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Published on: December 31, 2014
SMAD4 protein expression and cell proliferation in colorectal adenocarcinomas
Adriana Handra-Luca1, Sylviane Olschwang, Jean-François Fléjou
1Service d'Anatomie Pathologique, APHP Avicenne Université Paris 13/Nord Medecine, EA3406, 125 rue de Stalingrad, 93000 Bobigny, France. adriana.handra-luca@avc.aphp.fr
Abstract:
The TGFβ signalling pathway is a growth inhibitor system that operates in both normal and tumour cells. Alterations to components of this pathway, including SMAD4, result in resistance to growth inhibition and uncontrolled proliferation. The aim of this study was to analyse the relationships between SMAD4, a key protein in the growth-inhibiting TGFβ pathway; cell proliferation proteins Ki67, p27 and S-phase kinase-associated protein 2 (SKP2); and mismatch repair (MMR) proteins as well as prognostic indicators in colorectal adenocarcinomas. A series of 230 sporadic colorectal adenocarcinomas were studied using tissue microarrays by immunohistochemistry for SMAD4, Ki67, p27, SKP2 and MMR protein (hMLH1, hMSH2 and hMSH6) expression. Protein expression was analysed with respect to pathological prognostic criteria. Loss of SMAD4 nuclear expression (27/230, 12%) correlated with the presence of lymph node metastases, MMR protein expression and the absence of p27 in tumour cells (p = 0.04, p = 0.08 and p = 0.03, respectively). A high Ki67 index did not correlate with SMAD4 expression; however, it did correlate with moderate or poor histological differentiation, SKP2 expression and aberrant or absent MMR protein expression (p = 0.02, p < 0.01 and p < 0.01, respectively). In conclusion, the results of our study suggest that the loss of SMAD4, occurring in 12% of colorectal adenocarcinomas, correlated with the presence of lymph node metastases and absence of p27 expression but not with high cellular proliferation. However, high proliferation correlated with SKP2 and aberrant MMR protein expression. Although the advantage of immunohistochemistry is high throughput, our results allow only an initial evaluation, and subsequent studies, including genetic analyses, are required.
Insights
Loss of SMAD4 in colorectal cancer correlates with metastases and reduced p27, but not proliferation. High proliferation links to SKP2 and mismatch repair (MMR) protein loss.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- The TGFβ signaling pathway regulates cell growth and is often altered in cancer.
- SMAD4 is a key protein in the TGFβ pathway; its alterations can lead to uncontrolled cell proliferation.
- Understanding the interplay of SMAD4, proliferation markers, and mismatch repair (MMR) is crucial for colorectal cancer prognosis.
Purpose of the Study:
- To investigate the relationship between SMAD4 expression, cell proliferation markers (Ki67, p27, SKP2), and MMR proteins in colorectal adenocarcinomas.
- To assess the correlation of these markers with prognostic indicators in colorectal cancer.
- To evaluate the clinical significance of SMAD4 loss in the context of colorectal tumor progression.
Main Methods:
- Utilized immunohistochemistry on tissue microarrays from 230 sporadic colorectal adenocarcinomas.
- Assessed the expression of SMAD4, Ki67, p27, SKP2, and MMR proteins (hMLH1, hMSH2, hMSH6).
- Analyzed protein expression in relation to pathological prognostic criteria, including lymph node status and histological differentiation.
Main Results:
- Loss of SMAD4 nuclear expression (12% of cases) was associated with lymph node metastases, MMR protein expression, and absence of p27 (p=0.04, p=0.08, p=0.03).
- High Ki67 index did not correlate with SMAD4 but was linked to poor differentiation, SKP2 expression, and aberrant MMR protein expression (p=0.02, p<0.01).
- SMAD4 loss did not correlate with high cellular proliferation, while high proliferation was associated with SKP2 and aberrant MMR protein expression.
Conclusions:
- Loss of SMAD4 in colorectal adenocarcinomas correlates with metastatic potential and absence of p27, but not directly with high proliferation.
- High cellular proliferation in these tumors is associated with SKP2 expression and altered MMR protein status.
- While immunohistochemistry offers high-throughput analysis, further genetic studies are needed to fully elucidate these relationships.
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