The In vitro and In vivo Effects of Re-Expressing Methylated von Hippel-Lindau Tumor Suppressor Gene in Clear Cell Renal Carcinoma with 5-Aza-2′-deoxycytidine

Purpose: Clear cell renal carcinoma (ccRCC) is strongly associated with loss of the von Hippel-Lindau ( VHL ) tumor suppressor gene. The VHL gene is functionally lost through hypermethylation in up to 19% of sporadic ccRCC cases. We theorized that re-expressing VHL silenced by methylation in ccRCC c...

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Published in:	Clinical cancer research Vol. 10; no. 20; pp. 7011 - 7021
Main Authors:	ALLEMAN, Wade G, TABIOS, Ray L, CHANDRAMOULI, Gadisetti V. R, APRELIKOVA, Olga N, TORRES-CABALA, Carlos, MENDOZA, Arnulfo, RODGERS, Craig, SOPKO, Nikolai A, LINEHAN, W. Marston, VASSELLI, James R
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 15-10-2004
Subjects:	Adenocarcinoma, Clear Cell - genetics Adenocarcinoma, Clear Cell - pathology Animals Antimetabolites, Antineoplastic - pharmacology Antineoplastic agents Azacitidine - analogs & derivatives Azacitidine - pharmacology Biological and medical sciences Cytidine - analogs & derivatives Disease Models, Animal DNA Methylation Gene Silencing Humans Kidney Neoplasms - genetics Kidney Neoplasms - pathology Medical sciences Mice Pharmacology. Drug treatments Pyrimidine Nucleosides - pharmacology Reverse Transcriptase Polymerase Chain Reaction Transfection Transplantation, Heterologous Tumor Cells, Cultured Tumor Suppressor Proteins - biosynthesis Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Tumors Ubiquitin-Protein Ligases - biosynthesis Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism Von Hippel-Lindau Tumor Suppressor Protein Kidney disease Antineoplastic agent Urinary system disease Decitabine Malignant tumor Gene expression In vitro In vivo Azanucleoside Clear cell carcinoma Grawitz tumor Methylation Tumor suppressor gene
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Summary:	Purpose: Clear cell renal carcinoma (ccRCC) is strongly associated with loss of the von Hippel-Lindau ( VHL ) tumor suppressor gene. The VHL gene is functionally lost through hypermethylation in up to 19% of sporadic ccRCC cases. We theorized that re-expressing VHL silenced by methylation in ccRCC cells, using a hypo-methylating agent, may be an approach to treatment in patients with this type of cancer. We test the ability of two hypo-methylating agents to re-express VHL in cell culture and in mice bearing human ccRCC and evaluate the effects of re-expressed VHL in these models. Experimental Design: Real-time reverse transcription-PCR was used to evaluate the ability of zebularine and 5-aza-2′-deoxycytidine (5-aza-dCyd) to re-express VHL in four ccRCC cell lines with documented VHL gene silencing through hypermethylation. We evaluated if the VHL re-expressed after hypo-methylating agent treatment could recreate similar phenotypic changes in ccRCC cells observed when the VHL gene is re-expressed via transfection in cell culture and in a xenograft mouse model. Finally we evaluate global gene expression changes occurring in our cells, using microarray analysis. Results: 5-Aza-dCyd was able to re-express VHL in our cell lines both in culture and in xenografted murine tumors. Well described phenotypic changes of VHL expression including decreased invasiveness into Matrigel, and decreased vascular endothelial growth factor and glucose transporter-1 expression were observed in the treated lines. VHL methylated ccRCC xenografted tumors were significantly reduced in size in mice treated with 5-aza-dCyd. Mice bearing nonmethylated but VHL -mutated tumors showed no tumor shrinkage with 5-aza-dCyd treatment. Conclusion: Hypo-methylating agents may be useful in the treatment of patients having ccRCC tumors consisting of cells with methylated VHL .
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	1078-0432 1557-3265
DOI:	10.1158/1078-0432.CCR-04-0516