Immunohistochemical detection of the von Hippel-Lindau gene product (pVHL) in human tissues and tumors: A useful marker for metastatic renal cell carcinoma and clear cell carcinoma of the ovary and uterus

Departments of Laboratory Medicine, Geisinger Medical Center, Danville, PA 17822, USA.
American Journal of Clinical Pathology (Impact Factor: 2.51). 05/2008; 129(4):592-605. DOI: 10.1309/Q0FLUXFJ4FTTW1XR
Source: PubMed


Genetic alteration of the von Hippel-Lindau (VHL) tumor suppressor gene has been linked to hereditary and sporadic clear cell renal cell carcinomas (RCCs). Inconsistent data on immunodetection of the VHL gene product (pVHL) in normal tissues and tumors have been reported. We immunohistochemically reevaluated the usefulness of a specific rabbit polyclonal anti-pVHL antibody in 531 cases of renal and nonrenal neoplasms and normal tissues. Positive immunostaining was observed in nearly 100% of primary renal neoplasms, 95% of metastatic RCCs, and 90% of clear cell carcinomas of the ovary and uterus. In normal tissues, positive immunoreactivity was observed only in renal tubules, exocrine pancreas, islets, and bile ducts. Western blot and reverse transcription-polymerase chain reaction confirmed the immunostaining results. These data indicate that this anti-pVHL antibody is a useful marker in assisting diagnosis of metastatic RCC and may serve as a diagnostic marker for clear cell carcinomas of the ovary and uterus.

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    • "The expression status of tumor suppressor pVHL has been studied in several cancers including ovarian and uterine cancer ones [45], the colorectal cancer and liver metastases [36], as well as in the chondrosarcoma [37]. "
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    ABSTRACT: We investigate the expression and localization of the tumor suppressor protein pVHL as well as the oncoprotein Aurora A kinase in kidney cancer. Both Aurora A kinase and pVHL protein status were evaluated using immunohistochemistry. The Aurora A expression is correlated with the Fuhrman grade and the TNM stage, while the pVHL expression is correlated with the capsule rupture and the TNM stage. Aurora A kinase expression increases in malignant tissue comparing to the non-malignant one. And there is a decrease in pVHL expression from the adjacent healthy tissues to the tumor`s ones. The two kinds of opposite tumor profiles display significant distribution difference according to TNM stages. It could be proposed that the absence of Aurora A protein associated with a strong expression of pVHL in clear cells kidney carcinoma are of good prognosis for the disease.
    Disease markers 11/2012; 33(6). DOI:10.3233/DMA-2012-00942 · 1.56 Impact Factor
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    • "Functionally, since SPRY2 was reported to have anti-migratory and anti-proliferative effect on cancer cell growth through inhibiting ERK1/2 kinase pathway (Impagnatiello et al., 2001; Yigzaw et al., 2001), suppressing either PHD1 or pVHL blunted the effect of FGF-induced ERK kinase pathway due to increased SPRY2 protein level. In a subset of hepatocellular carcinoma, pVHL protein levels were upregulated, and this led to decrease of SPRY2 protein that contributed to cancer progression (Lin et al., 2008). However, about 70% renal cell carcinomas have defects in pVHL. "
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    ABSTRACT: The function of tumor suppressor VHL is compromised in the vast majority of clear cell renal cell carcinoma, and its mutations or loss of expression was causal for this disease. pVHL was found to be a substrate recognition subunit of an E3 ubiquitin ligase, and most of the tumor-derived mutations disrupt this function. pVHL was found to bind to the alpha subunits of hypoxia-inducible factor (HIF) and promote their ubiquitination and proteasomal degradation. Proline hydroxylation on key sites of HIFα provides the binding signal for pVHL E3 ligase complex. Beside HIFα, several other VHL targets have been identified, including activated epidermal growth factor receptor (EGFR), RNA polymerase II subunits RPB1 and hsRPB7, atypical protein kinase C (PKC), Sprouty2, β-adrenergic receptor II, and Myb-binding protein p160. HIFα is the most well studied substrate and has been proven to be critical for pVHL's tumor suppressor function, but the activated EGFR and PKC and other pVHL substrates might also be important for tumor growth and drug response. Their regulations by pVHL and their relevance to signaling and cancer are discussed.
    Frontiers in Oncology 04/2012; 2:35. DOI:10.3389/fonc.2012.00035
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    Article: The Ovary

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