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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 29  |  Issue : 4  |  Page : 971-978

Immunohistochemical expression of cadherin-17 in normal and nonmalignant liver tissues


1 Department of Pathology, National Liver Institute, Shebin El Kom, Egypt
2 Department of Pathology, Faculty of Medicine, Menoufia University, Shebin El Kom, Egypt

Date of Submission22-Sep-2015
Date of Acceptance13-Nov-2015
Date of Web Publication21-Mar-2017

Correspondence Address:
Shaymaa S El-Gammal
Tala, Menoufia, 32611
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.202518

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  Abstract 

Objectives
Study expression of cadherin-17 (CDH-17) in normal liver tissue and nonmalignant liver diseases.
Background
CDH-17 is present in the fetal liver and gastrointestinal tract during embryogenesis, and becomes silenced in healthy adult liver and stomach tissues. CDH-17 functions as a peptide transporter and a cell adhesion molecule to maintain tissue integrity in epithelia. Aberrant expression of CDH-17 occurs in major gastrointestinal malignancies including hepatocellular carcinoma (HCC), stomach and colorectal cancers and is clinically associated with tumor metastasis and advanced tumor stages. The aim of this study was the identification of expression of CDH-17 in normal liver tissue and nonmalignant liver diseases.
Materials and methods
This retrospective study included 99 cases of nonmalignant liver diseases, divided into 66 cases of cirrhosis adjacent to HCC, 22 cases of cirrhosis without HCC, seven cases of chronic hepatitis C virus infection, two cases of hepatocellular adenoma, two cases of focal nodular hyperplasia in addition to seven cases of donors for liver transplantation as a control group. Paraffin blocks were retrieved from the archives of Department of Pathology, National Liver Institute, Menoufia University during the period between March 2007 and March 2015.
Results
Regarding CDH-17 immunoexpression, 36 out of 66 cases of cirrhosis adjacent to HCC were positive, whereas all cases of each of cirrhosis without HCC, chronic hepatitis C virus infection, hepatocellular adenoma, focal nodular hyperplasia and liver donors were positive. Both the histoscore and the percentage of CDH-17 expression were high significantly increased in cases of cirrhosis without HCC than in cirrhosis with HCC (P < 0.001).
Conclusion
This study revealed positive expression of CHD-17 in normal adult liver tissue and in nonmalignant liver lesions, which may signify that it has the same function as the classical cadherin family.

Keywords: cadherin-17, liver.intestine cadherin, nonmalignant liver tissues


How to cite this article:
El-Azab DS, Ayad HA, Abdelnaby AS, El-Gammal SS. Immunohistochemical expression of cadherin-17 in normal and nonmalignant liver tissues. Menoufia Med J 2016;29:971-8

How to cite this URL:
El-Azab DS, Ayad HA, Abdelnaby AS, El-Gammal SS. Immunohistochemical expression of cadherin-17 in normal and nonmalignant liver tissues. Menoufia Med J [serial online] 2016 [cited 2020 Sep 27];29:971-8. Available from: http://www.mmj.eg.net/text.asp?2016/29/4/971/202518


  Introduction Top


Cadherin-17 (CDH-17), also named as liver–intestine cadherin (LI-cadherin) is a calcium-dependent transmembrane glycoprotein belonging to the seven domain-cadherin family under cadherin superfamily [1].

CDH-17 is known as nonclassical cadherin because of the structural differences from classical cadherin, such as E-cadherin [1]. Structurally, CDH-17 protein has seven extracellular ectodomains, one transmembrane domain, and one intracellular cytoplasmic domain. The cytoplasmic domain of human CDH-17 has only 23 amino acids, whereas other classical cadherins contain 150–160 conserved amino acids forming complexes with catenins [1–3]. The structural difference of CDH-17 makes this molecule unique among the known classical cadherin family members [1],[4].

CDH-17 was first identified in rat liver and small intestine [5]. In human and mouse, expression of CDH-17 is limited to intestinal epithelial cells and in pancreatic ductal epithelial cells and is not found in the liver [2]. Recently it has been reported that CDH-17 is expressed in colorectal [6], gastric [7],[8], and pancreatic cancers [9] as well as in more than 80% of hepatocellular carcinoma (HCC) [6],[10],[11].

Cadherin plays an important role in cell–cell adhesion [12],[13], morphogenesis, and junctional complex development [13],[14]. It functions as a peptide transporter and a cell adhesion molecule to maintain tissue integrity in epithelia. However, recent findings have reported aberrant expression of CDH-17 in major gastrointestinal malignancies [3] including HCC [1],[6],[10],[11], gastric [7],[8], pancreatic [9], and colorectal cancers [6],[15],[16], and its clinical association with tumor metastasis and advanced tumor stages [3]. CDH-17 may intersect with the Wnt pathway through its coordination with E-cadherin and/or associated partners. Together, these observations point toward a potential oncogenic role for CDH-17 in HCC [17]. The role of Wnt-signaling pathway is increasingly recognized in many different tissues, and new data indicate cross-talk with other key cancer pathways regulating angiogenesis, proliferation, invasion, and metastasis [18].

In our study, we worked on a large number and on variable types of nonmalignant liver tissues to assess CDH-17 expression in these groups, as there are only a few previous studies that worked on CDH-17 expression in nonmalignant liver tissue and they used a limited number of cases.

The aim of the present study was to evaluate immune-expression of CDH-17 in adult normal liver tissue and nonmalignant hepatic lesions.


  Materials and Methods Top


This is a case control retrospective study that included 106 liver specimens from 99 Egyptian patients with nonmalignant hepatic lesions divided into 66 cases of cirrhosis adjacent to HCC, 22 cases of cirrhosis without HCC, seven cases of chronic hepatitis C virus (HCV) infection, two cases of hepatocellular adenoma, two cases of focal nodular hyperplasia (FNH) in addition to seven specimens of normal liver tissue (donors for liver transplantation) as a control group. Materials required for analyses (paraffin blocks) were retrieved from the archive of Department of Pathology, National Liver Institute, Menoufia University, during the period between March 2007 and March 2015. The tissue microarray (TMA) construction technique was used in this study.

Tissue microarray construction

  • Hematoxylin and eosin-stained slides were used to identify viable, representative areas of each sample, which is circled with a pilot pen
  • Tissue cores with a diameter of 1.5 µm from the predefined regions of each specimen in the donor paraffin block were punched manually using a needle and arrayed in triplicate on a recipient paraffin block, into a readymade hole, guided by a defined xy position. A control normal tissue was placed in strategic regions throughout the blocks or asymmetrically at one end of the block
  • A TMA construction map was created, indicating the position and origin of each core in the TMA. This map was then used to set up the actual construction of the array. The TMA was divided into different rows designated by capital letters. These quadrants were further separated in a checkerboard order by letters and numbers
  • Sections (4 µm) of these tissue array blocks were cut and placed on positive charged slides and used for immunohistochemical analysis.


Immunohistochemical evaluation was performed according to standard protocols:

  • The streptavidin–biotin-amplified system was used in this work
  • The detection kit was ultravision detection system antipolyvalent horseradish peroxidase/diaminobenzidine (DAB) (ready to use) (cat. #TP-015-HD) (Lab Vision Cooperation 46360, Fremont, California, USA). In this system, two reagents were utilized:
    • The biotinylated secondary anti-immunoglobulin (anti-Ig), which is a purified goat polyvalent antimouse IgG capable of binding to the primary antibody
    • The streptavidin–biotin enzyme complex
  • Finally, the reaction can be visualized by an appropriate substrate/chromogen (DAB) reagent
  • Negative control slides were used for each run of immunohistochemical staining for CDH-17 by omitting the primary antibody
  • Positive control slides (as preferred by the data sheet for the antibody) were used in each run of immunohistochemical staining. Normal human colonic tissue was used as a positive control for CDH-17 primary antibody
  • The primary antibody wasCDH-17 (LI-cadherin): it is a gout monoclonal antibody. It was received as a concentrated antibody in a vial contained 200 µg IgG in 1.0 ml of PBS with less than 0.1% sodium azide and 0.1% gelatin (cat. #sc-6978; Santa Cruz Biotechnology Inc., Santa Cruz, California, USA).


Immunohistochemical staining

CDH-17-positive cells were characterized by the presence of a brownish granular cytoplasmic stain by DAB reaction [6],[10],[19]. Normal human colonic tissue was used as a positive control for CDH-17 primary antibody.

The histoscore (H-score) system was applied to evaluate the studied cases according to a previous study [20].

Statistical analysis

Data were collected, tabulated, and statistically analyzed using statistical package for the social science (SPSS) program for Windows (version 20; SPSS Inc., Chicago, Illinois, USA).

Descriptive statistics

  • Arithmetic mean was used as a measure of central tendency
  • SD was used as a measure of dispersion
  • Percentage
  • Median was used as a measure of central tendency
  • Range was used as a measure of dispersion.


Analytic statistics

  • The χ2-test was used to compare qualitative data such as sex
  • The Mann–Whitney U-test was a nonparametric test used to compare two quantitative variables if they were not normally distributed

    Differences were considered:
    • Statistically significant when P valueis less than and equal to 0.05.
    • Highly significant when P value is less than 0.01.
    • Not significant when P value is greater than 0.05 [21].



  Results Top


Immunohistochemical expression of cadherin-17 in the studied cases of normal liver tissue (donor), hepatitis C virus infection and cirrhosis with and without hepatocellular carcinoma

All cases of normal liver tissue (seven cases) showed positive immunoreactivity for CDH-17 [Table 1] and [Table 2].
Table 1 Clinical data of the studied cases of cirrhosis with and without hepatocellular carcinoma, donors, and hepatitis C virus infection

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Table 2 Immunohistochemical expression of cadherin-17 in donors and in cases with chronic hepatitis C virus infection, cirrhosis without hepatocellular carcinoma and cirrhosis adjacent to hepatocellular carcinoma

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The H-score for cases of normal liver tissue ranged between 20 and 250 with a median of 120 and a mean of 141.4 ± 88.6.

The percentage of CDH-17 expression in cases of liver donors was 100% with a mean of 100 ± 0 and a median of 100%.

All cases of chronic HCV infection (seven cases) showed positive immunoreactivity for CDH-17.

The H-score for chronic HCV infection cases ranged between 30 and 250 with a median of 150 and a mean of 147.1 ± 79.1.

The percentage of CDH-17 expression in cases of chronic HCV ranged between 30 and 100% with a mean of 87.1 ± 26.3 and a median of 100%.

All cases of cirrhosis without HCC (22 cases) showed positive immunoreactivity for CDH-17.

The H-score for CDH-17 ranged between 10 and 270 with a median of 150 and a mean of 157.3 ± 67.6.

The percentage of CDH-17expression in cases of cirrhosis without HCC ranged between 5 and 100% with a mean of 86.4 ± 26.1 and a median of 100%.

A total of 36 out of 66 cases of cirrhosis with HCC (54.5%) showed positive immunoreactivity for CDH-17.

The H-score for CDH-17-positive cases ranged between 20 and 275 with a median of 50 and a mean of 77.7 ± 85.5.

The percentage of CDH-17 expression in cases of cirrhosis with HCC ranged between 10 and 100% with a mean of 45.2 ± 47.3 and a median of 20%.

Immunohistochemical expression of cadherin-17 in the studied cases of hepatocellular adenoma

All cases of adenoma (two cases) showed positive immunoreactivity for CDH-17.

The H-score for adenoma cases was 205 and 110 with a median of 157.5.

The percentage of CDH-17 expression in both cases of adenoma was 100%.

Immunohistochemical expression of cadherin-17 in the studied cases of focal nodular hyperplasia

All cases of FNH (two cases) showed positive immunoreactivity for CDH-17.

The H-score for FNH cases was 240 and 130 with a median of 185.

The percentage of CDH-17 expression in both cases of FNH was 100%.

All cases of chronic HCV infection (seven cases) showed positive immunoreactivity for CDH-17.

Comparison between hepatitis C virus cases and cirrhosis adjacent to hepatocellular carcinoma regarding cadherin-17 expression

There was a statistically significant difference between cases of HCV and cirrhosis adjacent to HCC, regarding CDH-17 expression (P = 0.004) ([Table 3]).
Table 3 Comparison between cases of cirrhosis adjacent to hepatocellular carcinoma and cases of chronic hepatitis C virus infection regarding cadherin-17 expression

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Comparison between hepatitis C virus cases and cirrhosis without hepatocellular carcinoma regarding cadherin-17 expression

There was no statistically significant difference between cases of HCV infection and cirrhosis without HCC and CDH-17 expression (P > 0.05) ([Table 4]).
Table 4 Comparison between cases of cirrhosis without hepatocellular carcinoma and cases of chronic hepatitis C virus infection regarding cadherin-17 expression

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Comparison between cases of hepatitis C virus-associated cirrhosis and cases of cirrhosis not associated with hepatitis C virus infection regarding cadherin-17 expression

There was no statistical association between HCV infection in cirrhotic cases and CDH-17 expression (P > 0.05) ([Table 5]).
Table 5 Comparison between cases of hepatitis C virus-associated cirrhosis and cases of cirrhosis not associated with hepatiwtis C virus infection regarding cadherin-17 expression

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Comparison between cirrhosis adjacent to hepatocellular carcinoma and cirrhosis without hepatocellular carcinoma regarding cadherin-17 expression

Regarding the H-score of CDH-17 expression, there was a highly statistically significant difference between cases of cirrhosis without HCC and cirrhosis with HCC (P < 0.001) ([Table 6]).
Table 6 Comparison between cirrhosis adjacent to hepatocellular carcinoma and cirrhosis without hepatocellular carcinoma regarding cadherin-17 expression

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Regarding the percentage of CDH-17 expression, there was high statistical significance between cases of cirrhosis without HCC and cirrhosis with HCC (P < 0.001) [Figure 1],[Figure 2],[Figure 3],[Figure 4],[Figure 5],[Figure 6],[Figure 7].
Figure 1: A donor tissue with normal liver histology showing positivity for cadherin-17 in the form of granular staining of the cytoplasm. Immunohistochemical. ×200.

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Figure 2: A case of chronic hepatitis C virus infection with portal fibrosis and inflammation associated with parenchymalnecro.inflammation showing positivity for cadherin-17 in the form of granular staining of the cytoplasm. Immunohistochemical. ×100.

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Figure 3: A case of chronic hepatitis C virus showing positivity for cadherin-17 in the form of granular staining of the cytoplasm. Immunohistochemical. ×400.

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Figure 4: A case of liver cirrhosis showing multiple regenerative nodules and portal fibrosis (6/6) according to the Ishak scoring system, showing positivity for cadherin-17 in the form of granular staining of the cytoplasm. Immunohistochemical ×100.

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Figure 5: A case of liver cirrhosis showing positivity for cadherin-17 in the form of granular staining of the cytoplasm. Immunohistochemical. ×200.

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Figure 6: A case of focal nodular hyperplasia showing positivity for cadherin-17 in the form of granular staining of the cytoplasm. Immunohistochemical. ×100 with magnification of this photo. (red arrow).

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Figure 7: A case of hepatocellular adenoma showing positivity for cadherin-17 in the form of granular staining of the cytoplasm. Immunohistochemical. ×100 with magnification of this photo. (red arrow).

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  Discussion Top


LI-cadherin (CDH-17) is a calcium-dependent transmembrane glycoprotein [4] and functions as a peptide transporter and a cell adhesion molecule to maintain tissue integrity in epithelia [3].

CDH-17 is an oncofetal protein of the liver. Its expression is absent in normal adult liver [7],[8] and an up-regulation of CDH-17 expression occurs in malignant tissues of HCC. The aberrant expression of CDH-17 in liver cancer was first identified in 2003 in a previous study [10]. An increase in CDH-17 expression in HCC cell lines and in 80% of HCC clinical specimens was identified in another study [2].

In the current study, we included a large number (106 cases) of variable types of nonmalignant liver tissues, including seven cases of normal liver tissue obtained from donors for liver transplantation, seven cases of chronic HCV infection, 22 cases of cirrhosis without adjacent HCC, 66 cases of cirrhosis adjacent to HCC, two cases of hepatocellular adenoma and two cases of FNH.

The present study revealed positive CDH-17 immunoexpression in all donor liver tissue (seven cases), all cases of chronic HCV (seven cases), all cases of cirrhosis without HCC (22 cases), all cases of hepatocellular adenoma (two cases), all cases of FNH (two cases), and 54.5% cases of cirrhosis adjacent to HCC (36 out of 66 cases). The H-score of CHD-17-positive expression in the nonmalignant liver cases ranged between 10 and 270 with a median of 150 and a mean ± SD of 106.5 ± 88.2. The percentage of CHD-17 expression ranged between 0 and 100 with a median of 100% and a mean ± SD of 80.5 ± 33.8. These findings denoted that CDH-17 is expressed in nonmalignant liver tissues. These results disagree with previous studies that reported an absence of CDH-17 expression in normal liver tissue [3],[6],[10],[11],[22]. Other study reported weak patchy cytoplasmic expression of CDH-17 in normal hepatocytes [15]. The differences in the results between our study and previous studies may be due to differences in the methodology and interpretation. We used goat monoclonal antibody whereas other studies used a mouse monoclonal antibody [3],[11],[15]. We also considered granular cytoplasmic staining to be a positive result according to previous studies [6],[10],[19], and according to the data sheet of CDH-17 (LI-cadherin) of Santa Cruz Biotechnology, but other studies considered membranous staining as a positive result [11],[15]. Also, in this study, we worked on formalin-fixed paraffin-embedded tissue blocks, whereas in another study, frozen sections were used [10].

To the best of our knowledge, there are no previous researches that worked on CDH-17 expression in nonmalignant liver lesions. Positive expression of CDH-17 in nonmalignant liver diseases can be explained by the fact that being a member of the cadherin superfamily, CDH-17 may mimic members of classical cadherin family such as E-cadherin, which are normally expressed in normal adult liver tissue and in nonmalignant liver diseases, and thus play an important role in cell–cell adhesion and tissue stability [23],[24].

In this study, there was a statistically significant difference between cases of HCV and cirrhosis adjacent to HCC, regarding CDH-17 expression. However, we could not find a clear explanation for this result.

In the current study, there was a highly statistically significant difference between cases of cirrhosis without adjacent HCC and cases of cirrhosis with adjacent HCC regarding both the H-score and the percentage of CDH-17 expression, as both the H-score and the percentage of CDH-17 expression were much higher in cases of cirrhosis without HCC. There are no previous researches that compared CHD-17 expression in these two groups of cirrhosis. We can explain this by the possibility that downregulation of CDH-17 expression occurs in premalignant liver tissues due to structural changes during the process of carcinogenesis with loss of intercellular adhesiveness, tumor dedifferentiation and an invasive potential.

Finally, using goat monoclonal CDH-17 antibody, this study revealed positive expression of CHD-17 in normal adult liver tissue and in nonmalignant liver lesions, with some downregulation in cases of cirrhosis adjacent to HCC. With these results, we concluded positive expression of CHD-17 in normal adult liver tissue and in nonmalignant liver lesions, which may signify that it has the same function as the classical cadherin family.

Recommendations

  • Future studies are recommended on large-scale multicenter levels
  • Future studies are recommended to study the expression of CDH-17 in HCC cases
  • Further studies are recommended to assess the potential therapeutic role of CDH-17.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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