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The candidate tumor suppressor gene, RASSF1A, from human chromosome 3p21.3 is involved in kidney tumorigenesis
K Dreijerink1, E Braga, I Kuzmin
1Laboratory of Immunobiology and Intramural Research Support Program, Science Applications International Corporation, National Cancer Institute, Frederick, MD 21702, USA.
Abstract:
Clear cell-type renal cell carcinomas (clear RCC) are characterized almost universally by loss of heterozygosity on chromosome 3p, which usually involves any combination of three regions: 3p25-p26 (harboring the VHL gene), 3p12-p14.2 (containing the FHIT gene), and 3p21-p22, implying inactivation of the resident tumor-suppressor genes (TSGs). For the 3p21-p22 region, the affected TSGs remain, at present, unknown. Recently, the RAS association family 1 gene (isoform RASSF1A), located at 3p21.3, has been identified as a candidate lung and breast TSG. In this report, we demonstrate aberrant silencing by hypermethylation of RASSF1A in both VHL-caused clear RCC tumors and clear RCC without VHL inactivation. We found hypermethylation of RASSF1A's GC-rich putative promoter region in most of analyzed samples, including 39 of 43 primary tumors (91%). The promoter was methylated partially or completely in all 18 RCC cell lines analyzed. Methylation of the GC-rich putative RASSF1A promoter region and loss of transcription of the corresponding mRNA were related causally. RASSF1A expression was reactivated after treatment with 5-aza-2'-deoxycytidine. Forced expression of RASSF1A transcripts in KRC/Y, a renal carcinoma cell line containing a normal and expressed VHL gene, suppressed growth on plastic dishes and anchorage-independent colony formation in soft agar. Mutant RASSF1A had reduced growth suppression activity significantly. These data suggest that RASSF1A is the candidate renal TSG gene for the 3p21.3 region.
Insights
RAS association family 1 gene A (RASSF1A) is hypermethylated in clear cell renal cell carcinoma (clear RCC), silencing its tumor suppressor function. Reactivating RASSF1A suppressed clear RCC growth, identifying it as a key renal tumor suppressor gene.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Clear cell renal cell carcinoma (clear RCC) frequently exhibits chromosome 3p loss of heterozygosity, implicating tumor suppressor genes (TSGs) in 3p25-p26 (VHL), 3p12-p14.2 (FHIT), and 3p21-p22.
- The specific TSGs within the 3p21-p22 region responsible for clear RCC pathogenesis remain largely unknown.
- RAS association family 1 gene A (RASSF1A), a known lung and breast TSG candidate located at 3p21.3, is investigated for its role in clear RCC.
Purpose of the Study:
- To investigate the potential role of RASSF1A as a tumor suppressor gene in clear cell renal cell carcinoma.
- To determine if RASSF1A undergoes aberrant silencing via promoter hypermethylation in clear RCC.
- To assess the functional impact of RASSF1A expression and its inactivation in clear RCC development.
Main Methods:
- Analysis of RASSF1A promoter methylation status in primary clear RCC tumors and cell lines using methylation-specific techniques.
- Assessment of RASSF1A mRNA expression levels in relation to promoter methylation.
- Treatment of cell lines with 5-aza-2'-deoxycytidine to evaluate RASSF1A reactivation.
- Functional studies involving forced expression of wild-type and mutant RASSF1A in renal carcinoma cell lines to assess growth suppression.
Main Results:
- Aberrant hypermethylation of the RASSF1A GC-rich promoter region was detected in 91% of primary clear RCC tumors (39/43) and all analyzed RCC cell lines (18/18).
- RASSF1A promoter methylation strongly correlated with the loss of its corresponding mRNA transcription.
- Treatment with 5-aza-2'-deoxycytidine reactivated RASSF1A expression.
- Forced expression of RASSF1A significantly suppressed proliferation and anchorage-independent growth of renal carcinoma cells, with mutant RASSF1A exhibiting reduced activity.
Conclusions:
- RASSF1A is frequently silenced by promoter hypermethylation in clear cell renal cell carcinoma, irrespective of VHL gene status.
- RASSF1A functions as a critical tumor suppressor gene in the 3p21.3 region for renal cell carcinoma.
- RASSF1A inactivation through hypermethylation is a significant event in clear RCC pathogenesis.
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