von Hippel-Lindau mutants in renal cell carcinoma are regulated by increased expression of RSUME

Tedesco, Lucas; Elguero, Belén; Pacin, David Gonilski; Senin, Sergio; Pollak, Cora N.; Marchiñena, Patricio Aitor García; Jurado, Alberto; Isola, Mariana; Labanca, M.; Palazzo, Martín; Yankilevich, Patricio; Fuertes, Mariana; Arzt, Eduardo

doi:10.1038/s41419-019-1507-3

Cited by 18 publications

(31 citation statements)

References 48 publications

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“…Mutation of these genes such as von Hippel-Lindau (VHL) tumor suppressor gene can activate the hypoxia-inducible factor (HIF) pathway [3] and upregulate the phosphoinositide 3-kinase (PI3K)/ mammalian target of rapamycin (mTOR) pathway [4]. Inactivation of pVHL through protein modification also induces signaling of HIF-1α [5] and NF-κB [6]. Those activated pathways have been targeted for treatment, although there are no RCC-specific drugs with a specific therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

A Precision Strategy to Cure Renal Cell Carcinoma by Targeting Transglutaminase 2

Kim

Keillor

2020

IJMS

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In a recent report, no significance of transglutaminase 2 (TGase 2) was noted in the analyses of expression differences between normal and clear cell renal cell carcinoma (ccRCC), although we found that knock down of TGase 2 induced significant p53-mediated cell death in ccRCC. Generally, to find effective therapeutic targets, we need to identify targets that belong specifically to a cancer phenotype that can be differentiated from a normal phenotype. Here, we offer precise reasons why TGase 2 may be the first therapeutic target for ccRCC, according to several lines of evidence. TGase 2 is negatively regulated by von Hippel-Lindau tumor suppressor protein (pVHL) and positively regulated by hypoxia-inducible factor 1-α (HIF-1α) in renal cell carcinoma (RCC). Therefore, most of ccRCC presents high level expression of TGase 2 because over 90% of ccRCC showed VHL inactivity through mutation and methylation. Cell death, angiogenesis and drug resistance were specifically regulated by TGase 2 through p53 depletion in ccRCC because over 90% of ccRCC express wild type p53, which is a cell death inducer as well as a HIF-1α suppressor. Although there have been no detailed studies of the physiological role of TGase 2 in multi-omics analyses of ccRCC, a life-long study of the physiological roles of TGase 2 led to the discovery of the first target as well as the first therapeutic treatment for ccRCC in the clinical field.

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Section: Introductionmentioning

confidence: 99%

A Precision Strategy to Cure Renal Cell Carcinoma by Targeting Transglutaminase 2

Kim

Keillor

2020

IJMS

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“…Beside pituitary adenomas, RSUME was found to be expressed in other types of tumours with high angiogenic potential, among them gliomas (28) and pancreatic neuroendocrine tumours (29). Particularly, RSUME is expressed in tissues prone to tumour development in Von Hippel Lindau (VHL) syndrome and is upregulated in several tumours related to this disease (27,30). Accordingly, it has been associated with decreased survival in a group of renal cell carcinoma patients (30).…”

Section: Expression and Function Of Rsume In Pituitary Tumoursmentioning

confidence: 99%

“…Particularly, RSUME is expressed in tissues prone to tumour development in Von Hippel Lindau (VHL) syndrome and is upregulated in several tumours related to this disease (27,30). Accordingly, it has been associated with decreased survival in a group of renal cell carcinoma patients (30).…”

Section: Expression and Function Of Rsume In Pituitary Tumoursmentioning

confidence: 99%

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GEOFFREY HARRIS AWARD 2019: Translational research in pituitary tumours

Stalla

Dimopoulou

Jung-Sievers

et al. 2020

European Journal of Endocrinology

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Although effective treatment regimens (surgical resection, drug treatment with dopamine agonists or somatostatin analogues, radiotherapy) have been established for the therapy of most pituitary tumours, a considerable proportion of affected patients cannot completely cured due to incomplete resection or drug resistance. Moreover, even if hormone levels have been normalized, patients with hormone-secreting tumours still show persistent pathophysiological alterations in metabolic, cardiovascular or neuropsychiatric parameters and have an impaired quality of life. In this review reasons for the discrepancy between biochemical cure and incomplete recovery from tumour-associated comorbidities are discussed and the clinical management is delineated exemplarily for patients with acromegaly and Cushing’s disease. In view of the development of additional treatment concepts for the treatment of pituitary adenomas we speculate about the relevance of RSUME as a potential target for the development of an anti-angiogenic therapy. Moreover, the role of BMP-4 which stimulates prolactinoma development through the Smad signalling cascade is described and its role as putative drug target for the treatment of prolactinomas is discussed. Regarding the well-known resistance of a part of somatotropinomas to somatostatin analogue treatment, recently identified mechanisms responsible for the drug resistance are summarized and ways to overcome them in future treatment concepts are presented. Concerning novel therapeutic options for patients with Cushing’s disease the impact of retinoic acid, which is currently tested in clinical studies, is shown, and the action and putative therapeutic impact of silibinin to resolve glucocorticoid resistance in these patients is critically discussed.

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“…The screening projection for PCa is still unclear and recent large clinical trials have failed to exert notable reduction in the prostate-specific mortality and the all-cause mortality [6]. The current evidence shows that RCC and PCa are Von Hippel-Lindau tumor suppressor (VHL)-related cancers [7][8][9][10]. VHL protein is an E3 ubiquitin ligase that targets hypoxia inducible factor 1α (HIF1α) to the proteasome for degradation [11].…”

Section: Introductionmentioning

confidence: 99%

Association of hypoxia-inducible factor-1α (HIF1α) 1790G/A gene polymorphism with renal cell carcinoma and prostate cancer susceptibility: a meta-analysis

Zhou

Lin

et al. 2019

BMC Med Genet

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Background: This meta-analysis was performed to evaluate the relationship between hypoxia-inducible factor-1α (HIF1α) 1790G/A gene polymorphism and the susceptibility to renal cell carcinoma (RCC) and prostate cancer (PCa). Methods: Association investigations were identified and included from the Embase, Cochrane Library and PubMed databases on March 1, 2018, and eligible investigations were analyzed by meta-analysis. Odds ratios (OR) were used to express the dichotomous data, and the 95% confidence intervals (CI) were also calculated. Results: In this meta-analysis, we found that the AA genotype of HIF1α 1790G/A was positively associated with the risk of RCC in overall populations, Caucasians, but not for Asians. G allele and GG genotype were not associated with the susceptibility of RCC in overall populations, Caucasians, and Asians. The G allele was negatively associated with PCa susceptibility in overall populations, Asians, but not for Caucasians. GG genotype was negatively associated with PCa susceptibility in Asians, but not for overall populations and Caucasians. HIF1α 1790G/A AA genotype was not associated with PCa susceptibility in overall populations of Caucasians or Asians. Conclusion: AA genotype of HIF1α 1790G/A was positively associated with RCC risk in overall populations and Caucasians. Furthermore, the G allele was negatively associated with prostate cancer susceptibility in overall populations, Asians, and GG genotype was negatively associated with PCa susceptibility in Asians.

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von Hippel-Lindau mutants in renal cell carcinoma are regulated by increased expression of RSUME

Cited by 18 publications

References 48 publications

A Precision Strategy to Cure Renal Cell Carcinoma by Targeting Transglutaminase 2

A Precision Strategy to Cure Renal Cell Carcinoma by Targeting Transglutaminase 2

GEOFFREY HARRIS AWARD 2019: Translational research in pituitary tumours

Association of hypoxia-inducible factor-1α (HIF1α) 1790G/A gene polymorphism with renal cell carcinoma and prostate cancer susceptibility: a meta-analysis

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