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Expression of Smad2 and Smad4 in cervical cancer: absent nuclear Smad4 expression correlates with poor survival
Judith N Kloth1, Gemma G Kenter, H Siebe Spijker
1Department of Pathology, The Leiden University Medical Center, Leiden, The Netherlands.
Abstract:
Alterations in transforming growth factor-beta signaling, due to a decrease in Smad2 and especially Smad4 expression, has primarily been reported in pancreatic and colorectal cancers, although loss of the chromosomal region 18q21.1, containing the loci of Smad2 and Smad4, is among the most frequent molecular alterations in cervical cancer. The aim of our study was to investigate whether decreased Smad2 and Smad4 protein expression in primary cervical cancers is associated with molecular alterations at 18q21.1, mutations in the functional domains of Smad2 and Smad4 or hypermethylation, and to assess the biological relevance of decreased Smad2 and Smad4 expression. Subsequently, Smad2, Smad4 and p21 protein expression was determined by immunohistochemistry in 117 primary cervical carcinomas, assembled in a tissue array. Smad signaling was shown to be associated with p21 mRNA expression. All the tumors expressed Smad2 or Smad4. Weak cytoplasmic Smad2 or weak cytoplasmic Smad4 expression could not be attributed to loss of heterozygosity at 18q21.1. Despite weak/moderate Smad2 expression and absent nuclear Smad4 expression, the coding regions of the functional MH1 and MH2 domains of Smad2 and Smad4 were unchanged, as assessed by sequence analysis. The Smad4 promoter region was unmethylated in tumor samples with weak/moderate cytoplasmic Smad4 expression. Remarkably, both weak cytoplasmic Smad4 expression and absent nuclear Smad4 expression significantly correlated with poor disease-free (P=0.003 and P=0.003, respectively) and overall 5-year survival (P=0.003 and P=0.010, respectively). Our findings support the hypothesis that Smad4 is a target molecule for functional inactivation in cervical cancer.
Insights
Decreased Smad4 protein expression in cervical cancer correlates with poor survival. This study investigated Smad2 and Smad4 alterations, finding Smad4 inactivation is linked to poorer patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Transforming growth factor-beta (TGF-β) signaling, involving Smad2 and Smad4, is crucial in various cancers.
- Loss of the 18q21.1 chromosomal region, containing Smad2 and Smad4 loci, is frequent in cervical cancer.
- The role of Smad2 and Smad4 expression alterations in cervical cancer pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the association between decreased Smad2 and Smad4 protein expression in cervical cancer and molecular alterations at 18q21.1.
- To examine mutations and hypermethylation in Smad2 and Smad4 genes.
- To assess the biological relevance and prognostic impact of reduced Smad2 and Smad4 expression in cervical cancer.
Main Methods:
- Immunohistochemistry was used to determine Smad2, Smad4, and p21 protein expression in 117 primary cervical carcinomas.
- Loss of heterozygosity at 18q21.1 was analyzed.
- Sequence analysis of Smad2 and Smad4 functional domains (MH1 and MH2) and Smad4 promoter methylation were performed.
Main Results:
- All tumors expressed Smad2 or Smad4; however, weak cytoplasmic Smad2/Smad4 expression was not linked to 18q21.1 loss of heterozygosity.
- No mutations were found in the coding regions of Smad2 and Smad4 functional domains.
- Weak/absent nuclear Smad4 expression significantly correlated with poor disease-free and overall 5-year survival (P=0.003-0.010).
Conclusions:
- Smad4 protein expression, particularly nuclear localization, is a significant prognostic marker in cervical cancer.
- Functional inactivation of Smad4, rather than genetic mutations or promoter methylation, appears to be a key event in cervical cancer progression.
- These findings highlight Smad4 as a potential therapeutic target in cervical cancer treatment.
