Onconeuronal cerebellar degeneration-related antigen, Cdr2, is strongly expressed in papillary renal cell carcinoma and leads to attenuated hypoxic response.
The onconeuronal cerebellar degeneration-related antigen Cdr2 is associated with paraneoplastic syndromes. Neoplastic expression of Cdr2 in ovary and breast tumors triggers an autoimmune response that suppresses tumor growth by developing tumor immunity, but culminates in cerebellar degeneration when Cdr2-specific immune cells recognize neuronal Cdr2. We identified Cdr2 as a novel interactor of the hypoxia-inducible factor (HIF) prolyl-4-hydroxylase PHD1 and provide evidence that Cdr2 might represent a novel important tumor antigen in renal cancer. Strong Cdr2 protein expression was observed in 54.2% of papillary renal cell carcinoma (pRCC) compared with 7.8% of clear-cell RCC and no staining was observed in chromophobe RCC or oncocytoma. High Cdr2 protein levels correlated with attenuated HIF target gene expression in these solid tumors, and Cdr2 overexpression in tumor cell lines reduced HIF-dependent transcriptional regulation. This effect was because of both attenuation of hypoxic protein accumulation and suppression of the transactivation activity of HIF-1alpha. pRCC is known for its tendency to avascularity, usually associated with a lower pathological stage and higher survival rates. We provide evidence that Cdr2 protein strongly accumulates in pRCC, attenuates the HIF response to tumor hypoxia and may become of diagnostic importance as novel renal tumor marker.
Balamurugan
K
K
Institute of Physiology and Zürich Center for Integrative Human Physiology ZIHP, University of Zürich UZH, Zürich, Switzerland.
Luu
V-D
VD
Kaufmann
M R
MR
Hofmann
V S
VS
Boysen
G
G
Barth
S
S
Bordoli
M R
MR
Stiehl
D P
DP
Moch
H
H
Schraml
P
P
Wenger
R H
RH
Camenisch
G
G
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D010100:Oxygen; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D011485:Protein Binding; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D050880:p300-CBP Transcription Factors / Q000378:metabolism
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C095184:CDR2 protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009419:Nerve Tissue Proteins; D011393:Procollagen-Proline Dioxygenase; D050880:p300-CBP Transcription Factors; D010100:Oxygen