HIF1A

Gene Summary

Gene:HIF1A; hypoxia inducible factor 1 alpha subunit
Aliases: HIF1, MOP1, PASD8, HIF-1A, bHLHe78, HIF-1alpha, HIF1-ALPHA, HIF-1-alpha
Location:14q23.2
Summary:This gene encodes the alpha subunit of transcription factor hypoxia-inducible factor-1 (HIF-1), which is a heterodimer composed of an alpha and a beta subunit. HIF-1 functions as a master regulator of cellular and systemic homeostatic response to hypoxia by activating transcription of many genes, including those involved in energy metabolism, angiogenesis, apoptosis, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia. HIF-1 thus plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jul 2011]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:hypoxia-inducible factor 1-alpha
Source:NCBIAccessed: 11 March, 2017

Ontology:

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

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Latest Publications: HIF1A (cancer-related)

Jeong YJ, Jung JW, Cho YY, et al.
Correlation of hypoxia inducible transcription factor in breast cancer and SUVmax of F-18 FDG PET/CT.
Nucl Med Rev Cent East Eur. 2017; 20(1):32-38 [PubMed] Related Publications
BACKGROUND: Tumor hypoxia induces the expression of several genes via the hypoxia-inducible transcription factor-1 alpha (HIF-1a). It is associated with the prognosis of several cancers. We studied the immunohistochemical expression of HIF-1a in patients with invasive ductal cancer (IDC) of the breast and the possible correlation with the maximum standardized uptake value of the primary tumor (pSUVmax) as well as other biological parameters. Prognostic significance of pSUVmax and expression of HIF-1a for the prediction of progression-free survival (PFS) was also assessed.
MATERIAL AND METHODS: Two-hundred seven female patients with IDC who underwent pretreatment fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) were enrolled. The pSUVmax was compared with clinicopathological parameters including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), axillary lymph node (LN) metastasis, stage and HIF-1a expression. The prognostic value of pSUVmax for PFS was assessed using the Kaplan-Meier method.
RESULTS: pSUVmax was significantly higher in patients with HIF-1a expression ≥ 2 compared to patients with HIF-1a expression < 2 (5.2 ± 4.5 vs. 3.7 ± 3.1, p = 0.008). pSUVmax was also significantly higher in higher stage (p < 0.000001), ER-negative tumors (p < 0.0001), PR-negative tumors (p = 0.0011) and positive LN metastasis (p = 0.0013). pSUVmax was significantly higher in patients with progression compared to patients who were disease-free (6.8 ± 4.4 vs. 4.1 ± 3.7, p = 0.0005). A receiver-operating characteristic curve demonstrated a pSUVmax of 6.51 to be the optimal cutoff for predicting PFS (sensitivity: 53.6%, specificity: 86.0%). Patients with high pSUVmax (> 6.5) had significantly shorter PFS compared to patients with low pSUVmax (p < 0.0001).
CONCLUSIONS: pSUVmax on pretreatment F-18 FDG PET/ CT reflect expression of HIF-1a and can be used as a good surrogate marker for the prediction of progression in patients with IDC. The amount of FDG uptake is determined by the presence of glucose metabolism and hypoxia in breast cancer cell.

Lim YS, Cha W, Park MW, et al.
HIF1α in Tumorigenesis of Adenoid Cystic Carcinoma.
Anticancer Res. 2017; 37(2):599-606 [PubMed] Related Publications
BACKGROUND: Tumor hypoxia induces hypoxia-inducible factor-1α (HIF1α), which can influence tumorigenesis and metastasis. We evaluated the expression of HIF1α and the effect of HIF1α inhibitors in adenoid cystic carcinoma (ACC).
MATERIALS AND METHODS: HIF1α expression was demonstrated in ACC cell lines (ACC2 and ACCM). The effect of HIF1α inhibitors was evaluated. A systemic metastasis model was developed. The number of metastatic pulmonary nodules were analyzed.
RESULTS: The ACCM cell line demonstrated greater HIF1α expression and invasion than ACC2. The expression of HIF1α and invasion of ACC cells were blocked by HIF1α siRNA. HIF1α inhibitors 17-N-allylamino-17-demethoxygeldanamycin (17AAG) and echinomycin inhibited cell invasion. 17AAG inhibited metastasis in the animal model, although not statistically significantly.
CONCLUSION: HIF1α siRNA and 17AAG and echinomycin blocked invasion by ACC2 and ACCM cells. 17AAG exhibited therapeutic potential for inhibition of metastasis. Our results provide positive evidence that HIF1α is a promising research pathway for therapy of ACC.

Fraga A, Ribeiro R, Coelho A, et al.
Genetic polymorphisms in key hypoxia-regulated downstream molecules and phenotypic correlation in prostate cancer.
BMC Urol. 2017; 17(1):12 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In this study we sought if, in their quest to handle hypoxia, prostate tumors express target hypoxia-associated molecules and their correlation with putative functional genetic polymorphisms.
METHODS: Representative areas of prostate carcinoma (n = 51) and of nodular prostate hyperplasia (n = 20) were analysed for hypoxia-inducible factor 1 alpha (HIF-1α), carbonic anhydrase IX (CAIX), lysyl oxidase (LOX) and vascular endothelial growth factor (VEGFR2) immunohistochemistry expression using a tissue microarray. DNA was isolated from peripheral blood and used to genotype functional polymorphisms at the corresponding genes (HIF1A +1772 C > T, rs11549465; CA9 + 201 A > G; rs2071676; LOX +473 G > A, rs1800449; KDR - 604 T > C, rs2071559).
RESULTS: Immunohistochemistry analyses disclosed predominance of positive CAIX and VEGFR2 expression in epithelial cells of prostate carcinomas compared to nodular prostate hyperplasia (P = 0.043 and P = 0.035, respectively). In addition, the VEGFR2 expression score in prostate epithelial cells was higher in organ-confined and extra prostatic carcinoma compared to nodular prostate hyperplasia (P = 0.031 and P = 0.004, respectively). Notably, for LOX protein the immunoreactivity score was significantly higher in organ-confined carcinomas compared to nodular prostate hyperplasia (P = 0.015). The genotype-phenotype analyses showed higher LOX staining intensity for carriers of the homozygous LOX +473 G-allele (P = 0.011). Still, carriers of the KDR-604 T-allele were more prone to have higher VEGFR2 expression in prostate epithelial cells (P < 0.006).
CONCLUSIONS: Protein expression of hypoxia markers (VEGFR2, CAIX and LOX) on prostate epithelial cells was different between malignant and benign prostate disease. Two genetic polymorphisms (LOX +473 G > A and KDR-604 T > C) were correlated with protein level, accounting for a potential gene-environment effect in the activation of hypoxia-driven pathways in prostate carcinoma. Further research in larger series is warranted to validate present findings.

Fischer AP, Miles SL
Ascorbic acid, but not dehydroascorbic acid increases intracellular vitamin C content to decrease Hypoxia Inducible Factor -1 alpha activity and reduce malignant potential in human melanoma.
Biomed Pharmacother. 2017; 86:502-513 [PubMed] Related Publications
INTRODUCTION: Accumulation of hypoxia inducible factor-1 alpha (HIF-1α) in malignant tissue is known to contribute to oncogenic progression and is inversely associated with patient survival. Ascorbic acid (AA) depletion in malignant tissue may contribute to aberrant normoxic activity of HIF-1α. While AA supplementation has been shown to attenuate HIF-1α function in malignant melanoma, the use of dehydroascorbic acid (DHA) as a therapeutic means to increase intracellular AA and modulate HIF-1α function is yet to be evaluated. Here we compared the ability of AA and DHA to increase intracellular vitamin C content and decrease the malignant potential of human melanoma by reducing the activity of HIF-1α.
METHODS: HIF-1α protein accumulation was evaluated by western blot and transcriptional activity was evaluated by reporter gene assay using a HIF-1 HRE-luciferase plasmid. Protein expressions and subcellular localizations of vitamin C transporters were evaluated by western blot and confocal imaging. Intracellular vitamin C content following AA, ascorbate 2-phosphate (A2P), or DHA supplementation was determined using a vitamin C assay. Malignant potential was accessed using a 3D spheroid Matrigel invasion assay. Data was analyzed by One or Two-way ANOVA with Tukey's multiple comparisons test as appropriate with p<0.05 considered significant.
RESULTS: Melanoma cells expressed both sodium dependent vitamin C (SVCT) and glucose (GLUT) transporters for AA and DHA transport respectively, however advanced melanomas responded favorably to AA, but not DHA. Physiological glucose conditions significantly impaired intracellular vitamin C accumulation following DHA treatment. Consequently, A2P and AA, but not DHA treated cells demonstrated lower HIF-1α protein expression and activity, and reduced malignant potential. The ability of AA to regulate HIF-1α was dependent on SVCT2 function and SVCT2 was not significantly inhibited at pH representative of the tumor microenvironment.
CONCLUSIONS: The use of ascorbic acid as an adjuvant cancer therapy remains under investigated. While AA and A2P were capable of modulating HIF-1α protein accumulation/activity, DHA supplementation resulted in minimal intracellular vitamin C activity with decreased ability to inhibit HIF-1α activity and malignant potential in advanced melanoma. Restoring AA dependent regulation of HIF-1α in malignant cells may prove beneficial in reducing chemotherapy resistance and improving treatment outcomes.

Yang T, Yao Q, Cao F, et al.
Silver nanoparticles inhibit the function of hypoxia-inducible factor-1 and target genes: insight into the cytotoxicity and antiangiogenesis.
Int J Nanomedicine. 2016; 11:6679-6692 [PubMed] Free Access to Full Article Related Publications
Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that is activated upon exposure to hypoxic stress. It modulates a number of cellular responses including proliferation, apoptosis, angiogenesis, and metabolism by activating a panel of target genes in response to hypoxia. The HIF-1 level is often upregulated in the hypoxic microenvironment of solid tumors, which contributes to cancer treatment failure. Here we report that silver nanoparticles (AgNPs), which are widely used as an antimicrobial agent, are an effective inhibitor of HIF-1. AgNPs inhibited the activation of a HIF-dependent reporter construct after the cells were exposed to hypoxic conditions or treated with cobalt chloride, a hypoxia mimetic agent. The AgNPs also interfered with the accumulation of HIF-1α protein and the induction of the endogenous HIF target genes, VEGF-A and GLUT1. Since both HIF-1 and vascular endothelial growth factor-A play an important role in angiogenesis, AgNPs also inhibited angiogenesis in vitro. Our data reveal a new mechanism of how AgNPs act on cellular function, that is, they disrupt HIF signaling pathway. This finding provides a novel insight into how AgNPs can inhibit cancer cell growth and angiogenesis.

He W, Huang L, Shen X, et al.
Relationship between RSUME and HIF-1α/VEGF-A with invasion of pituitary adenoma.
Gene. 2017; 603:54-60 [PubMed] Related Publications
The RWD-containing sumoylation enhancer (RSUME) can stabilize hypoxia-inducible factor-1α (HIF-1α) which promotes vascular endothelial growth factor-A (VEGF-A) expression. RSUME plays an important role in promoting the invasion of pituitary adenoma. In this study, we compared the mRNA and protein levels of RSUME, HIF-1α, and VEGF-A in pituitary adenoma tissue and analyzed the correlation. We found that the expression levels of RSUME, HIF-1α, and VEGF-A in invasive pituitary adenoma were significantly higher than in noninvasive pituitary adenoma. Moreover, a positive correlation was found between RSUME and HIF-1α/VEGF pathways. RSUME and HIF-1α were treated with hypoxia-mimicking CoCl2 and transfected into AtT-20 and GT1.1 cell lines to determine the relationship between them. It was found that RSUME effects post-transcriptional expression of HIF-1α regulated VEGF-A secretion. Reducing RSUME expression using siRNA transfection resulted in a decrease of the invasion inhibition rate of AtT-20 cells, as determined using Transwell and MTT assays. Together, we found that RSUME silencing can inhibit the invasion of pituitary adenoma cells.

Sun LL, Song Z, Li WZ, Tang SY
Hypoxia facilitates epithelial-mesenchymal transition-mediated rectal cancer progress.
Genet Mol Res. 2016; 15(4) [PubMed] Related Publications
Rectal cancer is a commonly observed tumor in clinics, and epithelial-mesenchymal transition (EMT) is very important for tumor invasion and metastasis. We established a rectal cancer HCT-116 cell hypoxia model and detected cell proliferation, invasion, and EMT-related protein expression in this model, aiming to analyze the effect of hypoxia on rectal cancer cell EMT. Rectal cancer cell line HCT-116 was cultured in normoxic, hypoxic, or anaerobic environment, and hypoxia-inducible factor-1α (HIF-1α) mRNA expression was detected in the cells by real-time PCR. Cell proliferation was tested by MTT assay; cell invasion was determined by transwell assay, and HIF-1α, epithelial-cadherin, and Snail protein levels were evaluated by western blot analysis. HIF-1α mRNA level significantly increased in the anaerobic group compared to that in the normoxic and hypoxic groups (P < 0.05). HCT-116 cell proliferation in the anaerobic group was obviously higher than that in the other two groups, with the hypoxic group showing stronger proliferative ability than the normoxic group (P < 0.05). Compared to the normoxic group, the HCT-116 cells demonstrated enhanced cell invasion and migration in hypoxic and anaerobic groups. HIF-1α and Snail expressions were upregulated, whereas epithelial-cadherin expression had declined in the hypoxic and anaerobic groups, compared to those in the normal control (P < 0.05). Therefore, hypoxia promoted rectal cancer cell progress by increasing HIF-1α to induce EMT.

Guo Y, Han B, Luo K, et al.
NOX2-ROS-HIF-1α signaling is critical for the inhibitory effect of oleanolic acid on rectal cancer cell proliferation.
Biomed Pharmacother. 2017; 85:733-739 [PubMed] Related Publications
Rectal cancer is the second leading cause of cancer mortality in the western countries and accounts for 10% incidence and mortality of cancer in the whole world. Drug resistance and severe toxicity severely limited the efficiency of chemotherapy of rectal cancer. Oleanolic acid (OA) is a natural triterpenoid and an aglycone of many saponins. In the present study, we aimed to investigate the effect of OA on rectal cancer cell proliferation and its possible mechanism. We showed that OA concentration-dependently inhibited cell proliferation in HCT-15, HT-29, HCT-8 and Colo 205 human rectal cancer cell lines. OA significantly increased reactive oxygen species (ROS) generation and NADPH oxidase 2 (NOX2) expression in a concentration-dependent manner. In HCT-15 and HT-29 cells, siNOX2 notably suppressed OA-induced ROS generation, inhibition of cell proliferation, increase of S phase cell population and decrease of cyclin D1 and CDK2 expression. OA markedly decreased hypoxia-inducible factor 1α (HIF-1α) expression in HCT-15 and HT-29 cells in a concentration-dependent manner. Overexpression of HIF-1α significantly suppressed OA-induced inhibition of cell proliferation, increase of S phase cell population and decrease of cyclin D1 and CDK2 expression. Inhibition of NOX2 by siRNA notably blocked OA-induced suppression of HIF-1α expression. Our findings provide novel insights into OA-induced inhibition of rectal cancer cell proliferation and highlight NOX2/ROS/HIF-1α axis as a novel therapeutic target for the treatment of rectal cancer.

Tasharrofi B, Soudyab M, Nikpayam E, et al.
Comparative expression analysis of hypoxia-inducible factor-alpha and its natural occurring antisense in breast cancer tissues and adjacent noncancerous tissues.
Cell Biochem Funct. 2016; 34(8):572-578 [PubMed] Related Publications
Hypoxia-inducible factors (HIFs) have been shown to be upregulated in tumor tissues and linked with tumor progression and metastasis in breast cancer. Among regulatory mechanisms for HIF expression is a natural occurring antisense named aHIF, which has been shown to be overexpressed in breast cancer and influence the level of the HIF-1α transcript. In the present study, we analyzed the expression of HIF-1α and aHIF in breast cancer tissues versus adjacent noncancer tissues (ANCTs) in relation with the clinical and biological behavior of the tumors. aHIF has been shown to be expressed in 67.4% of invasive ductal carcinoma samples, while none of ANCTs showed its expression. HIF-1α has been expressed in all of tumors and 90% of ANCTs. Comparison of HIF-1α expression level between tumor and ANCT tissues showed a total upregulation in tumor samples. No statistically significant association has been found between the level of HIF-1α expression in tumor samples and clinicopathologic and demographic characteristics such as age, tumor size, estrogen receptor status, progesterone receptor status, HER2/neu expression level, lymph node status, histological grade, and stage except for a weak correlation between HIF-1α expression and Ki-67 status. Besides, we could not detect any significant correlation between relative expression of HIF-1α and aHIF in tumor samples. Collectively, these data suggest that aHIF overexpression can be used as a potential biomarker in breast cancer. However, further studies are needed for the evaluation of its mechanism of action in regulation of HIF-1α expression in different pathological conditions. HIF-1α overexpression results in the upregulation of several genes that participated in cancer-associated pathways such as proliferation, angiogenesis, and glucose metabolism. We showed that HIF-1α is upregulated in breast tumor samples compared with adjacent noncancerous tissues. Its expression has been associated with Ki-67 status. Its natural occurring antisense is only expressed in tumor tissues. Thus, it can be used as a potential biomarker in breast cancer.

Chen SW, Lin YC, Chen RY, et al.
Immunohistochemical overexpression of hypoxia-induced factor 1α associated with slow reduction in (18)fluoro-2-deoxy-D-glucose uptake for chemoradiotherapy in patients with pharyngeal cancer.
Eur J Nucl Med Mol Imaging. 2016; 43(13):2343-2352 [PubMed] Related Publications
BACKGROUND: This study examined genomic factors associated with a reduction in (18)fluoro-2-deoxy-D-glucose (FDG) uptake during positron emission tomography-computed tomography (PET-CT) for definitive chemoradiotherapy (CRT) in patients with pharyngeal cancer.
METHODS: The pretreatment and interim PET-CT images of 25 patients with advanced pharyngeal cancers receiving definitive CRT were prospectively evaluated. The maximum standardized uptake value (SUVmax) of the interim PET-CT and the reduction ratio of the SUVmax (SRR) between the two images were measured. Genomic data from pretreatment incisional biopsy specimens (SLC2A1, CAIX, VEGF, HIF1A, BCL2, Claudin-4, YAP1, MET, MKI67, and EGFR) were analyzed using tissue microarrays. Differences in FDG uptake and SRRs between tumors with low and high gene expression were examined using the Mann-Whitney test. Cox regression analysis was performed to examine the effects of variables on local control.
RESULTS: The SRR of the primary tumors (SRR-P) was 0.59 ± 0.31, whereas the SRR of metastatic lymph nodes (SRR-N) was 0.54 ± 0.32. Overexpression of HIF1A was associated with a high iSUVmax of the primary tumor (P < 0.001) and neck lymph node (P = 0.04) and a low SRR-P (P = 0.02). Multivariate analysis revealed that patients who had tumors with low SRR-P or high HIF1A expression levels showed inferior local control.
CONCLUSION: In patients with pharyngeal cancer requiring CRT, HIF1A overexpression was positively associated with high interim SUVmax or a slow reduction in FDG uptake. Prospective trials are needed to determine whether the local control rate can be stratified using the HIF1A level as a biomarker and SRR-P.

Huang Y, Tao Y, Hu K, et al.
Hypoxia-induced NIPP1 activation enhances metastatic potential and predicts poor prognosis in hepatocellular carcinoma.
Tumour Biol. 2016; 37(11):14903-14914 [PubMed] Related Publications
Hypoxia is known to promote hepatocellular carcinoma (HCC) invasion and metastasis and nuclear inhibitor of protein phosphatase 1 (NIPP1) overexpression contributes to the malignant phenotype in HCC. The aim of this study was to investigate the role of NIPP1 in HCC development under hypoxia. We first conducted a study with 106 cases to explore the association of NIPP1 and/or enhancer of zeste homolog 2 (EZH2) expression with poor prognosis in HCC. Then additional 352 independent cases were recruited to validate the results in the first stage. Hypoxia was induced by culturing HCC cells in 1 % O2 or of the treatment with hypoxic agent. The expression levels of NIPP1/EZH2 in both HCC tissues and HCC cell lines were detected by RT-PCR, Western blot, or immunohistochemistry. We also studied the effects of the loss of function of NIPP1 and EZH2 on malignant phenotypes, downstream pathway, and inflammatory factors activities using gene silencing strategy. Overall, we found that NIPP1 and EZH2 were overexpressed in both HCC tissue samples and HCC cell lines. High expression of HIPP1 was associated with poor prognosis and clinicopathological features in patients with advanced HCC. HIPP1 expression positively correlated with the expression of hypoxia marker (carbonic anhydrase IX). Hypoxia induced high expression of NIPP1. NIPP1/EZH2 knockdown in HCC cell lines under hypoxia suppressed the malignant phenotypes, reduced the expression of hypoxia-inducible Factor 1α, downstream molecules of EZH2, and inhibit the activity of inflammatory factors. In conclusion, we found that NIPP1 could be activated by hypoxia and contributed to hypoxia-induced invasive and metastatic potential in HCC.

Slemc L, Kunej T
Transcription factor HIF1A: downstream targets, associated pathways, polymorphic hypoxia response element (HRE) sites, and initiative for standardization of reporting in scientific literature.
Tumour Biol. 2016; 37(11):14851-14861 [PubMed] Related Publications
Hypoxia-inducible factor-1α (HIF-1α) has crucial role in adapting cells to hypoxia through expression regulation of many genes. Identification of HIF-1α target genes (HIF-1α-TGs) is important for understanding the adapting mechanism. The aim of the present study was to collect known HIF-1α-TGs and identify their associated pathways. Targets and associated genomics data were retrieved using PubMed, WoS ( http://apps.webofknowledge.com/ ), HGNC ( http://www.genenames.org/ ), NCBI ( http://www.ncbi.nlm.nih.gov/ ), Ensemblv.84 ( http://www.ensembl.org/index.html ), DAVID Bioinformatics Resources ( https://david.ncifcrf.gov /), and Disease Ontology database ( http://disease-ontology.org/ ). From 51 papers, we collected 98 HIF-1α TGs found to be associated with 20 pathways, including metabolism of carbohydrates and pathways in cancer. Reanalysis of genomic coordinates of published HREs (hypoxia response elements) revealed six polymorphisms within HRE sites (HRE-SNPs): ABCG2, ACE, CA9, and CP. Due to large heterogeneity of results presentation in scientific literature, we also propose a first step towards reporting standardization of HIF-1α-target interactions consisting of ten relevant data types. Suggested minimal checklist for reporting will enable faster development of a complete catalog of HIF-1α-TGs, data sharing, bioinformatics analyses, and setting novel more targeted hypotheses. The proposed format for data standardization is not yet complete but presents a baseline for further optimization of the protocol with additional details, for example, regarding the experimental validation.

Ni JY, Xu LF, Wang WD, et al.
Transarterial embolization combined with RNA interference targeting hypoxia-inducible factor-1α for hepatocellular carcinoma: a preliminary study of rat model.
J Cancer Res Clin Oncol. 2017; 143(2):199-207 [PubMed] Related Publications
PURPOSE: To study whether transarterial embolization (TAE) with RNA interference (RNAi) targeting hypoxia-inducible factor-1α (HIF-1α) can improve efficacy of TAE in treating hepatocellular carcinoma (HCC).
MATERIALS AND METHODS: CBRH-7919 rat hepatoma cell line was used and HCC models of rats were constructed. The siRNA transfection compound was made by mixing specific siRNA and Lipofectamine 2000™. Delivery and transfection of siRNA were administered by injecting iodized oil emulsion (diluted lipiodol and siRNA) via hepatic artery. The expression levels of mRNA and protein were detected using the real-time reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry and western blotting assays, respectively.
RESULTS: In vitro experiment, the specific HIF-1α-siRNA was proved to inhibit expression levels of HIF-1α and vascular endothelial growth factor (VEGF) effectively. In animal study, real-time RT-PCR assay showed the average relative mRNA expressions of HIF-1α were 0.31 ± 0.01, 0.65 ± 0.03, 0.46 ± 0.005, and 1.00 ± 0.00 in TAE + siRNA, siRNA, TAE, and control groups, respectively. Western blotting assay showed the average relative protein expressions of HIF-1α were 0.13 ± 0.02, 0.87 ± 0.02, 0.39 ± 0.02, and 1.02 ± 0.01 in TAE + siRNA, siRNA, TAE, and control groups, respectively. Compared with control, TAE, and siRNA groups, TAE + siRNA can significantly inhibit protein expressions of HIF-1α and VEGF (P HIF-1α < 0.001; P VEGF < 0.001). Overall survival of rats underwent TAE + siRNA was significantly longer than that of rats treated with TAE monotherapy (P = 0.001).
CONCLUSION: This animal study showed TAE combined with HIF-1α-RNAi could significantly improve efficacy of TAE in treating HCC by inhibiting expressions of HIF-1α and VEGF after TAE treatment.

Li X, Wu Y, Liu A, Tang X
Long non-coding RNA UCA1 enhances tamoxifen resistance in breast cancer cells through a miR-18a-HIF1α feedback regulatory loop.
Tumour Biol. 2016; 37(11):14733-14743 [PubMed] Related Publications
Recent studies reported that long non-coding RNAs (lncRNAs) might play critical roles in regulating endocrine resistance of breast cancer. Urothelial carcinoma-associated 1 (UCA1) is an lncRNA with an oncogenic role in breast cancer. This study aimed to investigate whether UCA1 is involved in acquired tamoxifen resistance in estrogen receptor (ER)-positive cancer cells. Our findings reveal that tamoxifen induces UCA1 upregulation in ER-positive breast cancer cells in a HIF1α-dependent manner. UCA1 upregulation results in significantly enhanced tamoxifen resistance. The upregulated UCA1 sponges miR-18a, which is a negative regulator of HIF1α. Therefore, UCA1 upregulation is further enhanced through a miR-18a-HIF1α feedback loop. In addition, our data also showed that miR-18a is a modulator of tamoxifen sensitivity due to its regulative effect on cell cycle proteins. miR-18a inhibitor reduced the sensitivity of MCF-7 cells to tamoxifen, while miR-18a mimics sensitized BT474 cells to tamoxifen. Therefore, miR-18a downregulation also partly contributes to acquired tamoxifen resistance in the cancer cells. These findings provide some useful information for future clinical treatment of tamoxifen resistance.

Terashima J, Sampei S, Iidzuka M, et al.
VEGF expression is regulated by HIF-1α and ARNT in 3D KYSE-70, esophageal cancer cell spheroids.
Cell Biol Int. 2016; 40(11):1187-1194 [PubMed] Related Publications
In 3D cultured cell systems, the cells form 3D spheroids that mimic cancer cell spheroids in vivo. Cancer cells form cell spheroids as they grow. The in vivo spheroids do not contain a vascular network; therefore, oxygen and nutrition supplies are insufficient. Specifically, the cells in the core region of the cluster are exposed to higher stress levels than the cells in the outer spheroid layer. As a result, the cells in the spheroid are exposed to low nutrition and hypoxia conditions. To overcome these shortages, angiogenesis is induced in cancer spheroids in vivo. Vascular endothelial growth factor (VEGF) is an important molecule involved in angiogenesis. VEGF is secreted by cancer cells in vivo in response to stress conditions such as hypoxia. VEGF expression in cancer cells is mediated by hypoxia-inducible factor 1α (HIF1α), which accumulates in cancer cells during hypoxia. In this report, we show that VEGF expression is regulated by HIF1α and that VEGF is secreted to the outside of the spheroid in vitro. Several investigators have reported that HIF1α forms a protein-protein complex with aryl hydrocarbon receptor translocator (ARNT). We report here that not only HIF1α but also ARNT regulates VEGF expression in 3D cancer spheroids. Our results suggest the utility of the in vitro 3D cancer spheroid model for investigating angiogenesis in cancerous tissues.

Park KJ, Yu MO, Park DH, et al.
Role of vincristine in the inhibition of angiogenesis in glioblastoma.
Neurol Res. 2016; 38(10):871-9 [PubMed] Related Publications
OBJECTIVE: Vincristine, a microtubule-destabilizing drug, was found to exhibit anti-angiogenic effects and anti-tumoral activity. However, the precise mechanism by which vincristine inhibits angiogenesis in glioblastomas is not well understood. Our aim was to investigate whether vincristine affects vascular endothelial growth factor (VEGF) expression in glioblastoma cells and determine whether it is mediated by the downregulation of hypoxia-inducible factor-1α (HIF-1α).
METHODS: We investigated the expression of HIF-1α in glioblastoma tissues resected from patients and in human glioblastoma cell lines using immunohistochemistry, Western blot analysis, and immunocytochemistry. In addition to an MTT assay assessing the effect of vincristine on cell proliferation and viability, the effects of vincristine on VEGF mRNA expression and HIF-1α protein were examined using real-time RT-PCR and Western blot analysis under 1% O2 (hypoxia).
RESULTS: HIF-1α was expressed in the majority of glioblastoma tissues and was detected mainly in the nucleus. Strong immunoreactivity for HIF- 1 α was found often in the hypercellular zones. Under hypoxic conditions, HIF-1α protein levels in the glioblastoma cell lines increased, primarily localizing into the nucleus similar to glioblastoma tissues. Exposure of glioblastoma cells to vincristine resulted in enrichment of the G2-M fraction of the cell cycle, which suggests that vincristine-mediated growth inhibition of glioblastoma is correlated with mitotic inhibition. Using doses lower than those found to reduce the viability and proliferation of cells by 50% (IC50), vincristine decreased both the expression of VEGF mRNA and the level of HIF-1α protein in hypoxic glioblastoma cells. In addition, following exposure to vincristine, the expression of VEGF mRNA was correlated with HIF-1α protein levels.
CONCLUSIONS: Our results suggest that the mechanism by which vincristine elicits an anti-angiogenic effect in glioblastomas under hypoxic conditions might be mediated, in part, by HIF-1α inhibition.

Yanagawa M, Morii E, Hata A, et al.
Dual-energy dynamic CT of lung adenocarcinoma: correlation of iodine uptake with tumor gene expression.
Eur J Radiol. 2016; 85(8):1407-13 [PubMed] Related Publications
OBJECTIVES: To compare iodine content (IC) of solitary lung cancer using dynamic measurements of CT attenuation (Hounsfield Units, HU) and to correlate their quantitative CT data with expressions of vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR) and hypoxia-inducible factor-1α (HIF-1α) using immunostaining methods.
METHODS: This study included 18 patients with adenocarcinoma, who undergone dual energy dynamic multiphase CT to examine solitary lung nodules (6 part-solid and 12 solid nodules). Tumor size was 21.1 mm±8.1 (9-39mm) [Mean±SD (range)]. Contrast volume was determined by weight (2ml/kg). Contrast volume and injection rate were 110.5 ml±17.2 (80-144ml) and 1.84ml/s±0.30 (1.3-2.4ml/s), respectively. Enhancement values ([CT value at each delayed scan-CT value at unenhanced scan]) and net enhancement values ([peak CT value-CT value at unenhanced scan]) were calculated in HU from 65keV monochromatic image. IC at each delayed scan was measured in mg/cm(3) from the iodine-water material decomposition pair on the advantage workstation VolumeShare4. Immunostaining using VEGF, EGFR, and HIF-1α was performed by two pathologists, who evaluated the expression level of them subjectively. Statistical analyses were performed with rank correlation tests and regression analysis.
RESULTS: IC at 2- and 3-minute delayed scan (x) and immunostaining score of HIF-1α (y) showed a significantly positive correlation (r=0.64 and 0.52, p=0.004 and 0.03): regression equation, y=1.34+0.58x and y=1.51+0.55x, respectively.
CONCLUSIONS: Dual-energy dynamic multiphase CT can measure iodine content in lung adenocarcinoma. Iodine content at 2- and 3-minute delayed scan might correlate with the expression level of HIF-1α.

Furukawa Y, Kikuchi J
Epigenetic regulation of cell adhesion-mediated drug resistance acquisition in multiple myeloma.
Rinsho Ketsueki. 2016; 57(5):546-55 [PubMed] Related Publications
Elucidation of the epigenetic mechanisms underlying drug resistance may greatly contribute to the advancement of cancer therapies. In the present study, we identified trimethylation of histone H3 at lysine-27 (H3K27me3) as a critical histone modification for cell adhesion-mediated drug resistance (CAM-DR), which is the most important form of drug resistance in multiple myeloma. Cell adhesion counteracted drug-induced hypermethylation of H3K27 via inactivating phosphorylation of EZH2, leading to sustained expression of anti-apoptotic genes including IGF1, BCL2 and HIF1A. Inhibition of the IGF-1R/PI3K/Akt pathway reversed CAM-DR by promoting EZH2 dephosphorylation and H3K27 hypermethylation both in vitro and in refractory murine myeloma models. To our knowledge, this is the first demonstration of an epigenetic mechanism underlying CAM-DR and provides a rationale for the inclusion of kinase inhibitors counteracting EZH2 phosphorylation in combination chemotherapy aimed at increasing the therapeutic index.

Chen Y, Zhang Z, Luo C, et al.
MicroRNA-18b inhibits the growth of malignant melanoma via inhibition of HIF-1α-mediated glycolysis.
Oncol Rep. 2016; 36(1):471-9 [PubMed] Related Publications
MicroRNAs (miRs) have been demonstrated to play critical roles in the development and progression of malignant melanoma (MM). However, the exact role and underlying mechanism of miR-18b in MM growth remains unclear. In the present study, real-time PCR data indicated that miR-18b was significantly downregulated in MM tissues compared to their matched adjacent non-tumor tissues. Low miR-18b expression was significantly associated with the tumor thickness and stage, although no significant association was observed between the miR-18b expression and the age, gender, or lymph node metastasis. Besides, miR-18b was also significantly downregulated in MM B16 and A375 cells compared to normal skin HACAT cells. Ectopic expression of miR-18b decreased the proliferation of A375 and B16 cells, while induced a remarkable cell cycle arrest at G1 stage. Besides, miR-18b overexpression also inhibited the glycolysis in A375 and B16 cells. HIF-1α, a key regulator in glycolysis, was then identified as a target gene of miR-18b, and its expression was negatively mediated by miR-18b in A375 and B16 cells. Overexpression of HIF-1α rescued the suppressive effect of miR-18b on MM cell proliferation and glycolysis. In vivo study further showed that overexpression of miR-18b inhibited the MM growth as well as the tumor-related death, accompanied with HIF-1α downregulation. Taken together, the present study suggests that miR-18b inhibits the growth of MM cells in vitro and in vivo through directly targeting HIF-1α.

Lim S, Liu H, Madeira da Silva L, et al.
Immunoregulatory Protein B7-H3 Reprograms Glucose Metabolism in Cancer Cells by ROS-Mediated Stabilization of HIF1α.
Cancer Res. 2016; 76(8):2231-42 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
B7-H3 is a member of B7 family of immunoregulatory transmembrane glycoproteins expressed by T cells. While B7-H3 overexpression is associated with poor outcomes in multiple cancers, it also has immune-independent roles outside T cells and its precise mechanistic contributions to cancer are unclear. In this study, we investigated the role of B7-H3 in metabolic reprogramming of cancer cells in vitro and in vivo We found that B7-H3 promoted the Warburg effect, evidenced by increased glucose uptake and lactate production in B7-H3-expressing cells. B7-H3 also increased the protein levels of HIF1α and its downstream targets, LDHA and PDK1, key enzymes in the glycolytic pathway. Furthermore, B7-H3 promoted reactive oxygen species-dependent stabilization of HIF1α by suppressing the activity of the stress-activated transcription factor Nrf2 and its target genes, including the antioxidants SOD1, SOD2, and PRX3. Metabolic imaging of human breast cancer xenografts in mice confirmed that B7-H3 enhanced tumor glucose uptake and tumor growth. Together, our results illuminate the critical immune-independent contributions of B7-H3 to cancer metabolism, presenting a radically new perspective on B7 family immunoregulatory proteins in malignant progression. Cancer Res; 76(8); 2231-42. ©2016 AACR.

Pruefer F, Vazquez-Santillan K, Munoz-Galindo L, et al.
TIMP4 Modulates ER-α Signalling in MCF7 Breast Cancer Cells.
Folia Biol (Praha). 2016; 62(2):75-81 [PubMed] Related Publications
Tissue inhibitor of metalloprotease 4 (TIMP4) contributes to poor prognosis in breast and other tumours. However, the mechanisms of how TIMP4 influences breast cancer cell behaviour are unknown. Our aim was to explore the signalling pathways modulated by TIMP4 in breast cancer cells. Human recombinant TIMP4 was added to MCF7 breast cancer cells and RNASeq was performed. TIMP4 RNASeq results were validated by RT-PCR. Network analyses of TIMP4-exposed cells showed that ER-α, HIF1A and TGF-β signalling were activated, whereas FOXO3 signalling was downregulated. ER-α protein levels were increased and concordantly, promoters of TIMP4-upregulated genes were significantly enriched in oestrogen-binding sites. We concluded that TIMP4 modulates multiple signalling pathways relevant in cancer in MCF7 cells, including the ER-α cascade.

Jin MS, Lee H, Park IA, et al.
Overexpression of HIF1α and CAXI predicts poor outcome in early-stage triple negative breast cancer.
Virchows Arch. 2016; 469(2):183-90 [PubMed] Related Publications
Dysregulated energy metabolism is one of the main mechanisms for uncontrolled growth in solid tumors. Hypoxia-inducible factor 1-alpha (HIF1α) is a transcription factor implicated in regulating several genes that are responsible for cell metabolism, including carbonic anhydrase IX (CAIX). The aim of this study is to determine the clinical significance of immunohistochemical metabolic alteration in early-stage triple negative breast cancer (TNBC) patients who received cyclophosphamide-based chemotherapy or radiotherapy and those with basal phenotype. Immunohistochemical staining for HIF1α and CAIX was performed to determine the correlation with clinicopathologic variables and survival outcome on tissue microarrays from 270 early-stage TNBC patients. In vitro experiments with multiple human TNBC cell lines, suppression of HIF1α by small interfering RNA (siRNA) significantly reduced CAIX protein expression in all cell lines. In multivariate analyses for different therapeutic modalities and basal phenotype, combined HIF1α and CAIX protein overexpression was significantly associated with disease-free survival in the total cohort (OR = 2.583, P = 0.002), stratified cohorts expressing basal phenotype (OR = 2.234, P = 0.021), and in those patients who received adjuvant chemotherapy (OR = 3.078, P = 0.023) and adjuvant radiotherapy (OR = 2.111, P = 0.050), respectively. In early TNBC, combined HIF1α and CAIX protein expression may serve as an unfavorable prognostic indicator particularly in patients treated with cyclophosphamide-based chemotherapy or radiotherapy as well as those with basal phenotype of breast cancer.

Abouhashem NS, Ibrahim DA, Mohamed AM
Prognostic implications of epithelial to mesenchymal transition related proteins (E-cadherin, Snail) and hypoxia inducible factor 1α in endometrioid endometrial carcinoma.
Ann Diagn Pathol. 2016; 22:1-11 [PubMed] Related Publications
The epithelial-mesenchymal transition (EMT) is an important step in the invasion and metastasis of cancer. E-cadherin downregulation, which is essentially controlled by EMT-mediated proteins such as Snail, is a main molecular feature of this process. Tumor hypoxia is one of the essential biological phenomena that are associated with the development and progression of various solid tumors. Recently, hypoxia and hypoxia-inducible factor 1α (HIF-1α) signaling pathway were identified to have an essential role in the regulation of EMT phenotype. The aim of the study was to evaluate the prognostic impact of EMT-related proteins (E-cadherin, Snail) and HIF-1α in endometrioid endometrial carcinoma (EEC) among Egyptian women. Immunohistochemical evaluation of E-cadherin, Snail, and HIF-1α expression was performed using 50 cases of EEC. The relationship between protein expression and clinicopathological features was investigated. The frequency of immunopositivity for E-cadherin, Snail, and HIF-1α in our cases of EEC was 82%, 28%, and 66%, respectively. Reduced E-cadherin and increased nuclear expression of Snail as well as HIF-1α were significantly associated with histopathologic grade, clinical stage myometrial invasion, and lymph node involvement. Statistical analysis showed a positive correlation between HIF-1α overexpression and Snail upregulation (τ= +0.252, P= .025); however, E-cadherin expression level was inversely correlated with enhanced Snail expression (τ= -0.450, P< .001) as well as with HIF-1α overexpression (τ= -0.439, P< .001). The overall survival and progression-free survival were inversely related to Snail immunoreactivity and positively related to E-cadherin expression. E-cadherin and Snail have a predictive value in EEC. In conclusion, the current study reveals that both Snail and HIF-1α expressions are significantly associated with poor prognosis in EEC; however, E-cadherin expression is considered a marker of good prognosis. E-cadherin and Snail expression has a predictive value in EEC management.

Sadahiro S, Suzuki T, Tanaka A, et al.
Increase in Gene Expression of TYMP, DPYD and HIF1A Are Associated with Response to Preoperative Chemoradiotherapy Including S-1 or UFT for Rectal Cancer.
Anticancer Res. 2016; 36(5):2433-40 [PubMed] Related Publications
AIM: The aim of the study was to identify biomarkers capable of predicting response to preoperative chemoradiotherapy (CRT) including S-1 or UFT for rectal cancer using biopsy specimens obtained before CRT (Pre-samples) and 7 days after the start of CRT (Day-7 samples).
MATERIALS AND METHODS: Preoperative CRT including S-1 or UFT was performed in 82 patients with locally advanced rectal cancer. The expression levels of 18 genes related to 5-fluorouracil, folate, and radiation in the Pre-samples and the Day-7 samples were evaluated using reverse transcription polymerase chain reaction (RT-PCR) assay.
RESULTS: The gene expression levels of hypoxia inducible factor 1 alpha subunit (HIF1A), dihydropyrimidine dehydrogenase (DPYD) and thymidine phosphorylase (TYMP) were found significantly increased in Day-7 samples compared to Pre-samples in responders, but not in non-responders.
CONCLUSION: Increases in gene expression levels of TYMP, DPYD, and HIF1A in tumor tissues at 7 days after the start of CRT may be useful for predicting the efficacy of CRT including S-1 or UFT.

Tonissi F, Lattanzio L, Astesana V, et al.
Reoxygenation Reverses Hypoxia-related Radioresistance in Head and Neck Cancer Cell Lines.
Anticancer Res. 2016; 36(5):2211-5 [PubMed] Related Publications
BACKGROUND/AIM: Head and neck cancer (HNC) is characterized by epidermal growth factor receptor (EGFR) overexpression and radiotherapy (RT) resistance. Cancer cells are able to survive and proliferate in hypoxic conditions. Hypoxia can be transiently interrupted by phases of reoxygenation. This work aimed to analyze the reoxygenation effect on proliferation in response to radiation in HNC cells.
MATERIALS AND METHODS: HNC cell lines CAL33 and CAL166 were subjected to an 8-Gy radiation dose in hypoxia and/or after reoxygenation. Cell proliferation and molecular factors involved in response to treatments were studied.
RESULTS: Cytotoxicity test confirmed radioresistance in hypoxia and highlighted that reoxygenation before RT restores sensitivity in both cell lines. Our results showed a similar proliferation inhibition effect and EGFR modulation but a different cell death mechanism in the two cell lines after treatment.
CONCLUSION: Reoxygenation before RT rescued radiosensitivity in HNC cells.

Himoto T, Fujita K, Nomura T, et al.
Roles of Copper in Hepatocarcinogenesis via the Activation of Hypoxia-Inducible Factor-1α.
Biol Trace Elem Res. 2016; 174(1):58-64 [PubMed] Related Publications
Hypoxia-inducible factor-1α (HIF-1α) is involved in the pathogenesis of hepatocellular carcinoma (HCC). However, the roles of trace elements in the activation of HIF-1α during hepatocarcinogenesis have been unclear. We investigated whether copper (Cu) and zinc (Zn) participated in the activation of HIF-1α in the process of hepatocarcinogenesis or not. Nine patients with chronic hepatitis (CH), five with liver cirrhosis (LC), 12 with HCC, and nine normal healthy controls were enrolled in this study. Their serum HIF-1α, Cu, and Zn levels were determined in the enrolled patients. Hepatic HIF-1α expression was evaluated, using an immunohistochemical procedure. The HCC patients had significantly higher serum HIF-1α levels than the CH patients (6.47 ± 1.57 vs. 5.09 ± 1.22 ng/ml, p = 0.0344). The serum Cu level in the HCC patients was also significantly higher than those in the CH and LC patients (137 ± 24 vs. 107 ± 15 μg/dl, 114 ± 24 μg/dl). Interestingly, a positive correlation was observed between serum HIF-1α and Cu levels in the enrolled patients (r = 0.425, p = 0.0137). In contrast, no significant differences in serum Zn levels were present between the HCC patients and the CH or LC patients. The serum HIF-1α was not positively correlated with the serum Zn level in the enrolled patients, either. Immunohistochemical analysis revealed that two of the five HCC patients had HIF-1α expression in the tumor tissues, whereas none of CH and LC had hepatic HIF-1α expression in the liver tissues. These data suggest that the activation of HIF-1α derived from a Cu accumulation in the liver may cause hepatocarcinogenesis.

Li M, Wang YX, Luo Y, et al.
Hypoxia inducible factor-1α-dependent epithelial to mesenchymal transition under hypoxic conditions in prostate cancer cells.
Oncol Rep. 2016; 36(1):521-7 [PubMed] Related Publications
Prostate cancer is the most commonly diagnosed cancer in men and the second leading cause of cancer death. Hypoxia is an environmental stimulus that plays an important role in the development and cancer progression especially for solid tumors. The key regulator under hypoxic conditions is stabilized hypoxia-inducible factor (HIF)-1α. In the present study, immune-fluorescent staining, siRNAs, qRT-PC, immunoblotting, cell migration and invasion assays were carried out to test typical epithelial to mesenchymal transition under hypoxia and the key regulators of this process in PC3, a human prostate cancer cell line. Our data demonstrated that hypoxia induces diverse molecular, phenotypic and functional changes in prostate cancer cells that are consistent with EMT. We also showed that a cell signal factor such as HIF-1α, which might be stabilized under hypoxic environment, is involved in EMT and cancer cell invasive potency. The induced hypoxia could be blocked by HIF-1α gene silencing and reoxygenation of EMT in prostate cancer cells, hypoxia partially reversed accompanied by a process of mesenchymal-epithelial reverting transition (MErT). EMT might be induced by activation of HIF-1α-dependent cell signaling in hypoxic prostate cancer cells.

Nel I, Gauler TC, Bublitz K, et al.
Circulating Tumor Cell Composition in Renal Cell Carcinoma.
PLoS One. 2016; 11(4):e0153018 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
PURPOSE: Due to their minimal-invasive yet potentially current character circulating tumor cells (CTC) might be useful as a "liquid biopsy" in solid tumors. However, successful application in metastatic renal cell carcinoma (mRCC) has been very limited so far. High plasticity and heterogeneity of CTC morphology challenges currently available enrichment and detection techniques with EpCAM as the usual surface marker being underrepresented in mRCC. We recently described a method that enables us to identify and characterize non-hematopoietic cells in the peripheral blood stream with varying characteristics and define CTC subgroups that distinctly associate to clinical parameters. With this pilot study we wanted to scrutinize feasibility of this approach and its potential usage in clinical studies.
EXPERIMENTAL DESIGN: Peripheral blood was drawn from 14 consecutive mRCC patients at the West German Cancer Center and CTC profiles were analyzed by Multi-Parameter Immunofluorescence Microscopy (MPIM). Additionally angiogenesis-related genes were measured by quantitative RT-PCR analysis.
RESULTS: We detected CTC with epithelial, mesenchymal, stem cell-like or mixed-cell characteristics at different time-points during anti-angiogenic therapy. The presence and quantity of N-cadherin-positive or CD133-positive CTC was associated with inferior PFS. There was an inverse correlation between high expression of HIF1A, VEGFA, VEGFR and FGFR and the presence of N-cadherin-positive and CD133-positive CTC.
CONCLUSIONS: Patients with mRCC exhibit distinct CTC profiles that may implicate differences in therapeutic outcome. Prospective evaluation of phenotypic and genetic CTC profiling as prognostic and predictive biomarker in mRCC is warranted.

Lv F, Du R, Shang W, et al.
HIF-1α Silencing Inhibits the Growth of Osteosarcoma Cells by Inducing Apoptosis.
Ann Clin Lab Sci. 2016; 46(2):140-6 [PubMed] Related Publications
BACKGROUND: Osteosarcoma (OS) is a malignant tumor of mesenchymal origin, which is generally locally aggressive and tends to produce early systemic metastases. Therefore, an identification of a novel therapeutic target is required.
METHODS: We investigated the effect of small interfering RNA (siRNA) targeting hypoxia-inducible factor 1α (HIF-1α) on the growth of Osteosarcoma MG-63 and U2-OS cells. Two cell-lines were transfected with various concentrations of HIF-1α or control siRNA, and the effect on HIF-1α expression was analyzed by using quantitative polymerase chain reaction and western blot analysis. The effects of HIF-1α siRNA on growth inhibition and apoptosis were then evaluated by standard methods.
RESULT: HIF-1α siRNA treatment reduced HIF-1α mRNA and protein expression in MG-63 and U2-OS cells significantly. The downregulation of HIF-1α expression upregulated caspase-3 expression subsequently inhibited the growth of MG-63 and U2-OS cells and induced apoptosis of the two cells. Our in vitro data indicate that the downregulation of HIF-1α is capable of suppressing OS cells growth, through the induction of apoptosis. HIF-1α inhibition may be a new strategy for the treatment of Osteosarcoma.

Jia X, Shan C, Xu O, Wang J
[Expression and clinical significance of MTDH, HIF-1α and TKTL1 in laryngeal carcinoma].
Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2015; 29(24):2133-8 [PubMed] Related Publications
OBJECTIVE: To investigate the functional mechanism of metadherin (MTDH), hypoxia-inducible factor-1 alpha (HIF-1α) and transketolase-like gene 1 (TKTL1) and their interaction with each other in laryngeal carcinoma development.
METHOD: Thirty laryngeal carcinoma samples and 20 samples of para-carcinoma tissue were taken from the patients received operation treatment. The expression levels of MTDH, HIF-1α and TKTL1 were detected in all the samples by SP immunohistochemical methods. The data were analyzed by the SPSS13.0 statistical software.
RESULT: The positive expression rate of MTDH, HIF-1α and TKTL1 in the 30 cases of laryngeal carcinoma was 56.67%, 60.00% and 63.33%, respectively, which was 20.00%,10.00% and 15.00% respectively in the para-carcinoma tissue, the difference of the positive expression rate of the tested objects between these two groups was statistically significant (P < 0.05 or P < 0.01). Of the 30 cases of laryngeal carcinoma, the positive expression rate of MTDH, HIF-1α and TKTL1 in the cases with lymphnode metastasis was 84.62%, 84.62% and 79.62%, respectively, compared with the rate in those without lymph nodes metastasis, which was 35.29%, 41.18% and 35.29%. The difference of the positive expression rate of the tested objects between these two groups was statistically significant (P < 0.05). In the tissue of poorly differentiated squamons cell carcinoma verified by pathology, the positive expression rates of MTDH and HIF-1α was 73.68% and 84.21%, respectively, while that in the tissue of well differentiated squamous carcinoma was 27.27% and 18.18%. The difference of the positive expression rate of the tested objects between these two groups was statistically significant (P < 0.05 or (P < 0.01). The positive expression rate of TKTL1 in laryngeal carcinoma at stage I-II was 25.00% and that at stage III-IV was 72.22%, the difference between which was statistically significant (P < 0.05). The positive expression rate of HIF-1α in laryngeal carcinoma at stage I-II was 33.33% and that at stage III-IV was 77. 78%, the difference between which was statistically significant (P < 0.05). The expression of MTDH, HIF-1α and TKTL1 showed no relationship with age,smoking amount or the tumor location (P > 0.05). The Spearman's rank correlation analysis showed that the positive expression rates of MTDH and HIF-1α in laryngeal carcinoma had positive correlation (r = 0.384, P < 0.05); the positive expression rates of TKTL1 and HIF-1α in laryngeal carcinoma had positive correlation (r = 0.508, P < 0.01); But there was no significant correlation between the positive expression rates of MTDH and TKTL1 in laryngeal carcinoma (r = -0.107, P > 0.05).
CONCLUSION: It suggested that these three proteins may have close relationship with the occurrence, invasion and metastasis of the laryngeal carcinoma. MTDH and TKTL1 may be expected to be new clinical targets for laryngeal carcinoma treatment and it could offer theoretical basis for the prognosis of the laryngeal carcinoma.

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