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  Table of Contents    
ORIGINAL ARTICLE  
Year : 2011  |  Volume : 54  |  Issue : 1  |  Page : 32-36
Clinicopathologic significance of fascin, extracellular matrix metalloproteinase inducer, and ezrin expressions in colorectal adenocarcinoma


1 Department of Surgery, Konkuk University College of Medicine, Seoul, South Korea
2 Department of Pathology, Korea University College of Medicine, Seoul, South Korea
3 Department of Surgery, Korea University College of Medicine, Seoul, South Korea

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Date of Web Publication7-Mar-2011
 

   Abstract 

Background: The over expression of fascin, extracellular matrix metalloproteinase inducer (EMMPRIN), and ezrin proteins has been associated with poor prognosis in various carcinomas and sarcomas. However, very few studies have reported the relationship between the expression of fascin, EMMPRIN, and ezrin proteins and the clinico-pathologic parameters of colorectal carcinomas. Aims: The aim was to investigate the relationship between fascin, EMMPRIN, and ezrin proteins in colorectal adenocarcinomas and their correlation with clinico-pathologic parameters. Settings and Design: The expression of fascin, EMMPRIN, and ezrin proteins was studied in 210 colorectal adenocarcinoma patients through immunohistochemical staining. Materials and Methods: Immunohistochemical staining by the avidin-biotin peroxidase method was done. The scoring of each protein expression was done and divided into three groups (negative, low-, and high-expression groups). Statistical Analysis: A chi-square test, and Kendall's tau-b correlation test were used for comparing. Survival analysis was performed using the Kaplan-Meier method with log-rank tests and the Cox proportional hazard model. Results: The percentages of the high-expression group of fascin, EMMPRIN, and ezrin proteins in colorectal adenocarcinomas were 24%, 73%, and 62%, respectively. Weak positive correlations were observed among these protein expressions. An increased expression of the fascin protein was significantly associated with advanced tumor depth and shorter survival times, and a high expression of fascin protein was an independent prognostic factor in univariate and multivariate survival analyses. EMMPRIN and ezrin protein expressions were not associated with the clinico-pathologic parameters. Conclusions: The high expression of fascin protein may be an unfavorable prognostic marker for individual colorectal cancer patients.

Keywords: Colorectal cancer, extracellular matrix metalloproteinase inducer, ezrin, fascin, prognosis

How to cite this article:
Jung EJ, Lee JH, Min BW, Kim YS, Choi JS. Clinicopathologic significance of fascin, extracellular matrix metalloproteinase inducer, and ezrin expressions in colorectal adenocarcinoma. Indian J Pathol Microbiol 2011;54:32-6

How to cite this URL:
Jung EJ, Lee JH, Min BW, Kim YS, Choi JS. Clinicopathologic significance of fascin, extracellular matrix metalloproteinase inducer, and ezrin expressions in colorectal adenocarcinoma. Indian J Pathol Microbiol [serial online] 2011 [cited 2019 Nov 22];54:32-6. Available from: http://www.ijpmonline.org/text.asp?2011/54/1/32/77320



   Introduction Top


Fascin is an actin-binding protein that rearranges the cytoskeleton and promotes cellular motility. [1],[2] Recently, the overexpression of fascin has been reported in carcinomas of different organs including colon, stomach, breast, and lung. [3],[4],[5],[6],[7],[8] Moreover, the over-expression of fascin has been shown to correlate with poor prognosis. [3],[4],[5],[6],[7],[8] Extracellular matrix metalloproteinase inducer (EMMPRIN), also known as CD147, is a trans-membrane protein that stimulates matrix metalloproteases (MMPs). [9],[10],[11] High expression of EMMPRIN protein has been observed in various carcinomas including colorectal cancers. [12] Ezrin is a membrane cytoskeleton linker and is involved in cell adhesion, cell survival, cell motility, and metastasis of some sarcomas and carcinoma. [13],[14],[15],[16],[17]

However, the relationship between the expression of fascin, EMMPRIN, and ezrin proteins and the clinico-pathologic parameters of colorectal carcinomas remains incompletely defined. In this study, we compared the expression of fascin, EMMPRIN, and ezrin proteins with clinicopathologic parameters of 210 colorectal adenocarcinoma patients. In addition, we evaluated the relationship among fascin, EMMPRIN, and ezrin expressions. We also tested the hypothesis that increased expression of these proteins has prognostic significance in colorectal carcinomas.


   Materials and Methods Top


Patients

A cohort of archival formalin-fixed, paraffin-embedded specimens was selected from 210 patients who underwent surgical resection between June 1997 and December 2000. The selection of specimens was predicated on the availability of complete clinical follow-up information, and on the availability of the corresponding paraffin blocks for immunohistochemical studies. The 210 patients included 114 males and 96 females, mean age = 58 (range: 16-83) years. None of the patients had received chemotherapy or radiation therapy before surgery. Clinicopathologic data were based on the original pathologic reports and the patients' clinical records. According to the TNM system, there were 15 Stage I cases, 102 Stage II cases, 81 Stage III cases, and 12 Stage IV cases. [18] Informed consent was obtained from all patients.

Tissue Array and Immunohistochemistry

Core biopsies of the representative areas of the corresponding paraffin blocks were taken with a precision instrument. We selected one central and one peripheral portion in each colorectal cancer. Immunohistochemical interpretation was performed in all field of each case. Two tissue cores from each specimen, with a diameter of 2 mm each, were punched out and arrayed on a recipient paraffin block. Each block contained an internal control consisting of non-neoplastic colonic mucosa. These tissue array blocks were cut into 4 μm sections, which were used for the immunohistochemical analysis.

The avidin-biotin complex (ABC) method was used for immunostaining. Primary monoclonal antibodies against fascin (FCN01, Thermo, CA, USA, 1:100), EMMPRIN (AB1843, Novocastra, UK, 1:100), and ezrin (3C12, Zymed, CA, USA, 1:100) were used. In the evaluation of immunohistochemical staining, both the intensity and the percentage of positive stained tumor cells were recorded. A staining index (with values from 0 to 9) was obtained as the intensity of staining (negative = 0, weak = 1, moderate or strong = 3) times the proportion of immunopositive tumor cells (<10% = 1, 10-50% = 2, >50% = 3). We interpreted a staining index of 0-2 as the negative group, 3-5 as the low-expression group, and 6-9 as the high-expression group.

Statistical Analysis

Statistical significance was evaluated using the chi-square test for the expression of each protein according to clinico-pathologic parameters. Kendall's tab-b correlation test was used to determine the relation among the expression of the three proteins. Univariate and multivariate analyses were performed using the Kaplan-Meier method with log-rank tests and the Cox proportional hazard model, respectively. Significance was assumed if the P-values were less than 0.05. All statistical analyses were performed using the SPSS statistical software package (version 10.0; SPSS Inc., USA).


   Results Top


No staining of fascin protein was observed in normal colonic mucosa, but it was detected in normal blood vessels [Figure 1]a. Both EMMPRIN and ezrin proteins were expressed focally in normal colonic mucosa [Figure 1]b. Staining patterns of fascin, EMMPRIN, and ezrin proteins in tumor cells were seen in cell membrane and in the cytoplasm [Figure 1]c and d. Of the 210 colorectal adenocarcinomas, 51 (24%) cases were of the high-expression group, 32 (15%) cases of the low-expression group, and 127 (61%) cases were of the negative group for fascin protein. One hundred fifty-three (73%) cases were of the high-expression group, 45 (21%) cases were of the low-expression group, and 12 (6%) cases were of the negative group for EMMPRIN protein. One hundred thirty (62%) cases were of the high-expression group, 65 (31%) cases were of the low-expression group, and 15 (7%) cases were of the negative group for ezrin protein.
Figure 1: Immunohistochemical expression of fascin, EMMPRIN, and ezrin proteins in colorectal carcinoma. Negative (a) and focally positive (b) expression of fascin and ezrin proteins in normal colonic mucosa (IHC, ×200). Strong cytoplasmic and membranous expression of fascin (c) and EMMPRIN (d) proteins in tumor cells (IHC, ×200)

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As shown in [Table 1], the increase in fascin protein expression was significantly correlated with advanced tumor depth (P = 0.035), but it was not associated with age, sex, lymph node metastasis, distant metastasis, and TNM stage. Increased expression of EMMPRIN and ezrin proteins was not associated with age, sex, tumor depth, lymph node metastasis, distant metastasis, and TNM stage.
Table 1: Fascin, EMMPRIN, and ezrin expressions according to clinicopathologic parameters

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Weak positive correlations were observed among the expressions of the three proteins [Table 2]. A very weak correlation was observed between fascin and EMMPRIN expression (Kendall's tab-b correlation coefficient = 0.132, P = 0.042). There were weak correlations between fascin and ezrin expressions (Kendall's tab-b correlation coefficient = 0.344, P < 0.001), and between EMMPRIN and ezrin expressions (Kendall's tab-b correlation coefficient = 0.391, P < 0.001).
Table 2: The correlation of fascin, EMMPRIN, and ezrin protein expressions

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In univariate survival analyses, lymph node metastasis (present versus absent; P < 0.001), distant metastasis (present versus absent; P < 0.001), advanced TNM stage (III, IV versus I, II; P < 0.001), and fascin protein expression (high-expression group versus low-expression or negative group; P = 0.016) [Figure 2] correlated with poor overall survival. However, age (P = 0.188), sex (P = 0.411), tumor depth (T3, 4 versus T1, 2; P = 0.181), EMMPRIN protein expression (high-expression group versus low-expression or negative group; P = 0.263), and ezrin protein expression (high-expression group versus low-expression or negative group; P = 0.855) did not correlate with overall survival.
Figure 2: Overall survival rate according to fascin protein expression. The survival curve shows that low- or negative expression group of fascin protein is favorable survival outcome than the high-expression group of fascin protein (P = 0.016)

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In multivariate survival analysis, distant metastasis (hazard ratio [HR]: 5.797; 95% confidence interval [CI]: 2.641-12.722; P < 0.000), lymph node metastasis (HR: 3.625; 95% CI: 1.872-7.021; P < 0.000), and high expression of fascin protein (HR: 1.373; 95% CI: 1.012-1.865; P = 0.042) correlated with overall survival.


   Discussion Top


The invasion and metastasis of carcinoma cells require an increase in extracellular matrix (ECM) proteases, decreased cell-cell adhesion, and altered expression of cellactin interaction is regulated by -ECM adhesion receptors. [1],[2] The rearrangement of the actin cytoskeleton is also important for the invasion of tumor cells. [1],[2] The fascin-ECM, peptide factors, and other actin-binding proteins.

A few studies have demonstrated the relationship between the overexpression of fascin protein and clinicopathologic parameters in colorectal carcinoma. [3],[4],[5] Hashimoto et al.[3] and Puppa et al.[4] reported that the overexpression of fascin protein was significantly associated with poor prognosis and with a decreased survival rate in stage III-IV colorectal carcinomas. Tsai et al.[5] reported that the increased expression of fascin protein significantly correlated with TNM stage and grade. Recently, Vignjevic et al.[19] reported that fascin was expressed at the invasive front of colon cancer. In this study, over-expression of fascin protein significantly correlated with advanced tumor depth and with poor overall survival rates, but not with lymph node metastasis or distant metastasis. Because fascin protein can be easily examined at the time of conventional pathologic diagnosis of colorectal cancer, it may be used as a prognostic marker of colorectal adenocarcinoma in addition to known prognostic indicators.

EMMPRIN is known to be a stimulator of MMPs, which lead to tumor invasion. [9],[10],[11] Recently, Xie et al.[20] reported that the effect of fascin on tumor cell invasion depended on the activation of MMP-2 and MMP-9. However, the relationship between fascin and EMMPRIN proteins in colorectal cancers has not been previously investigated. Our study showed a weak positive correlation between fascin and EMMPRIN expression. We have also demonstrated weak positive correlations between ezrin and the other two proteins. This result may suggest that a relationship exists between these proteins that creates a synergistic effect during tumor invasion.

Studies have reported that clinico-pathologic parameters in colorectal cancers are related to EMMPRIN and ezrin expression. Jin et al.[21] reported that EMMPRIN over expression was observed in colorectal carcinoma compared to normal mucosa, but EMMPRIN over expression did not correlate with the TNM stage. This study also showed that the EMMPRIN over expression was not associated with clinico-pathogic parameters. Elzagheid et al.[22] reported that ezrin over expression was significantly associated with poor survival outcomes in colorectal cancers; however, our results did not show a significant correlation between overexpression of ezrin protein and clinico-pathologic parameters.

In conclusion, the over expression of fascin protein may be an effective prognostic marker in colorectal cancer patients. The clinicopathologic significance of EMMPRIN and ezrin proteins may not be evident in colorectal cancers.

 
   References Top

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Correspondence Address:
Jong Sang Choi
Department of Pathology, Korea University College of Medicine, 126-1, 5Ga, Anam-dong, Seongbuk-gu, Seoul - 136 701
South Korea
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.77320

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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]

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