S100A4 over-expression underlies lymph node metastasis and poor prognosis in colorectal cancer

Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
World Journal of Gastroenterology (Impact Factor: 2.37). 01/2011; 17(1):69-78. DOI: 10.3748/wjg.v17.i1.69
Source: PubMed


To develop lymph node metastasis (LNM)-associated biomarkers for colorectal cancer (CRC) using quantitative proteome analysis.
Differences in protein expression between primary CRC with LNM (LNM CRC) and without LNM (non-LNM CRC) were assessed using methyl esterification stable isotope labeling coupled with 2D liquid chromatography followed by tandem mass spectrometry (2D-LC-MS/MS). The relationship to clinicopathological parameters and prognosis of candidate biomarkers was examined using an independent sample set.
Forty-three proteins were found to be differentially expressed by at least 2.5-fold in two types of CRC. S100A4 was significantly upregulated in LNM CRC compared with non-LNM CRC, which was confirmed by Western blotting, immunohistochemistry and real-time quantitative polymerase chain reaction. Further immunohistochemistry on another 112 CRC cases showed that overexpression of S100A4 frequently existed in LNM CRC compared with non-LNM CRC (P<0.001). Overexpression of S100A4 was significantly associated with LNM (P<0.001), advanced TNM stage (P<0.001), increased 5-year recurrence rate (P<0.001) and decreased 5-year overall survival rate (P<0.001). Univariate and multivariate analyses indicated that S100A4 expression was an independent prognostic factor for recurrence and survival of CRC patients (P<0.05).
S100A4 might serve as a powerful biomarker for LNM and a prognostic factor in CRC.

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Available from: Li Qi Xie, Nov 11, 2014
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    • "Overexpression of S100A4 has been implicated in tumor growth, angiogenesis, epithelial-mesenchymal transition (EMT), extracellular matrix remodeling and metastasis 16, 17. Thus, S100A4 is assumed to be a marker for poor prognosis and high risk of distant metastasis 3, 7, 8. However, the precise role and potential molecular mechanism of S100A4 in CRC tumorigenesis still remain to be fully elucidated. "
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    ABSTRACT: The S100 protein family member S100A4 regulates various cellular functions. Previous studies have shown that elevated expression of S100A4 is associated with progression and metastasis of colorectal cancer (CRC). However, little is known about whether and how S100A4 contributes to CRC development. In our present study, the elevated expression of S100A4 in CRC tissues compared to matched adjacent normal tissues was confirmed by immunohistochemistry, semi-quantitative RT-PCR and Western blot. Adenovirus-mediated S100A4 overexpression obviously enhanced viability and migration of CRC cells, which was detected by MTT assay and transwell assay, respectively. Additionally, S100A4 overexpression increased the phosphorylation levels of Akt, mTOR and p70S6K. These effects of S100A4 were abolished by treatment with either the specific PI3K/Akt inhibitor LY294002, or the specific mTOR/p70S6K inhibitor rapamycin. Furthermore, overexpression of S100A4 resulted in upregulation of VEGF and downregulation of E-cadherin, which were strongly reversed by either LY294002 or rapamycin. Altogether, our results demonstrate that activation of the PI3K/Akt/mTOR/p70S6K signaling pathway is involved in S100A4-induced viability, migration, upregulation of VEGF and downregulation of E-cadherin in CRC cells.
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    • "Nevertheless, inconsistent data have emerged regarding the ability of S100A4 to predict disease progression and survival in CRC. Multiple studies have shown that CRC patients with S100A4 overexpression have worse overall survival (OS) and disease-free survival (DFS) [17,21,23,24,26,27,29,32]; however, one study failed to achieve statistical significance on this association in a multivariate analysis [22]. "
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    ABSTRACT: Accumulated evidence has indicated a correlation between S100A4 expression and colorectal cancer (CRC) progression. However, its prognostic significance for patients with CRC remains inconclusive. To clarify their relationship, a meta-analysis of the relevant published studies was performed. PubMed, Cochrane Library, and Web of Science databases were electronically searched. All studies evaluating the prognostic value of S100A4 expression in CRC patients regarding survival and a series of clinicopathological parameters were included. The effect of S100A4 expression on the overall survival (OS) and disease-free survival (DFS) were measured by pooled hazard ratios (HRs) and 95% confidence intervals (CIs), while the effect of S100A4 expression on the clinicopathological parameters were measured by the pooled odds ratios (ORs) and their 95% CIs. Eleven studies (2,824 patients in total) were included in the meta-analysis. Overall, S100A4 overexpression was significantly associated with worse OS (HR = 1.90, 95% CI: 1.58--2.29, P <0.001), and worse DFS (HR = 2.16, 95% CI: 1.53--3.05, P <0.001) in patients with CRC. Subgroup analyses showed that S100A4 overexpression was significantly correlated with poor OS in Asian, European, and Australian patients and patients treated with surgery or chemotherapy. Additionally, there were significant associations between S100A4 expression and several clinicopathological parameters (tumour location, lymph node metastasis, nodal status, TNM stage, and tumour depth). This meta-analysis indicates that S100A4 overexpression seems to correlate with tumour progression and poor prognosis of CRC patients. It may be a useful marker to predict progression and prognosis of CRC.Virtual slidesThe virtual slide(s) for this article can be found here:
    Full-text · Article · Nov 2013 · Diagnostic Pathology
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    • "Overexpression was shown to be associated with lymph node metastasis, advanced TNM stage, and poor outcomes (ie, increased recurrence and decreased overall survival), but not Duke subtypes of CRC (99-101). Thus, it was suggested that S100A4 may be necessary for dissemination to distant metastatic sites rather than for local tumor invasion, and it could possibly be a good biomarker for metastasis and prognosis (102). Boye et al. have identified differences in CRC prognosis in terms of cellular localization. "
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    ABSTRACT: Clinical and experimental studies have suggested a link between S100 gene ex-pression and neoplastic disorders, however, the molecular mechanisms of this associa-tion are not well understood. The aim of this review was to conduct a comprehensive literature search in order to understand the possible underlying molecular mechanisms of this association. We also discuss their application as diagnostic and prognostic mark-ers in colorectal and hepatocellular carcinoma. EVIDENCE ACQUISITIONS: We searched Pubmed (NLM) and Web of Science (ISI Web of Knowledge). S100 genes display a complex expression pattern in colorectal and hepatocel- lular carcinoma. They are expressed in tumor and/or tumor stroma cells, and they exert both pro- and antitumorigenic actions. In view of this complexity, it becomes clear that S100 proteins might act as both friend and foe. The biological role of the S100 genes is predicted to depend on the relative contributions of the different cell types at specific stages of tumor progression. Further research is required in order to uncover the functional role of S100 genes in tumorigenesis. Answers to this issue are needed before we can more fully un-derstand the clinical relevance of S100 protein expression within epithelial tumors, with regard to their potential applicability as biomarkers for diagnosis and therapy decisions.
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