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An Orthotopic Murine Model of Human Prostate Cancer Metastasis
Published on: September 18, 2013
Genetic and epigenetic inactivation of TNFRSF10C in human prostate cancer
Yu Cheng1, Jin Woo Kim, Wennuan Liu
1Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Background:
TNFRSF10C, is located on 8p21.3, one of the most frequently deleted loci in the genome of prostate cancer (PCa). Hypermethylation of TNFRSF10C promoter CpG island (CGI) had been reported in many tumors including PCa. However, the interplay between somatic deletion and promoter hypermethylation of TNFRSF10C on PCa development has not been investigated.
Methods:
Methylation status of promoter CGI and deletion status of the TNFRSF10C locus was investigated by bisulfite sequencing and Affymetrix SNP array, respectively, in 59 pairs of PCa tumor and matched normal samples with three PCa cell lines. TNFRSF10C gene expression changes in relation to cancer-associated genetic/epigenetic changes in clinical specimens, and change of TNFRSF10C expression before and after 5-aza-2'-deoxycytidine treatment in the PC3 PCa cell line was assessed by real-time RT-PCR.
Results:
We found that TNFRSF10C promoter CGI was differentially methylated in 46 of 59 primary cancers (78.0%). Hemizygous deletion at TNFRSF10C was found in 44 of the 59 prostate tumors (74.5%). Interestingly, in 94.9% of the tumors (56 out of 59), TNFRSF10C was either hemizygously deleted or its promoter CGI hypermethylated. Deletion and/or methylation of the TNFRSF10C gene were correlated with decreased mRNA expression of the gene in clinical specimens. Demethylation of the TNFRSF10C promoter CGI was accompanied by transcriptional re-activation of TNFRSF10C in the PCa cell line PC3.
Conclusion:
We found a notably high frequency of promoter CGI methylation and deletion of TNFRSF10C in PCa tissues. Our results indicated that inactivation of TNFRSF10C by chromosomal deletion and promoter methylation may play an important role in PCa development.
Insights
Inactivation of TNFRSF10C, a gene frequently altered in prostate cancer (PCa), occurs through deletion or promoter methylation. This dual inactivation mechanism is common in PCa and impacts gene expression, suggesting a role in disease development.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- TNFRSF10C is located at 8p21.3, a frequently deleted region in prostate cancer (PCa).
- Hypermethylation of the TNFRSF10C promoter CpG island (CGI) is observed in various tumors, including PCa.
- The combined effect of somatic deletion and promoter hypermethylation of TNFRSF10C in PCa development remains uninvestigated.
Purpose of the Study:
- To investigate the interplay between somatic deletion and promoter hypermethylation of TNFRSF10C in prostate cancer.
- To assess the impact of these genetic and epigenetic alterations on TNFRSF10C gene expression.
- To determine the role of TNFRSF10C inactivation in PCa pathogenesis.
Main Methods:
- Investigated TNFRSF10C promoter CGI methylation using bisulfite sequencing.
- Assessed deletion status of the TNFRSF10C locus via Affymetrix SNP array in 59 PCa tumors and matched normal samples.
- Evaluated TNFRSF10C gene expression changes using real-time RT-PCR before and after 5-aza-2'-deoxycytidine treatment in PC3 cell line.
Main Results:
- TNFRSF10C promoter CGI was differentially methylated in 78.0% (46/59) of primary PCa.
- Hemizygous deletion at TNFRSF10C was detected in 74.5% (44/59) of prostate tumors.
- A high frequency (94.9%) of tumors exhibited either deletion or promoter hypermethylation of TNFRSF10C, correlated with decreased mRNA expression.
Conclusions:
- TNFRSF10C inactivation through chromosomal deletion and promoter methylation is frequent in PCa tissues.
- These combined alterations may play a significant role in the development of prostate cancer.
- Re-activation of TNFRSF10C expression was observed upon promoter demethylation in a PCa cell line.
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