Onconeuronal cerebellar degeneration-related antigen, Cdr2, is strongly expressed in papillary renal cell carcinoma and leads to attenuated hypoxic response

Abstract

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-1a. 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.

The Onconeural Antigen cdr2 Is a Novel APC/C Target that Acts in Mitosis to Regulate C-Myc Target Genes in Mammalian Tumor Cells

“…Our findings of a functional interaction between cdr2 and c-myc in mitosis, together with the fact that cdr2 is expressed in gynecologic [4] and renal [42] tumors raised the question whether cdr2 can promote tumor growth. Remarkably, several validated cdr2-regulated c-myc target genes in HeLa cells have roles in cell cycle biology (Table 1, Fig.…”

Regulated oxygen sensing by protein hydroxylation in renal erythropoietin-producing cells

“…Of note, also PHD2 appears to directly inhibit HIF-1 transcriptional activity, independently of protein hydroxylation and without affecting HIF-1␣ protein levels (128,137). Two other PHD interactors, the iron-only hydrogenase-like protein 1 (IOP1) and the onconeuronal cerebellar degeneration-related protein 2 (Cdr2) additionally affect HIF-␣ mRNA and protein, respectively, by unknown mechanisms (9,50).…”

Prolyl-4-hydroxylase PHD2- and hypoxia-inducible factor 2-dependent regulation of amphiregulin contributes to breast tumorigenesis

“…Immunoblot analyses were performed as previously described (Balamurugan et al, 2009). Antibodies used were mouse monoclonal antibody (mAb) anti-HIF-1a (Transduction Laboratories, BD Biosciences, Allschwil, Switzerland), anti-HIF-2a (Novus Biologicals, LuBioScience, Lucerne, Switzerland), mAb anti-V5 (Invitrogen), mAb anti-b-actin (Sigma), rabbit polyclonal anti-PHD2 antibody (Novus), mAb anti-PHD3 was kindly provided by PJ Ratcliffe (Oxford, UK).…”