Human HIF‐3α4 is a dominant‐negative regulator of HIF‐1 and is down‐regulated in renal cell carcinoma

Maynard, Mindy A.; Evans, Andrew; Hosomi, Tomoko; Hara, Shuntaro; Jewett, Michael A.S.; Ohh, Michael

doi:10.1096/fj.05-3788com

Cited by 161 publications

(150 citation statements)

References 27 publications

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“…28 Briefly, first-strand cDNA synthesis was performed as follows: 1 ml of oligo(dT) 23 primer (Sigma, St Louis, MI, USA) was incubated with 5 mg of RNA and dH 2 O (total reaction volume was 20 ml) for 10 min at 701C in a thermal cycler (MJ research, Boston, MA, USA). The mixture was cooled to 41C, at which time 4 ml of 5 Â first-strand reaction buffer, 2 ml of 0.1 M DTT, 1 ml of 10 mM dNTPs and 1 ml Superscript II reverse transcriptase (Invitrogen, Carlsbad, CA, USA) were added.…”

Section: Rna Extractionmentioning

confidence: 99%

Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

Gervais

Henry

Saravanan

et al. 2007

Laboratory Investigation

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The loss of functional von Hippel-Lindau (VHL) tumor suppressor gene is associated with the development of clear-cell renal cell carcinoma (CC-RCC). Recently, VHL was shown to promote the transcription of E-cadherin, an adhesion molecule whose expression is inversely correlated with the aggressive phenotype of numerous epithelial cancers. Here, we performed immunohistochemistry on CC-RCC tissue microarrays to determine the prognostic value of E-cadherin and VHL with respect to Fuhrman grade and clinical prognosis. Low Fuhrman grade and good prognosis associated with positive VHL and E-cadherin immunoreactivity, whereas poor prognosis and high-grade tumors associated with a lack of E-cadherin and lower frequency of VHL staining. A significant portion of CC-RCC with positive VHL immunostaining correlated with nuclear localization of C-terminally cleaved E-cadherin. DNA sequencing revealed in a majority of nuclear E-cadherin-positive CC-RCC, subtle point mutations, deletions and insertions in VHL. Furthermore, nuclear E-cadherin was not observed in chromophobe or papillary RCC, as well as matched normal kidney tissue. In addition, nuclear E-cadherin localization was recapitulated in CC-RCC xenografts devoid of functional VHL or reconstituted with synthetic mutant VHL grown in SCID mice. These findings provide the first evidence of aberrant nuclear localization of E-cadherin in CC-RCC harboring VHL mutations, and suggest potential prognostic value of VHL and E-cadherin in CC-RCC. [4][5][6][7] Currently, a prediction of patient survival is based on traditional clinical parameters, including tumor size and Fuhrman nuclear grade. 8 However, the emerging understanding of the molecular pathways implicated in CC-RCC genesis and progression is providing previously unappreciated markers, which may serve as additional or better prognostic indicators of CC-RCC.The principal cause of sporadic CC-RCC and familial von Hippel-Lindau (VHL) disease-associated CC-RCC is the inactivating mutations of VHL. Although VHL patients also develop tumors in other organs including the central nervous system, retina and the adrenal gland, CC-RCC remains to be the leading cause of morbidity and death for VHL patients. 9 The most well-established function of VHL is its role in the oxygen-dependent negative regulation of hypoxia-inducible factor (HIF). VHL is a substrate-conferring component of an E3 ubiquitin ligase ECV (elongins/Cul2/VHL) that polyubiquitylates the catalytic a-subunit of HIF that has undergone hydroxylation on conserved prolyl residues within the oxygen-dependent degradation (ODD) domain. Prolyl hydroxylation is mediated by a class of prolyl hydroxylases (PHD1-3) in an oxygen-dependent manner. Thus, under hypoxia or in the absence of a functional VHL, HIFa becomes stabilized and binds to its common and constitutively expressed b-subunit, forming an active HIF transcription factor capable of transactivating numerous hypoxia-inducible genes such as vascular endothelial growth factor (VEGF),

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Section: Rna Extractionmentioning

confidence: 99%

Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

Gervais

Henry

Saravanan

et al. 2007

Laboratory Investigation

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“…HIF-3a differs from HIF-1a and HIF-2a in both its protein structure and its effect on gene expression. HIF-3a was previously believed to mainly function by opposing hypoxiainduced HIF-1a-and HIF-2a-dependent gene expression (15,16). Under hypoxic conditions, HIF-3a competes with HIF-1a and HIF-2a for binding to the promoter region of their target genes and thus negatively regulates gene expression (14,15,17,18).…”

Section: Introductionmentioning

confidence: 99%

HIF-3α Promotes Metastatic Phenotypes in Pancreatic Cancer by Transcriptional Regulation of the RhoC–ROCK1 Signaling Pathway

Zhou

Guo

Chen

et al. 2018

Molecular Cancer Research

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Hypoxia contributes to pancreatic cancer progression and promotes its growth and invasion. Previous research principally focused on hypoxia-inducible factor-1 alpha (HIF-1a) and HIF2a (HIF1A and EPAS1) as the major hypoxia-associated transcription factors in pancreatic cancer. However, the role of HIF-3a (HIF3A) has not been investigated. Therefore, HIF-1a, HIF-2a, and HIF-3a expression levels were measured under normoxic and hypoxic conditions. In addition, HIF-3a expression was measured in human pancreatic cancer tissue specimens and the impact of altered HIF-3a expression on cell invasion and migration was investigated in vitro and in vivo, as well as the underlying mechanisms. Under hypoxic conditions, HIF-3a expression was stimulated in pancreatic cancer cells to a greater degree than HIF-1a and HIF-2a expression. HIF-3a protein levels were also elevated in pancreatic cancer tissues and correlated with reduced survival and greater local invasion and distant metastasis, whereas knockdown of HIF-3a, under hypoxic conditions, suppressed pancreatic cancer cell invasion and migration. Under normoxia, HIF-3a overexpression promoted pancreatic cancer cell invasion and migration and stimulated F-actin polymerization. In summary, HIF-3a promotes pancreatic cancer cell invasion and metastasis in vivo and promotes pancreatic cancer cell invasion and metastasis by transcriptionally activating the RhoC-ROCK1 signaling pathway.Implications: HIF3a is overexpressed in pancreatic cancer, and targeting the HIF3a/RhoC-ROCK1 signaling pathway may be a novel therapeutic approach for the treatment of pancreatic cancer invasion and metastasis.

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“…They have distinct or even opposite functions when tested by overexpression approaches [35]. For instance, while the full-length human HIF3α-1 can stimulate HRE-dependent reporter construct activity and upregulate unique target genes [8,12], human HIF3α-4 isoform, a shorter isoform that lacks the TAD domain, inhibits the activity of HIF-1α and HIF-2α [11,60] in a similar manner as mouse IPAS was shown to inhibit HIF-1α activity [9].…”

Section: Post-transcriptional Modification By Alternative Splicingmentioning

confidence: 99%

“…But while it has been clearly established that HIF1α and HIF2α function as master regulators of the response to hypoxia and are critical regulators of tumorigenesis, the roles played by HIF3α under hypoxia and in cancer biology are far less clear. The reasons of this reside not only on the initial discovery of a large array of HIF3α variants which has posed enormous challenges to study HIF3α-mediated physiological roles, but mainly on the prevailing view of HIF3α as a negative regulator of HIF1α and HIF2α actions, on the basis of the initial finding that two of its variants, lacking transactivation domains, act as negative regulators of HIF1α and HIF2α transactivating gene functions [9][10][11]. However, this dogma was refuted in 2014 by Zhang et al [12], which demonstrated that HIF3α functions as a transcriptional activator in zebrafish embryos.…”

Section: Introductionmentioning

confidence: 99%

The Role of Hypoxia-Inducible Factors in Cancer Resistance

Saint-Martin¹,

Castañeda-Patlán²,

Robles-Flores³

2017

J Cell Signal

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Diminished oxygen availability (hypoxia) is a hallmark of the tumor microenvironment. A major regulator of cellular adaptation to hypoxia is the hypoxia-inducible factor (HIF) family of transcription factors, which play key roles in many crucial aspects of cancer biology including angiogenesis, stem cell maintenance, metabolic reprogramming, resistance to apoptosis, autocrine growth factor signaling, the EMT program, invasion and metastasis.Resistance to chemotherapy/radiotherapy is the primary cause for treatment failure in clinical oncology. Hypoxia and accumulation of hypoxia-inducible factors (HIFs) in solid tumors have been associated with resistance to treatment and poor prognosis. HIFs causes autophagy establishment to promote survival of cancer cells, and is also associated with the promotion and maintenance of cancer stem cells, a minority subpopulation within the tumor responsible for tumor recurrence and resistance to chemotherapy.In this review, we provide a concise comparative description of the structure, regulation, transcribed genes and roles played by each HIFα subunit in coordinating the transcriptional responses to hypoxia and on the roles they play in the promotion of resistance to anti-cancer therapy.

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Human HIF‐3α4 is a dominant‐negative regulator of HIF‐1 and is down‐regulated in renal cell carcinoma

Cited by 161 publications

References 27 publications

Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

HIF-3α Promotes Metastatic Phenotypes in Pancreatic Cancer by Transcriptional Regulation of the RhoC–ROCK1 Signaling Pathway

The Role of Hypoxia-Inducible Factors in Cancer Resistance

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