A HIF1α Regulatory Loop Links Hypoxia and Mitochondrial Signals in Pheochromocytomas

Dahia, Patricia L.M.; Ross, Ken N.; Wright, Matthew; Hayashida, C Y; Santagata, Sandro; Barontini, Marta; Kung, Andrew L.; Sansó, Gabriela; Powers, James F.; Tischler, Arthur S.; Hodin, Richard A.; Heitritter, Shannon M; Moore, F. E.; Dluhy, Robert G.; Sosa, Julie Ann; Ocal, Idris Tolgay; Benn, Diana E.; Marsh, Deborah J.; Robinson, Bruce G.; Schneider, Katherine A.; Garber, Judy E.; Arum, Seth; Korbonits, Márta; Grossman, Ashley; Pigny, Pascal; Toledo, S. P. A.; Nosé, Vânia; Li, Chengcheng; Stiles, Charles D.

doi:10.1371/journal.pgen.0010008

Cited by 401 publications

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“…Loss of 3p or that of whole chromosome 3 could be detected in 94% of von Hippel-Lindau disease pheochromocytomas. 35 Among the hypoxiaresponsive/angiogenesis genes previously described to be significantly underexpressed in multiple endocrine neoplasia type 2 relative to von Hippel-Lindau disease pheochromocytomas, 11 laminin subunits (LAMB4, LAMA5, LAMC2), collagene type 4 (COL4A5) and proline 4-hydroxilase a-1 precursor (P4HA1) could be identified to be targets potentially downregulated by miR-885-5p by our in silico target prediction approach.…”

Section: Discussionmentioning

confidence: 95%

“…Transcriptomic studies representing targets of miRNA-based regulation are pivotal for the correct interpretation of miRNA findings. There have been six previous studies 11,[37][38][39][40][41] on gene expression profiling involving malignant pheochromocytomas to date. The studies of Dahia et al, 11 Björklund et al 37 and the most recent study of Waldmann et al 41 included only two, three and five malignant pheochromocytomas, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…There have been six previous studies 11,[37][38][39][40][41] on gene expression profiling involving malignant pheochromocytomas to date. The studies of Dahia et al, 11 Björklund et al 37 and the most recent study of Waldmann et al 41 included only two, three and five malignant pheochromocytomas, respectively. Brouwers et al 38 examined 20 malignant tumors along with 70 sporadic and syndromic benign tumors: Gene Ontology Analysis of benign and malignant tumor comparison revealed the relevance of signal transduction changes.…”

Section: Discussionmentioning

confidence: 99%

“…10 Several studies including reports on mRNA expression profiling revealed two major pathways of pheochromocytoma pathogenesis: (1) activation of the Ras oncogene pathways (multiple endocrine neoplasia type 2 and neurofibromatosis type 1), (2) activation of hypoxia-inducible factor 1a (HIF1a)-related neoangiogenesis pathways (von Hippel-Lindau and paraganglioma syndromes). 11 To the best of our knowledge, there have been no reports on the expression of miRNAs in these tumors to date. Therefore, in this study, we have performed miRNA expression profiling of various groups of human adrenal pheochromocytomas including sporadic benign, multiple endocrine neoplasia type 2-related, von Hippel-Lindau disease-associated and neurofibromatosis type 1-related benign, and sporadic recurring tumors.…”

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confidence: 99%

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MicroRNA expression profiling in benign (sporadic and hereditary) and recurring adrenal pheochromocytomas

et al. 2010

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MicroRNAs are involved in the pathogenesis of several tumors, however, there have been no data on microRNA expression in pheochromocytomas to date. The objective of our study was to perform microRNA expression profiling in sporadic and hereditary benign, and recurring adrenomedullary tumors. Furthermore, the applicability of formalin-fixed paraffin-embedded tissue samples for the analysis of microRNA expression in pheochromocytomas was examined. MicroRNA expression data of three matched frozen and formalin-fixed paraffin-embedded samples were correlated. A total of 21 formalin-fixed paraffin-embedded samples (sporadic benign, multiple endocrine neoplasia 2, von Hippel-Lindau disease, sporadic recurring) were subjected to microRNA expression profiling using microarrays. MicroRNAs with significant differences in expression were validated and sample sizes were extended including tumors from neurofibromatosis type 1 patients by real-time quantitative reverse-transcription PCR (n ¼ 33). MicroRNA target prediction was carried out by TargetScan and MicroCosm Targets. Pathway analysis of targets was performed by Ingenuity Pathway Analysis and DIANA mirPath. Furthermore, microRNA expression profiles of a malignant pheochromocytoma and a pair of primary and recurrent tumors were studied by TaqMan Human MicroRNA Cards. MicroRNA expression correlated well between frozen and formalin-fixed paraffinembedded samples (70-92%). Microarray analysis revealed 16 significantly differentially expressed microRNAs. Five of these were validated by real-time RT-PCR. miR-139-3p, miR-541 and miR-765 were significantly differentially expressed between sporadic benign and von Hippel-Lindau-related pheochromocytomas. Significantly higher expression of miR-885-5p and miR-1225-3p was found in multiple endocrine neoplasia type 2 and sporadic recurring pheochromocytomas, respectively. Pathway analysis revealed the possible involvement of Notch-and G-proteincoupled receptor signaling in tumor recurrence. MicroRNA expression profiles in the primary recurrent and recurring malignant comparisons have been similar. In conclusion, we have proved that formalin-fixed paraffinembedded samples can be used for the analysis of microRNA expression in pheochromocytomas. MicroRNA expression patterns differ between various sporadic, hereditary and recurring tumors and miR-1225-3p may be useful for identifying recurring pheochromocytomas.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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MicroRNA expression profiling in benign (sporadic and hereditary) and recurring adrenal pheochromocytomas

et al. 2010

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“…This study explained the high vascular density observed in these paragangliomas. More recently, an extensive gene expression analysis of 76 phaeochromocytomas with different genetic lesions revealed a 'HIF signature' pattern of gene expression in a cluster of phaeochromocytomas with SDHB, SDHD or VHL mutations (Dahia et al, 2005). Interestingly, in the past year, it was shown that FH-deficient tumours also display high vascularity (Pollard et al, 2005a), increased HIFa levels and activity (Pollard et al, 2005b) and increased expression of glycolytic genes (measured by gene profiling) (Vanharanta et al, 2006).…”

Section: Mechanisms Linking Loss Of Mitochondrial Tumour Suppressors mentioning

confidence: 99%

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

2006

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The phenomenon of enhanced glycolysis in tumours has been acknowledged for decades, but biochemical evidence to explain it is only just beginning to emerge. A significant hint as to the triggers and advantages of enhanced glycolysis in tumours was supplied by the recent discovery that succinate dehydrogenase (SDH) and fumarate hydratase (FH) are tumour suppressors and which associated, for the first time, mitochondrial enzymes and their dysfunction with tumorigenesis. Further steps forward showed that the substrates of SDH and FH, succinate and fumarate, respectively, can mediate a 'metabolic signalling' pathway. Succinate or fumarate, which accumulate in mitochondria owing to the inactivation of SDH or FH, leak out to the cytosol, where they inhibit a family of prolyl hydroxylase enzymes (PHDs). Depending on the PHD inhibited, two newly recognized pathways that support tumour maintenance may ensue: affected cells become resistant to certain apoptotic signals and/or activate a pseudohypoxic response that enhances glycolysis and is conveyed by hypoxia-inducible factor.

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Genetics of Pheochromocytoma

Martucci

Pacák

2014

Encyclopedia of Life Sciences

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Pheochromocytoma (PHEO) and paraganglioma (PGL) are closely related neuroendocrine tumours of the chromaffin tissues of the sympathetic and parasympathetic nervous system. These rare tumours have a strong genetic component, with underlying germline and somatic mutations in one of 17 genes found in approximately 50%. Clinical presentations of PHEO/PGL vary based on the affected gene, and understanding these differences can help guide genetic testing, an important part of PHEO/PGL patient management. Despite the differences in presentation and gene function, all 17 genes may affect a single pathway. Particularly, recent proposals have focused on hypoxia‐inducible factors (HIFs) as key players in PHEO/PGL, due to the known pseudohypoxic environment found in these tumours and the central role played by HIFs in cellular processes. By linking the susceptibility genes to a central potential therapeutic target like HIF, new treatment methods could soon be introduced to improve the outcomes of PHEO/PGL patients. Key Concepts: Pheochromocytomas and paragangliomas have the strongest genetic component of any endocrine tumour; half or more are linked to germline and somatic mutations in 17 genes. The clinical presentations associated with each gene vary, particularly with regard to tumour location, multiplicity, biochemical phenotype, average patient age at diagnosis and risk of metastases. Genetic testing is an essential component of PHEO/PGL management, but can be costly and time‐consuming; newer techniques to resolve these limitations are being explored. Messenger RNA expression profiles can help broadly classify PHEO/PGL into two well‐established clusters based on their broader mechanistic errors. Additional clustering mechanisms are being proposed based on other analyses, including miRNA, transcriptomic, metabolomic and proteomic studies. Beyond clustering, unifying theories to link PHEO/PGL susceptibility genes have been proposed to link all 17 genes to a common signalling pathway, focusing particularly on the processes of apoptosis and hypoxia response. Identifying common targets between the genes could aid in the identification of novel treatment strategies for patients with these rare neuroendocrine tumours.

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A HIF1α Regulatory Loop Links Hypoxia and Mitochondrial Signals in Pheochromocytomas

Cited by 401 publications

References 44 publications

MicroRNA expression profiling in benign (sporadic and hereditary) and recurring adrenal pheochromocytomas

MicroRNA expression profiling in benign (sporadic and hereditary) and recurring adrenal pheochromocytomas

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

Genetics of Pheochromocytoma

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