Methylation of the gamma-catenin gene is associated with poor prognosis of renal cell carcinoma

Julia E Breault, Hiroaki Shiina, Mikio Igawa, Leopoldo A Ribeiro-Filho, Masao Deguchi, Hideki Enokida, Shinji Urakami, Masaharu Terashima, Masayuki Nakagawa, Christopher J Kane, Peter R Carroll, Rajvir Dahiya
Clinical Cancer Research 2005 January 15, 11 (2 Pt 1): 557-64

PURPOSE: Gamma-catenin is a cell adhesion protein, and its functional loss is associated with tumor invasion and metastasis. We hypothesize that (1) promoter CpG methylation regulates the expression and function of the gamma-catenin gene in renal cell carcinoma (RCC) and (2) methylation of the gamma-catenin gene is associated with poor prognosis of RCC. To test these hypotheses, we analyzed the CpG methylation status of the gamma-catenin gene and its correlation with clinical outcome in RCC.

EXPERIMENTAL DESIGN: Genomic DNA and total RNA were extracted from three renal cancer cell lines (A498, Caki-1, and Caki-2) and 54 RCC tissue samples with their corresponding normal kidney tissue samples. Expression of gamma-catenin gene was analyzed by reverse transcription-PCR and immunostaining. Promoter methylation was analyzed by two different methylation-specific PCR (MSP-A and MSP-B), and the results were verified by DNA sequencing.

RESULTS: The demethylating agent (5-aza-2'-deoxycytidine) increased levels of mRNA transcript of the gamma-catenin gene in three renal cancer cell lines. Gamma-catenin mRNA and protein expression were significantly reduced in RCC samples compared with normal kidney samples, respectively (P < 0.05). MSP-A and MSP-B bands were detected in 45 of 54 (83.3%) and 49 of 54 (90.7%) RCC samples, respectively. In normal kidney, weak products of MSP-A and MSP-B were detected in 5 of 54 (9.3%) and 6 of 54 (11.1%) samples, respectively. Likewise, both MSP-A and MSP-B ratios were significantly higher in RCC samples compared with normal kidney samples, respectively (P < 0.01). Multivariate analysis revealed that the MSP-B ratio was a powerful and independent predictor superior to nuclear grade and Robson stage with respect to survival and disease progression (P = 0.029 and 0.0071, respectively). No mutations in the NH(2)-terminal region of gamma-catenin were found in this study.

CONCLUSION: Expression of gamma-catenin is regulated by promoter CpG methylation, and the balance between methylated and unmethylated RCC cell populations could determine its functional role. Because the conventional nuclear grade and/or staging system have some limitations to predict precise clinical outcome, this is the first report demonstrating that promoter CpG methylation of gamma-catenin can be an independent and superior predictor for survival and disease progression.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"