Hypoxia-inducible factors (HIFs) are transcription factors controlling energy, iron metabolism, erythropoiesis, and development. Dysregulation of these proteins contributes to tumorigenesis and cancer progression. Recent findings revealed the important role of HIFs in the pathogenesis of neuroendocrine tumors, especially pheochromocytoma (PHEO) and paraganglioma (PGL). PHEOs and PGLs are catecholamine-producing tumors arising from sympathetic- or parasympathetic-derived chromaffin tissue. To date, eighteen PHEO/PGL susceptibility genes have been identified. Based on the main signaling pathways, PHEOs/PGLs have been divided into two clusters, pseudohypoxic cluster 1 and cluster 2, rich in kinase receptor signaling and protein translation pathways. Recent data suggest that both clusters are interconnected via the HIF signaling and its role in tumorigenesis is supported by newly described somatic and germline mutations in HIF2A gene in patients with PHEOs/PGLs associated with polycythemia, and in some of them also with somatostatinoma. Moreover, HIFalpha signaling has also been shown to be upregulated in neuroendocrine tumors other than PHEO/PGL. Some of these tumors are components of hereditary tumor syndromes which can be associated with PHEO/PGL, but also in ileal carcinoids or melanoma. HIF signaling appears to be one of the crucial players in tumorigenesis, which could suggest new therapeutic approaches for treatment of neuroendocrine tumors.

• MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa metabolismus   MeSH
• feochromocytom genetika   metabolismus   patologie   MeSH
• lidé MeSH
• nádory nadledvin genetika   metabolismus   patologie   MeSH
• neuroendokrinní nádory genetika   metabolismus   patologie   MeSH
• prognóza MeSH
• signální transdukce * MeSH
• transkripční faktory bHLH genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• endothelial PAS domain-containing protein 1 MeSH Prohlížeč
• faktor 1 indukovatelný hypoxií - podjednotka alfa MeSH
• transkripční faktory bHLH MeSH

UNLABELLED: Backround. There is increasing evidence of the role of hypoxia or pseudohypoxia in tumorigenesis, including pheochromocytoma (PHEO) and paraganglioma (PGL). (Pseudo)hypoxia leads to activation of hypoxia-inducible transcription factors (HIFs) and thus, promotes the transcription of hypoxia-responsive genes which are involved in tumorigenesis. Recently identified is a new syndrome consisting of multiple and recurrent PGLs or PHEOs, somatostatinoma, and congenital polycythemia, due to somatic hypoxia-inducible factor 2α gene (HIF2A) mutations. METHODS AND RESULTS: PubMed and Web of Science online databases were used to search reviews and original articles on the HIF, PHEO/PGL, and Pacak-Zhuang syndrome. CONCLUSIONS: The novel somatic and germline gain-of-function HIF2A mutations described latterly emphasize the role of the HIF-2α in the PHEO/PGL development and these findings designate HIF, especially HIF-2α, as a promising treatment target.

• MeSH
• karcinogeneze genetika   MeSH
• lidé MeSH
• mutace MeSH
• paragangliom farmakoterapie   genetika   MeSH
• polycytemie vrozené   farmakoterapie   genetika   MeSH
• somatostatinom farmakoterapie   genetika   MeSH
• syndrom MeSH
• transkripční faktory bHLH genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• endothelial PAS domain-containing protein 1 MeSH Prohlížeč
• transkripční faktory bHLH MeSH

• MeSH
• lidé MeSH
• mutace MeSH
• nádory duodena genetika   metabolismus   patologie   MeSH
• paragangliom genetika   metabolismus   patologie   MeSH
• transkripční faktory bHLH genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• Research Support, N.I.H., Intramural MeSH
• Názvy látek
• endothelial PAS domain-containing protein 1 MeSH Prohlížeč
• transkripční faktory bHLH MeSH

Generally, patients with renal cell carcinoma (RCC) are viewed as potential candidates for antiangiogenic targeted therapy. Tubulocystic RCC (TCRC) is a recently described entity which may behave aggressively, and the rationale for antiangiogenic therapy in this group of renal tumors has yet to be determined. Seven TCRCs and five non-tumor tissue samples from seven patients were subjected to relative expression analysis of mRNA levels of 16 genes involved in three angiogenic signal pathways: (1) VHL/HIF, (2) RTK/mitogen-activated protein kinase (MAPK), and (3) PI3K/Akt/mTOR. Two of them, pathways (2) and (3), are often targeted by antiangiogenic agents. We also determined the mutation and methylation status of the VHL gene. Finally, the levels of vascular endothelial growth factor A (VEGFA), HIF-1α, HIF-2α proteins, and phosphorylated mTOR protein were also determined. The comparison of tumor and control samples revealed no changes of mRNA levels of the following genes: VHL, HIF-1α, HIF-2α, PTEN, Akt2, Akt3, mTOR, VEGFA, KDR, HRas, C-Jun, EGFR, and FGF2. Significantly elevated mRNA level of TP53 was found, while the mRNA levels of FLT1 and C-FOS were reduced in tumor samples. No mutations or methylation in the VHL gene were found. Changes in levels of studied proteins VEGFA, HIF-1α, HIF-2α, and increased phosphorylation of mTOR protein were not found. Three studied angiogenic pathways (VHL/HIF, RTK/MAPK, and PI3K/Akt/mTOR) seem not to be upregulated in TCRC samples, so there appears to be no rationale for a general recommendation of antiangiogenic targeted therapeutic protocols for patients with these tumors.

• MeSH
• cílená molekulární terapie metody   MeSH
• dospělí MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa metabolismus   MeSH
• fosforylace MeSH
• inhibitory angiogeneze farmakologie   terapeutické užití   MeSH
• karcinom z renálních buněk krevní zásobení   farmakoterapie   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorový supresorový protein VHL metabolismus   MeSH
• nádory ledvin krevní zásobení   farmakoterapie   metabolismus   MeSH
• patologická angiogeneze farmakoterapie   genetika   MeSH
• senioři MeSH
• signální transdukce účinky léků   genetika   MeSH
• TOR serin-threoninkinasy metabolismus   MeSH
• transkripční faktory bHLH metabolismus   MeSH
• vaskulární endoteliální růstový faktor A metabolismus   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• endothelial PAS domain-containing protein 1 MeSH Prohlížeč
• faktor 1 indukovatelný hypoxií - podjednotka alfa MeSH
• HIF1A protein, human MeSH Prohlížeč
• inhibitory angiogeneze MeSH
• MTOR protein, human MeSH Prohlížeč
• nádorový supresorový protein VHL MeSH
• TOR serin-threoninkinasy MeSH
• transkripční faktory bHLH MeSH
• vaskulární endoteliální růstový faktor A MeSH
• VEGFA protein, human MeSH Prohlížeč
• VHL protein, human MeSH Prohlížeč

OBJECTIVES: Both decreased and increased risk of cardiovascular events/mortality have been reported with high adiponectin levels. Only a few studies have reported an association of adiponectin with markers of hemostasis/endothelial dysfunction which might explain the reported discrepancies. DESIGN AND METHODS: We evaluated the association of total adiponectin with von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (t-PA), soluble thrombomodulin (sTM), adhesion molecules sICAM-1 and sVCAM-1, lipids and markers of insulin resistance (IR) in 308 asymptomatic dyslipidemic subjects and healthy controls. Subjects were divided into 4 dyslipidemic phenotypes (DLP): DLP1 (TG < 1.5 mmol/L + ApoB < 1.2 g/L), DLP2 (TG ≥ 1.5 + ApoB < 1.2), DLP3 (TG < 1.5 + ApoB ≥ 1.2) and DLP4 (TG ≥ 1.5 + ApoB ≥ 1.2). The results were evaluated also according to the presence (+) and absence (-) of metabolic syndrome (MS). RESULTS: In hyperlipidemic subjects (DLP2-4), PAI-1, t-PA and sICAM-1 correlated with markers of IR but only t-PA correlated inversely with adiponectin. In contrast positive association of adiponectin with vWF, sTM and sVCAM-1 was found but none of these parameters correlated with markers of insulin resistance. In multiple regression analysis, adiponectin remained independently associated with vWF [in DLP3, DLP4, DLP2-4, MS(-)], with sTM [in DLP2, DLP4, DLP2-4, MS(+)] and with sVCAM-1 [in DLP2, DLP3, DLP4, DLP2-4, MS(+)]. In healthy controls (DLP1), no association between adiponectin and markers of hemostasis/endothelial dysfunction was found. CONCLUSION: The independent positive association of adiponectin with vWF, sTM and sVCAM-1 deserves further evaluation in connection with the risk of atherothrombotic cardiovascular events.

• MeSH
• adiponektin krev   MeSH
• apolipoproteiny B krev   MeSH
• asymptomatické nemoci MeSH
• biologické markery krev   MeSH
• chemokiny CXC MeSH
• chemokiny krev   MeSH
• dospělí MeSH
• dyslipidemie krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mezibuněčná adhezivní molekula-1 krev   MeSH
• studie případů a kontrol MeSH
• trombomodulin krev   MeSH
• von Willebrandův faktor metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adiponektin MeSH
• apolipoproteiny B MeSH
• biologické markery MeSH
• chemokiny CXC MeSH
• chemokiny MeSH
• CXCL17 protein, human MeSH Prohlížeč
• mezibuněčná adhezivní molekula-1 MeSH
• THBD protein, human MeSH Prohlížeč
• trombomodulin MeSH
• von Willebrandův faktor MeSH

Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare, neuroendocrine tumors derived from adrenal or extra-adrenal chromaffin cells, respectively. Metastases are discovered in 3-36% of patients at the time of diagnosis. Currently, only suboptimal treatment options exist. Therefore, new therapeutic compounds targeting metastatic PHEOs/PGLs are urgently needed. Here, we investigated if anthracyclines were able to suppress the progression of metastatic PHEO. We explored their effects on experimental mouse PHEO tumor cells using in vitro and in vivo models, and demonstrated that anthracyclines, particularly idarubicin (IDA), suppressed hypoxia signaling by preventing the binding of hypoxia-inducible factor 1 and 2 (HIF-1 and HIF-2) to the hypoxia response element (HRE) sites on DNA. This resulted in reduced transcriptional activation of HIF target genes, including erythropoietin (EPO), phosphoglycerate kinase 1 (PGK1), endothelin 1 (EDN1), glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and vascular endothelial growth factor (VEGFA), which consequently inhibited the growth of metastatic PHEO. Additionally, IDA downregulated hypoxia signaling by interfering with the transcriptional activation of HIF1A and HIF2A. Furthermore, our animal model demonstrated the dose-dependent suppressive effect of IDA on metastatic PHEO growth in vivo. Our results indicate that anthracyclines are prospective candidates for inclusion in metastatic PHEO/PGL therapy, especially in patients with gene mutations involved in the hypoxia signaling pathway.

• Klíčová slova
• anthracyclines, hypoxia-inducible factors, metastatic, paraganglioma, pheochromocytoma,
• MeSH
• buňky - růstové procesy účinky léků   MeSH
• endotelin-1 genetika   metabolismus   MeSH
• erythropoetin genetika   metabolismus   MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa metabolismus   MeSH
• feochromocytom farmakoterapie   patologie   MeSH
• fosfoglycerátkinasa genetika   metabolismus   MeSH
• hypoxie farmakoterapie   patologie   MeSH
• idarubicin terapeutické užití   MeSH
• lidé MeSH
• metastázy nádorů MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory nadledvin farmakoterapie   patologie   MeSH
• protinádorové látky terapeutické užití   MeSH
• signální transdukce účinky léků   MeSH
• transkripční faktory bHLH metabolismus   MeSH
• vazba proteinů MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• endotelin-1 MeSH
• endothelial PAS domain-containing protein 1 MeSH Prohlížeč
• erythropoetin MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa MeSH
• fosfoglycerátkinasa MeSH
• Hif1a protein, mouse MeSH Prohlížeč
• idarubicin MeSH
• Pgk1 protein, mouse MeSH Prohlížeč
• protinádorové látky MeSH
• transkripční faktory bHLH MeSH

Hypoxia is relevant to several physiological and pathological processes and this also applies for the tooth. The adaptive response to lowering oxygen concentration is mediated by hypoxia-inducible factors (HIFs). Since HIFs were shown to participate in the promotion of angiogenesis, stem cell survival, odontoblast differentiation and dentin formation, they may play a beneficial role in the tooth reparative processes. Although some data were generated in vitro, little is known about the in vivo context of HIFs in tooth development. In order to contribute to this field, the mouse mandibular first molar was used as a model.The expression and in situ localisation of HIFs were examined at postnatal (P) days P0, P7, P14, using RT-PCR and immunostaining. The expression pattern of a broad spectrum of hypoxia-related genes was monitored by customised PCR Arrays. Metabolic aspects were evaluated by determination of the lactate level and mRNA expression of the mitochondrial marker Nd1.The results show constant high mRNA expression of Hif1a, increasing expression of Hif2a, and very low expression of Hif3a during early postnatal molar development. In the examined period the localisation of HIFs in the nuclei of odontoblasts and the subodontoblastic layer identified their presence during odontoblastic differentiation. Additionally, the lower lactate level and higher expression of mitochondrial Nd1 in advanced development points to decreasing glycolysis during differentiation. Postnatal nuclear localisation of HIFs indicates a hypoxic state in specific areas of dental pulp as oxygen demands depend on physiological events such as crown and root dentin mineralization.

• Klíčová slova
• Dental pulp, Development, Hypoxia-inducible factors, In vivo,
• MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa * metabolismus   genetika   MeSH
• metabolické sítě a dráhy MeSH
• moláry * metabolismus   růst a vývoj   MeSH
• myši MeSH
• odontoblasty metabolismus   MeSH
• proteiny regulující apoptózu MeSH
• represorové proteiny MeSH
• transkripční faktory bHLH * metabolismus   genetika   MeSH
• vývojová regulace genové exprese MeSH
• zubní dřeň * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• endothelial PAS domain-containing protein 1 MeSH Prohlížeč
• faktor 1 indukovatelný hypoxií - podjednotka alfa * MeSH
• Hif1a protein, mouse MeSH Prohlížeč
• Hif3a protein, mouse MeSH Prohlížeč
• proteiny regulující apoptózu MeSH
• represorové proteiny MeSH
• transkripční faktory bHLH * MeSH

UNLABELLED: Tibetans have lived at high altitude for generations and are thought to be genetically adapted to hypoxic environments. Most are protected from hypoxia-induced polycythemia, and a haplotype of EPAS1, encoding hypoxia-inducible factor (HIF-2α), has been associated with lower hemoglobin levels. We earlier reported a Tibetan-specific EGLN1 haplotype encoding PHD2 which abrogates HIF augmentation in hypoxia. We genotyped 347 Tibetan individuals from varying altitudes for both the Tibetan-specific EGLN1 haplotype and 10 candidate SNPs in the EPAS1 haplotype and correlated their association with hemoglobin levels. The effect of the EGLN1 haplotype on hemoglobin exhibited age dependency at low altitude, while at higher altitudes, it showed a trend to lower hemoglobin levels in the presence of the Tibetan-selected EPAS1 rs142764723 C/C allele. The observed gene-environment and gene-gene interactions and the moderate effect of the EGLN1 and EPAS1 haplotypes on hemoglobin indicate that other modifiers exist. It remains to be determined whether a blunting of erythropoiesis or other physiological consequences of HIF downregulation are the primary drivers of these genetic adaptations among Tibetans. KEY MESSAGE: Most Tibetans are protected from polycythemia while living in high altitude. An EGLN1 co-adapted haplotype, EGLN1 c.12C>G, c.380G>C is uniquely Tibetan. The Tibetan EPAS1 haplotype has introgressed from the Denisovan genome. While EGLN1 and EPAS1 genotypes lower Hb, this study indicates additional Hb modifiers.

• Klíčová slova
• Genetic adaptation, High altitude, High-resolution melting assay, Hypoxia, Polycythemia,
• MeSH
• aklimatizace genetika   MeSH
• Asijci genetika   MeSH
• dospělí MeSH
• erythropoetin krev   MeSH
• ferritiny krev   MeSH
• haplotypy MeSH
• hemoglobiny analýza   MeSH
• interakce genů a prostředí MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• nadmořská výška MeSH
• prolyl-4-hydroxylasy HIF genetika   MeSH
• transkripční faktory bHLH genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Tibet MeSH
• Názvy látek
• EGLN1 protein, human MeSH Prohlížeč
• endothelial PAS domain-containing protein 1 MeSH Prohlížeč
• erythropoetin MeSH
• ferritiny MeSH
• hemoglobiny MeSH
• prolyl-4-hydroxylasy HIF MeSH
• transkripční faktory bHLH MeSH

Recent technological advancements have permitted high-throughput measurement of the human genome, epigenome, metabolome, transcriptome, and proteome at the population level. We hypothesized that subsets of genes identified from omic studies might have closely related biological functions and thus might interact directly at the network level. Therefore, we conducted an integrative analysis of multi-omic datasets of non-small cell lung cancer (NSCLC) to search for association patterns beyond the genome and transcriptome. A large, complex, and robust gene network containing well-known lung cancer-related genes, including EGFR and TERT, was identified from combined gene lists for lung adenocarcinoma. Members of the hypoxia-inducible factor (HIF) gene family were at the center of this network. Subsequent sequencing of network hub genes within a subset of samples from the Transdisciplinary Research in Cancer of the Lung-International Lung Cancer Consortium (TRICL-ILCCO) consortium revealed a SNP (rs12614710) in EPAS1 associated with NSCLC that reached genome-wide significance (OR = 1.50; 95% CI: 1.31-1.72; p = 7.75 × 10-9). Using imputed data, we found that this SNP remained significant in the entire TRICL-ILCCO consortium (p = .03). Additional functional studies are warranted to better understand interrelationships among genetic polymorphisms, DNA methylation status, and EPAS1 expression.

• Klíčová slova
• Hypoxia-inducible factor, Integrated analysis, Lung adenocarcinoma, Network analysis, Non-small cell lung cancer,
• MeSH
• adenokarcinom plic MeSH
• adenokarcinom genetika   patologie   MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa genetika   MeSH
• genetická predispozice k nemoci MeSH
• genetické asociační studie MeSH
• jednonukleotidový polymorfismus MeSH
• lidé středního věku MeSH
• lidé MeSH
• metylace DNA genetika   MeSH
• nádory plic genetika   patologie   MeSH
• nemalobuněčný karcinom plic genetika   patologie   MeSH
• regulace genové exprese u nádorů MeSH
• senioři MeSH
• transkripční faktory bHLH genetika   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• endothelial PAS domain-containing protein 1 MeSH Prohlížeč
• faktor 1 indukovatelný hypoxií - podjednotka alfa MeSH
• HIF1A protein, human MeSH Prohlížeč
• transkripční faktory bHLH MeSH

BACKGROUND: Head and neck paragangliomas (HNPGLs) are typically slow-growing, hormonally inactive tumors of parasympathetic paraganglia. Inactivation of prolyl-hydroxylase domain-containing 2 protein causing indirect gain-of-function of hypoxia-inducible factor-2α (HIF-2α), encoded by EPAS1, was recently shown to cause carotid body hyperplasia. We previously described a syndrome with multiple sympathetic paragangliomas caused by direct gain-of-function variants in EPAS1 (Pacak-Zhuang syndrome, PZS) and developed a corresponding mouse model. METHODS: We evaluated a cohort of patients with PZS (n = 9) for HNPGL by positron emission tomography, magnetic resonance imaging, and computed tomography and measured carotid body size compared to literature reference values. Resected tumors were evaluated by histologic sectioning and staining. We evaluated the corresponding mouse model at multiple developmental stages (P8 and adult) for lesions of the head and neck by high resolution ex vivo imaging and performed immunohistochemical staining on histologic sections of the identified lesions. RESULTS: hree patients had imaging consistent with HNPGL, one of which warranted resection and was confirmed on histology. Three additional patients had carotid body enlargement (Z-score > 2.0), and 3 had carotid artery malformations. We found that 9 of 10 adult variant mice had carotid body tumors and 6 of 8 had a paraganglioma on the cranio-caval vein, the murine homologue of the superior vena cava; these were also found in 4 of 5 variant mice at post-natal day 8. These tumors and the one resected from a patient were positive for tyrosine hydroxylase, synaptophysin, and chromogranin A. Brown fat in a resected patient tumor carried the EPAS1 pathogenic variant. CONCLUSIONS: These findings (1) suggest HNPGL as a feature of PZS and (2) show that these pathogenic variants are sufficient to cause the development of these tumors, which we believe represents a continuous spectrum of disease starting from hyperplasia.

• MeSH
• dospělí MeSH
• hyperplazie MeSH
• karotická tělíska * patologie   diagnostické zobrazování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie * MeSH
• mladý dospělý MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nádory hlavy a krku * genetika   patologie   diagnostické zobrazování   MeSH
• paragangliom * genetika   diagnostické zobrazování   patologie   MeSH
• počítačová rentgenová tomografie MeSH
• pozitronová emisní tomografie MeSH
• transkripční faktory bHLH * genetika   analýza   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• endothelial PAS domain-containing protein 1 MeSH Prohlížeč
• transkripční faktory bHLH * MeSH