抑制选择性的药物进行研究,可能为肾透明细胞癌的治疗提供新的方法。本文就HIF在VHL蛋白缺陷型肾透明细胞癌中作用的研究进展进行了综述。     

VHL基因的研究进展及其在肾癌基因治疗中的应用

VHL基因是抑癌基因,定位于染色体3p25-26,其产物pVHL与Wnt-β-catenin信号通路、缺氧诱导因子、氧化磷酸化的调控有关。VHL基因的失活会导致VHL蛋白不能正常合成,这与散发性肾透明细胞癌的发生、发展有着密切的关系。VHL基因的失活机制主要包括基因突变,杂合性缺失和甲基化。通过对VHL基因失活机制的研究有助于筛选用于肾透明细胞癌早期诊断与预后的新分子标志物。目前利用VHL基因开展了肾癌基因治疗的试验探索。     

缺氧诱导因子与肾细胞癌关系的研究进展

缺氧诱导因子(hypoxia inducible factor,HIF)对维持肿瘤细胞的能量代谢、肿瘤血管生成、促进肿瘤细胞增殖和转移起着重要作用,是肿瘤细胞低氧条件下产生的关键信号分子。本综述旨在总结前人研究,阐述HIF与肾癌细胞之间的内在关系。HIF成员是参与肾癌细胞对缺氧应答反应中的关键因子,并通过靶基因的调节,促进新生血管的生成,导致肿瘤生长。其中,HIF-1α及HIF-2α在促进新生血管的生成方面发挥着主要作用。HIF-1α及HIF-2α与VEGF密切相关,随着其的表达增高,VEGF在数量上及m RNA水平上均显著增高,显示其可通过调控VEGF参与肾癌血管生成,而HIF-2α转录激活VEGF m RNA的特异性较HIF-1α更强。HIF-3α可能存在的负性调控作用,其异构体-4的作用可能与HIF-lα的负性调节有关,其可以阻止HIF-lα与下游靶基因的缺氧反应元件(hypoxia response elements,HRE)结合,同时可在转录水平抑制HIF-lα。HIF在未来可能有成为肾细胞癌治疗的靶点。     

缺氧诱导因子-1α在缺氧预处理预防心肌细胞损伤中的作用

本工作旨在研究缺氧预处理(hypoxic preconditioning,HPC)对于心肌细胞外信号调节激酶(extracellular signal-regulated proteinkinases,ERK)活性、缺氧诱导因子-1α(hypoxia-inducible factor-1α,HIF-1α)表达的影响,及其在缺氧复氧诱导心肌细胞损伤中的作用。通过在培养的SD乳鼠心肌细胞缺氧／复氧(H／R)模型上,观察HPC对于24h后H／R诱导心肌细胞损伤的影响,以台盼蓝排斥实验检测心肌细胞存活率、以TUNEL法检测细胞凋亡、并用荧光素染料Hoechst33258测定心肌细胞凋亡率：制备心肌细胞蛋白提取物,以磷酸化的ERK1／2抗体测定ERK1／2活性,以抗HIF-1α抗体检测HIF-1α的表达,并观察ERKs的上游激酶(MEK1／2)抑制剂PD98059对于HPC诱导的ERKs磷酸化、HIF-1α表达以及心肌细胞保护作用的影响,并分析细胞损伤与ERK1／2活性、HIF-1α表达量之间的相互关系。结果 显示缺氧复氧造成心肌细胞损伤,HPC可以增加心肌细胞H／R后存活率,降低凋亡率,并激活ERKll2,诱导HIF-1α表达：细胞凋亡与ERKs活性、HIF-1α表达量之间存在负相关,即ERKs活化、HIF-1α表达与预防细胞损伤有关：而ERKs活性与HIF-1α表达量之间存在正相关,ERKs的上游激酶MEK抑制剂PD98059可以消除HPC诱导的ERKs磷酸化、HIF-1α表达和心肌细胞保护作用。由此得出的结论是HPC可以提高乳鼠心肌细胞对于H／R的耐受性,其机制涉及ERKs介导的HIF-1α表达。     

缺氧诱导因子1

缺氧诱导因子1是缺氧诱导细胞所产生的一种蛋白质,由一个120 ku的α亚基和一个91～94 ku的β亚基组成的异源二聚体.在缺氧条件下,促进红细胞生成素和糖酵解酶等基因的转录和表达,维持机体氧稳态.     

缺氧诱导因子1与缺氧信号转导机制

缺氧诱导因子1(HIF-1)不仅作为维持氧自稳平衡的核心调控因子,调控一系列缺氧相关基因的表达,而且在感受缺氧,传递缺氧信号的过程中发挥重要作用。氧依赖的羟化酶的发现,证明胞内氧浓度直接调控HIF-1α亚基的表达,为揭示缺氧信号调控HIF-1表达的分子机制提供了有力的证据。     

缺氧诱导因子-1在病毒感染中的作用

缺氧诱导因子-1(hypoxia-inducible factor-1,HIF-1)是一种由β亚单位和α亚单位组成的异二聚体转录因子,其表达产物参与细胞的许多生理过程。越来越多的研究提示HIF-1在病毒感染中发挥着重要作用。通过检索相关文献,对人病毒感染中HIF-1活性改变及其在病毒感染中的作用进行了综述,为研究HIF-1在病毒感染中的作用提供参考。     

缺氧诱导因子及相关circRNAs在肝细胞癌中的研究现状

肝细胞癌(hepatocellular carcinoma,HCC)死亡率高、预后差,严重危害人类健康.HCC发生发展机制复杂多样.研究表明,缺氧诱导因子(hypoxia inducible factor,HIF)对HCC的发生发展具有重要作用,并且HIF相关环状RNA分子(circular RNAs,circRNAs...     

缺氧诱导因子在慢性肾脏病进展至终末期肾病中的作用机制

慢性肾脏病(chronic kidney disease,CKD)已经成为影响全球健康的难题,延缓其进展至终末期肾病(end-stage renal disease,ESRD)阶段是治疗CKD的重要目标。缺氧和缺氧诱导因子(hypoxia inducible factor,HIF)与CKD的发生和发展有着密切的联系,HIF表达的增加可以延缓CKD的进程,减少CKD并发症的发生。本文主要从CKD贫血、肾间质纤维化、炎症、血管钙化以及急性肾损伤方面论述了HIF在其中发挥的作用,旨在为延缓CKD进展至ESRD阶段提供新的靶点和思路,改善CKD患者的预后。     

缺氧诱导因子与肺癌关系研究进展

缺氧诱导因子(Hypoxia-inducible factors,HIFs)是在缺氧条件下广泛存在于人和哺乳动物体内的一种转录因子,在细胞的增殖、存活、血管发生、新陈代谢、肿瘤侵袭和转移等过程中起着重要作用。缺氧是实体瘤的一个重要特征,缺氧诱导因子与肿瘤的发生、发展关系密切,通过分析缺氧诱导因子与肺癌的关系,为研发新靶点的肺癌药物奠定一定的理论基础。     

Nobiletin inhibits hypoxia-induced epithelial-mesenchymal transition in renal cell carcinoma cells

Hypoxia is a universal characteristic of solid tumor and involving cancer metastasis via epithelial-mesenchymal transition (EMT). Nobiletin (3′,4′,5,6,7,8-hexamethoxyflavone), a dietary polymethoxylated flavonoid found in citrus fruits, has been reported to have anticancer effects. However, the possible role of nobiletin in renal cell carcinoma (RCC) remains unclear. Thus, the aim of this study was to identify the effect of nobiletin on hypoxia-induced EMT in RCC cells. We found that nobiletin significantly inhibited the migration and invasion induced by hypoxia in RCC cells. In addition, nobiletin reversed the hypoxia-induced EMT process in RCC cells. Furthermore, nobiletin suppressed the activation of NF-κB and Wnt/β-catenin signaling pathways in hypoxia-stimulated RCC cells. In conclusion, these findings demonstrate that nobiletin inhibits hypoxia-induced EMT in human RCC cells via the inactivation of the NF-κB and Wnt/β-catenin signaling pathways.     

Serum exosomal miR-210 as a potential biomarker for clear cell renal cell carcinoma

Exosomal microRNAs (miRNAs) are suggested to reflect molecular changes occurring in their cells of origin and are potential indicators in the early detection of cancers. This study aimed to determine whether certain exosomal miRNAs from tumor tissue can be used as noninvasive biomarkers for clear cell renal cell carcinoma (ccRCC). Based on ccRCC miRNA expression profiles and the literature, we selected six miRNAs (miR-210, miR-224, miR-452, miR-155, miR-21, and miR-34a) and analyzed their expression in tissues, sera, and serum exosomes through quantitative real-time polymerase chain reaction in hypoxia-induced (with CoCl₂) renal cell lines. miR-210, miR-224, miR-452, miR-155, and miR-21 were upregulated in tumor tissues compared with normal tissues. Serum miR-210 and miR-155 levels were higher in patients with ccRCC than in healthy controls (HCs). Furthermore, only exosomal miR-210 was significantly upregulated in patients with ccRCC than in HCs. Moreover, receiver operating characteristic (ROC) curve analysis revealed an area under the ROC curve of 0.8779 (95% confidence interval, 0.7987-0.9571) and a sensitivity and specificity of 82.5% and 80.0%, respectively. Moreover, exosomal miR-210 was upregulated at an advanced stage, and Fuhrman grade and metastasis decreased significantly one month after surgery. Acute hypoxia exposure activates miR-210 and release of exosomes with upregulated miR-210 in both normal and tumor RCC cell lines and interferes with vacuole membrane protein 1 mRNA expression, especially in the metastatic ccRCC cell line. In conclusion, Serum exosomal miR-210 originating from tumor tissue has potential as a novel noninvasive biomarker for the detection and prognosis of ccRCC.     

Connexin 32 down-regulates the fibrinolytic factors in metastatic renal cell carcinoma cells

Fibrinolytic factors have an important role in tumor progression through the degradation of extracellular matrix. The increased levels of urokinase-type plasminogen activator (uPA), uPA-receptor (uPAR) and type-1 PA inhibitor (PAI-1) are reported in human renal cell carcinoma (RCC). Connexin (Cx) gene, a member of gap junction, is known to act as a tumor suppressor gene. We have reported that Cx32 improves malignant phenotypes of metastatic RCC cells via the inhibition of Src-dependent signaling. In this study, we examined the effect of expression of Cx32 gene on the production of uPA, uPAR and PAI-1, and on the induction of PAI-1 stimulated by hypoxia in a human metastatic RCC cell line, Caki-1 cells. Cx32 expression decreased both mRNA level and production of PAI-1, uPA and uPAR in Caki-1 cells. Cx32 also decreased hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha mRNA level. PP1, a Src inhibitor, significantly decreased PAI-1, uPA, uPAR and HIF-alpha mRNA levels in Caki-1 cells. Furthermore, Cx32 suppressed the induction of HIF-2alpha protein in Caki-1 cells under hypoxia. PAI-1 mRNA level in Cx32-transfected Caki-1 cells was lower than that of mock transfectant under hypoxic conditions. These results suggest that Cx32 might reduce PAI-1, uPA and uPAR production in metastatic RCC cells via the inhibition of Src-dependent induction of HIF-1alpha and HIF-2alpha gene expression and that Cx32 might suppress hypoxia-inducible gene expression under hypoxic conditions.     

Inter- and intra-tumor heterogeneity of genetic and immune profiles in inherited renal cell carcinoma

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Study of FABP's interactome and detecting new molecular targets in clear cell renal cell carcinoma

Fatty acids (FAs) play a crucial role in the development of clear cell renal cell carcinoma (ccRCC), FAs function requires the participation of fatty-acid-binding protein (FABP). Current studies have shown that different members of the FABP's family play different roles in the tumorigenesis of ccRCC. Therefore, the systematic analysis of FABPs will be of great significance. However, the diverse expression patterns and prognostic values of nine FABPs have yet to be elucidated. In this study, through multiple analysis and verification of multiple databases, such as ONCOMINE, The Human Protein Atlas, UALCAN, Gene Expression Profiling Interactive Analysis, and cBioPortal, we found that the expression of FABP1 was significantly downregulated and the expression of FABP5/6/7 was significantly upregulated in ccRCC compared with renal tissues, and the patients with high messenger RNA (mRNA) levels of the FABP5/6/7 or low mRNA levels of FABP1 were predicted to have a lower overall survival or disease-free survival. Further analysis by the protein–protein interaction (PPI), Gene Ontology pathway, and Kyoto Encyclopedia of Genes and Genomes pathway showed that FABPs were mainly involved in the peroxisome proliferator-activated receptor (PPAR) pathway. In coexpression analysis, we found that FABP1/5/6/7 was coexpressed with transforming growth factor-β1 (TGF-β1), PPARA, and LPL. This study implied that FABP1/5/6/7 could act as an important tumor biomarker of ccRCC; the role of FABPs may be related to PPAR or TGF-β pathway.     

Resistance to tyrosine kinase inhibitors in clear cell renal cell carcinoma: From the patient's bed to molecular mechanisms

The introduction of anti-angiogenic drugs especially tyrosine kinase inhibitors (TKIs) was a breakthrough in the treatment of renal cell carcinoma (RCC). Although TKIs have significantly improved outcome in patients with metastatic disease, the majority still develop resistance over time. Because different combinations and sequences of TKIs are tested in clinical trials, resistance patterns and mechanisms underlying this phenomenon should be thoroughly investigated. From a clinical point of view, resistance occurs either as a primary phenomenon (intrinsic) or as a secondary phenomenon related to various escape/evasive mechanisms that the tumor develops in response to vascular endothelial growth factor (VEGF) inhibition. Intrinsic resistance is less common, and related to the primary redundancy of available angiogenic signals from the tumor, causing unresponsiveness to VEGF-targeted therapies. Acquired resistance in tumors is associated with activation of an angiogenic switch which leads to either upregulation of the existing VEGF pathway or recruitment of alternative factors responsible for tumor revascularization. Multiple mechanisms can be involved in different tumor settings that contribute both to evasive and intrinsic resistance, and current endeavor aims to identify these processes and assess their importance in clinical settings and design of pharmacological strategies that lead to enduring anti-angiogenic therapies.     

Serum markers change for intraocular metastasis in renal cell carcinoma

Objective: Renal cell carcinoma is prone to early metastasis. In general, intraocular metastasis (IOM) is not common. In the present study, we studied the relationship between different biochemical indicators and the occurrence of IOM in renal cancer patients, and identified the potential risk factors.Methods: A retrospective analysis of the clinical data of 214 patients with renal cell carcinoma from October 2001 to August 2016 was carried out. The difference and correlation of various indicators between the two groups with or without IOM was analyzed, and binary logistic regression analysis was used to explore the risk factors of IOM in renal cancer patients. The diagnostic value of each independent related factor was calculated according to the receiver operating curve (ROC).Results: The level of neuron-specific enolase (NSE) in renal cell carcinoma patients with IOM was significantly higher than that in patients without IOM (P<0.05). There was no significant difference in alkaline phosphatase (ALP), hemoglobin (Hb), serum calcium concentration, α fetoprotein (AFP), carcinoembryonic antigen (CEA), CA-125 etc. between IOM group and non-IOM (NIOM) group (P>0.05). Binary logistic regression analysis showed that NSE was an independent risk factor for IOM in renal cell carcinoma patients (P<0.05). ROC curve shows that the factor has high accuracy in predicting IOM, and the area under the curve (AUC) is 0.774. The cut-off value of NSE was 49.5 U/l, the sensitivity was 72.2% and the specificity was 80.1%.Conclusion: NSE concentration is a risk factor for IOM in patients with renal cell cancer. If the concentration of NSE in the patient’s body is ≥49.5 U/l, disease monitoring and eye scans should be strengthened.     

Identification of a glycolysis-related lncRNA prognostic signature for clear cell renal cell carcinoma

Background: The present study investigated the independent prognostic value of glycolysis-related long noncoding (lnc)RNAs in clear cell renal cell carcinoma (ccRCC).Methods: A coexpression analysis of glycolysis-related mRNAs–long noncoding RNAs (lncRNAs) in ccRCC from The Cancer Genome Atlas (TCGA) was carried out. Clinical samples were randomly divided into training and validation sets. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses were performed to establish a glycolysis risk model with prognostic value for ccRCC, which was validated in the training and validation sets and in the whole cohort by Kaplan–Meier, univariate and multivariate Cox regression, and receiver operating characteristic (ROC) curve analyses. Principal component analysis (PCA) and functional annotation by gene set enrichment analysis (GSEA) were performed to evaluate the risk model.Results: We identified 297 glycolysis-associated lncRNAs in ccRCC; of these, 7 were found to have prognostic value in ccRCC patients by Kaplan–Meier, univariate and multivariate Cox regression, and ROC curve analyses. The results of the GSEA suggested a close association between the 7-lncRNA signature and glycolysis-related biological processes and pathways.Conclusion: The seven identified glycolysis-related lncRNAs constitute an lncRNA signature with prognostic value for ccRCC and provide potential therapeutic targets for the treatment of ccRCC patients.