Autoantibody against hypoxia-inducible factor prolyl hydroxylase-3 is a potential serological marker for renal cell carcinoma

Tanaka, Toshiaki; Kitamura, Hiroshi; Torigoe, Toshihiko; Hirohashi, Yoshihiko; Sato, Eiji; Masumori, Naoya; Sato, Noriyuki; Tsukamoto, Taiji

doi:10.1007/s00432-010-0940-6

Cited by 14 publications

(14 citation statements)

References 18 publications

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“…The oxygen sensing prolyl hydroxylase family member PHD3 displays high expression levels in ccRCC tumours and derived cell lines [23, 24]. Recent studies have suggested a number of both hydroxylase-dependent and hydroxylase-independent roles for PHD3 also beyond the HIF pathway.…”

Section: Discussionmentioning

confidence: 99%

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HIF prolyl hydroxylase PHD3 regulates translational machinery and glucose metabolism in clear cell renal cell carcinoma

et al. 2017

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BackgroundA key feature of clear cell renal cell carcinoma (ccRCC) is the inactivation of the von Hippel-Lindau tumour suppressor protein (pVHL) that leads to the activation of hypoxia-inducible factor (HIF) pathway also in well-oxygenated conditions. Important regulator of HIF-α, prolyl hydroxylase PHD3, is expressed in high amounts in ccRCC. Although several functions and downstream targets for PHD3 in cancer have been suggested, the role of elevated PHD3 expression in ccRCC is not clear.MethodsTo gain insight into the functions of high PHD3 expression in ccRCC, we used PHD3 knockdown by siRNA in 786-O cells under normoxic and hypoxic conditions and performed discovery mass spectrometry (LC-MS/MS) of the purified peptide samples. The LC-MS/MS results were analysed by label-free quantification of proteome data using a peptide-level expression-change averaging procedure and subsequent gene ontology enrichment analysis.ResultsOur data reveals an intriguingly widespread effect of PHD3 knockdown with 91 significantly regulated proteins. Under hypoxia, the response to PHD3 silencing was wider than under normoxia illustrated by both the number of regulated proteins and by the range of protein expression levels. The main cellular functions regulated by PHD3 expression were glucose metabolism, protein translation and messenger RNA (mRNA) processing. PHD3 silencing led to downregulation of most glycolytic enzymes from glucose transport to lactate production supported by the reduction in extracellular acidification and lactate production and increase in cellular oxygen consumption rate. Moreover, upregulation of mRNA processing-related proteins and alteration in a number of ribosomal proteins was seen as a response to PHD3 silencing. Further studies on upstream effectors of the translational machinery revealed a possible role for PHD3 in regulation of mTOR pathway signalling.ConclusionsOur findings suggest crucial involvement of PHD3 in the maintenance of key cellular functions including glycolysis and protein synthesis in ccRCC.Electronic supplementary materialThe online version of this article (doi:10.1186/s40170-017-0167-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

“…Most recently, PHD3 has been suggested to function as an activator of fatty acid oxidation via ACC2 [22]. PHD3 overexpression has been seen in many types of cancer, including ccRCC [23, 24]. Importantly, high PHD3 expression serves as a marker for poor prognosis in ccRCC patients [25] as well as in other types of cancer [26].…”

Section: Introductionmentioning

confidence: 99%

HIF prolyl hydroxylase PHD3 regulates translational machinery and glucose metabolism in clear cell renal cell carcinoma

et al. 2017

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“…A study demonstrated that PHD3 mRNA level was increased in different anatomical sites including tongue, mouth floor and tonsils [45]. Increased PHD3 expression under hypoxia enhances cell cycle progression and survival of carcinoma cells [46]. …”

Section: The Function Of Phd3 In Different Cancersmentioning

confidence: 99%

“…found that PHD3 was overexpressed in 21 of the 22 renal cell carcinoma (RCC) specimens through RT-PCR analysis and anti-PHD3 antibody may be a novel serological marker for RCC [47]. PHD3 is mainly overexpressed in RCCs, but rarely in normal tissues and was recognized as a cancer-specific antigen and might be a target in immunotherapy for RCC [48].…”

Section: The Function Of Phd3 In Different Cancersmentioning

confidence: 99%

State of the art paper Function and expression of prolyl hydroxylase 3 in cancers

Liu

Liang²,

Li³

et al. 2013

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Hypoxia inducible factor (HIF) is a product of tumor cells that plays an important role in protecting tumor cells and adjusting to low oxygen tension through driving the progression and aggressiveness of tumors and changing the growth, angiogenesis, differentiation and metastasis of tumors. Prolyl hydroxylase 3 (PHD3) is a member of PHDs that are induced in hypoxia. Many studies have shown that PHD3 not only can hydroxylate HIF-1α, but also has various other biological functions. Thus PHD3 plays significant roles in suppressing the growth, angiogenesis, differentiation and metastasis of tumors and promoting apoptosis of tumors under hypoxic conditions. It may become a new tumor suppressor gene and also may become a new approach to investigate tumors.

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“…Prolyl hydroxylase-3 (PHD3/ENGL3) is a member of the PHD family, which is involved in the degradation of HIF proteins in cooperation with VHL protein under normoxic conditions. PHD3 was found frequently over-expressed in RCC tissues, with high specificity to cancer samples (Zhao et al, 2006) and its usefulness as a novel tumor antigen for RCC immunotherapy has been recently demonstrated in clinical serum samples from RCC patients (Sato, 2008;Tanaka, 2011). Insulin-like growth factor binding protein 3 (IGFBP3) is one of the most over-expressed genes in ccRCC (Takahashi, 2005;Yao, 2005) and its increased protein expression has been demonstrated in 74% of ccRCCs by IHC and associated with higher Fuhrman nuclear grade (Chuang et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Molecular Portrait of Clear Cell Renal Cell Carcinoma: An Integrative Analysis of Gene Expression and Genomic Copy Number Profiling

Battaglia¹,

Mangano²,

Bicciato³

et al. 2012

Emerging Research and Treatments in Renal Cell Carcinoma

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Autoantibody against hypoxia-inducible factor prolyl hydroxylase-3 is a potential serological marker for renal cell carcinoma

Abstract: The present study suggests that the anti-PHD3 Ab may be a novel serological marker for RCC and the titer may reflect the tumor burden in each individual.

Cited by 14 publications

References 18 publications

HIF prolyl hydroxylase PHD3 regulates translational machinery and glucose metabolism in clear cell renal cell carcinoma

HIF prolyl hydroxylase PHD3 regulates translational machinery and glucose metabolism in clear cell renal cell carcinoma

State of the art paper Function and expression of prolyl hydroxylase 3 in cancers

Molecular Portrait of Clear Cell Renal Cell Carcinoma: An Integrative Analysis of Gene Expression and Genomic Copy Number Profiling

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