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Published on: May 16, 2012
SPINT2 Deregulation in Prostate Carcinoma
Márcia Santos Pereira1, Gisele Caravina de Almeida2, Filipe Pinto3,1
1ICVS/3B’s– PT Government Associate Laboratory, Braga/Guimarães, Portugal (MSP, FP, MVP, RMR)
Abstract:
SPINT2 is a tumor suppressor gene that inhibits proteases implicated in cancer progression, like HGFA, hepsin and matriptase. Loss of SPINT2 expression in tumors has been associated with gene promoter hypermethylation; however, little is known about the mechanisms of SPINT2 deregulation in prostate cancer (PCa). We aimed to analyze SPINT2 expression levels and understand the possible regulation by SPINT2 promoter hypermethylation in PCa. In a cohort of 57 cases including non-neoplastic and PCa tissues, SPINT2 expression and promoter methylation was analyzed by immunohistochemistry and methylation-specific PCR, respectively. Methylation status of the SPINT2 promoter was also evaluated by bisulfite sequencing and 5-aza-2'-deoxycytidine treatment. Oncomine and TCGA databases were used to perform in silico PCa analysis of SPINT2 mRNA and methylation levels. A reduction in SPINT2 expression levels from non-neoplastic to PCa tissues was observed; however, none of the cases exhibited SPINT2 promoter methylation. Both bisulfite sequencing and 5-aza demonstrated that SPINT2 promoter is not methylated in PCa cells. Bioinformatics approaches did not show downregulation of SPINT2 at the mRNA level and, in corroboration with our results, SPINT2 promoter region is reported to be unmethylated. Our study suggests an involvement of SPINT2 in PCa tumorigenesis, probably in association with a post-translational regulation of SPINT2.
Insights
SPINT2, a tumor suppressor, shows reduced expression in prostate cancer (PCa). Promoter hypermethylation does not cause this downregulation, suggesting post-translational regulation of SPINT2 in PCa progression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- SPINT2 acts as a tumor suppressor by inhibiting proteases involved in cancer progression.
- Loss of SPINT2 expression in tumors is often linked to gene promoter hypermethylation.
- Mechanisms of SPINT2 deregulation in prostate cancer (PCa) remain largely unknown.
Purpose of the Study:
- To investigate SPINT2 expression levels in PCa.
- To determine if SPINT2 promoter hypermethylation contributes to its downregulation in PCa.
Main Methods:
- Immunohistochemistry and methylation-specific PCR on 57 PCa and non-neoplastic tissues.
- Bisulfite sequencing and 5-aza-2'-deoxycytidine treatment to assess SPINT2 promoter methylation.
- In silico analysis using Oncomine and TCGA databases for SPINT2 mRNA and methylation levels.
Main Results:
- SPINT2 expression was reduced in PCa tissues compared to non-neoplastic tissues.
- No SPINT2 promoter hypermethylation was detected in any of the analyzed PCa cases.
- In silico analyses corroborated the absence of SPINT2 promoter methylation and showed no significant mRNA downregulation.
Conclusions:
- SPINT2 is likely involved in PCa tumorigenesis.
- Promoter hypermethylation is not the mechanism driving SPINT2 downregulation in PCa.
- Post-translational regulation may be responsible for SPINT2 alterations in prostate cancer.
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