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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 34  |  Issue : 2  |  Page : 605-610

Role of cytoplasmic localization of discoidin domain receptor 1 in basal-cell carcinoma


1 Department of Pathology, Venereology and STDs, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Dermatology, Venereology and STDs, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Student's Hospital, General Administration of Medical Affairs, Sadat University, Sadat City, Egypt

Date of Submission09-Sep-2019
Date of Decision24-Oct-2019
Date of Acceptance28-Oct-2019
Date of Web Publication30-Jun-2021

Correspondence Address:
May E Attia
Shebin El-Kom, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_281_19

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  Abstract 


Objective
The objective of this study was to investigate the role of discoidin domain receptors (DDR1) in the pathogenesis of basal-cell carcinoma (BCC) through its immunohistochemical expression and to correlate its expression with clinicopathological parameters.
Background
BCC is the most common type of nonmelanoma skin cancer. The pathogenesis is usually combined with environmental factors, mainly ultraviolet irradiation through long-term sun exposure.
Patients and methods
This retrospective case–control study was carried out on 77 patients presented with BCC and 20 age-matched and gender-matched apparently healthy volunteers. Skin biopsies from controls and BCC cases were retrieved from the archives of Pathology Department, Faculty of Medicine, Menoufia University for histopathological and immunohistochemical DDR1 evaluation.
Results
Cytoplasmic localization of DDR1 could be incriminated in the development and progression of BCC. DDR1 offers potential targeted therapy in cancer, as none of the control groups showed cytoplasmic epithelial localization DDR1, whereas (90.9%) cytoplasmic epithelial localizations were demonstrated in BCC (P < 0.001). A significant difference between BCC and control group regarding DDR1 expression in stroma was noted (P < 0.002). There was also significant association between cytoplasmic localization of DDR1 and head and neck localization and ulcer clinical presentation (P > 0.001 and 0.005, respectively).
Conclusion
Cytoplasmic localization of DDR1 has a role in the pathogenesis of BCC which can be a new therapeutic target in BCC.

Keywords: basal-cell carcinoma, discoidin domain receptor 1, immunohistochemistry, pathogenesis


How to cite this article:
Samaka RM, Basha MA, Attia ME. Role of cytoplasmic localization of discoidin domain receptor 1 in basal-cell carcinoma. Menoufia Med J 2021;34:605-10

How to cite this URL:
Samaka RM, Basha MA, Attia ME. Role of cytoplasmic localization of discoidin domain receptor 1 in basal-cell carcinoma. Menoufia Med J [serial online] 2021 [cited 2024 Mar 28];34:605-10. Available from: http://www.mmj.eg.net/text.asp?2021/34/2/605/319685




  Introduction Top


Skin cancer is one of the most common cancers in the world. Nonmelanoma skin cancer (NMSC) refers to a group of cancers that slowly develop in the upper layers of the skin [1].

The two most common types of NMSCs are basal-cell carcinoma (BCC) and squamous-cell carcinoma. BCC starts in the cells lining the bottom of the epidermis and accounts for about 75% of skin cancers [2].

BCC is the most common malignancy in fair-skinned population worldwide in populations with high levels of ultraviolet (UV) radiation exposure [3].

The pathogenesis of BCC is usually combined with environmental factors, mainly UV irradiation through long-term sun exposure. UV-light can randomly induce DNA damage in keratinocytes and exposure to indoor tanning is a risk factor for early-onset BCC [4].

Discoidin domain receptors (DDRs), DDR1 and DDR2, lie at the intersection of two large receptor families, namely the extracellular matrix and tyrosine kinase receptors (RTKs). As such, DDRs are uniquely positioned to function as sensors for extracellular matrix and to regulate a wide range of cell functions [5].

Almost all human cancers display dysregulated expression and/or function of one or more RTKs. The strong causative association between altered RTK function and cancer progression has been translated into novel therapeutic strategies that target these cell surface receptors in cancer [6].

The full spectrum of RTKs that may alter the oncogenic process is not completely understood. Thus, there is still a considerable gap in our knowledge of DDR actions in cancer tissues [6].

Both DDRs have been implicated in cancer progression[7]. In solid tissues, DDR1 expression is restricted to epithelial tumors such as renal cell carcinoma, ovarian carcinoma, and esophageal cancer [8].

Therefore, the aim of this study is to assess the role of DDR1 in the pathogenesis of BCC through its immunohistochemical (IHC) expression and to correlate its expression with clinicopathological parameters.


  Patients and methods Top


This retrospective case–control study was carried out on 77 patients presented with BCC and 20 age-matched and gender-matched apparently healthy volunteers. Skin biopsies from controls and cases were taken for histopathological and IHC DDR1 evaluation and collected from the archives of Pathology Department, Faculty of Medicine, Menoufia University during the period from January 2017 to December 2018.

Inclusion criteria: all cases of BCC.

Exclusion criteria: all cases of NMSC except BCC and MSC.

A written consent form approved by The Local Ethics Research Committee of Menoufia Faculty of Medicine was obtained from every subject before the study initiation.

Tissue microarray

All formalin-fixed, paraffin-embedded tissues of BCC were carefully assessed by Hematoxylin and Eosin staining to choose the most proper sections. Then tissue microarray was done.

Clinicopathological data

Clinical parameters including age, sex, localization, and clinical presentation.

Pathological parameters including size, margin, lymphovascular invasion, perineural invasion, and extent of staining.

Immunohistochemistry

Sections were cut at 5 μm and stained as follows: They were dewaxed and rehydrated in graded alcohol solutions. For heat retrieval, the sections were placed in citrate buffer (1: 10 dilution, pH: 7.2) and heated at 120°C for 3–5 min. Endogenous peroxidase activity was neutralized using a peroxidase block for 5 min. Nonspecific binding was blocked by preincubation with a protein block for 5 min at room temperature. Slides were then incubated for 1 h at room temperature with the primary diluted antibodies, rabbit polyclonal antibodies raised against DDR1 at a dilution of 1/100. The slides were washed with PBS (2–5 min) and then incubated with secondary antibody for 10 min. The color reaction was developed in diaminobenzidine for 5 min. Sections were then counterstained with hematoxylin, dehydrated, and mounted. Positive control slides were prepared of formalin-fixed tissues of breast carcinoma. Negative control slides were prepared, by omitting the primary antibodies from the staining procedure [9].

Immunohistochemical interpretation

Expression of DDR1 was assessed in all groups. DDR1 positivity and localization either cytoplasmic or membranocytoplasmic were assessed [10].

Statistical analysis

The statistical analysis is conducted using the Statistical Package for the Social Sciences (SPSS), version 20 on IBM compatible computer (SPSS Inc., Chicago, Illinois, USA). Qualitative data are expressed as number and percentage. Quantitative data are expressed as: arithmetic mean, SD, percentage, and median. χ2-test was used for comparing qualitative variables. Student's t-test was used in comparing between two groups having quantitative parametric variables while Mann–Whitney U-test was used in comparing two nonparametric quantitative variables.

Spearman's correlation coefficient test (r-test) was used to study the correlation between nonparametric quantitative variables. The results were considered statistically significant for P less than or equal to 0.05 and highly significant for P less than 0.01.


  Results Top


Comparison between control group and basal-cell carcinoma regarding demographic data (age, sex, and localization) [Table 1].
Table 1: Comparison between control group and basal-cell carcinoma regarding demographic data (age, sex, and localization)

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There was no significant difference between control group and BCC.

Clinicopathological parameters of basal-cell carcinoma is demonstrated in [Table 2].
Table 2: Clinicopathological parameters of basal-cell carcinoma

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Comparison between basal-cell carcinoma and control group regarding immunohistochemical expression of DDR1 [Table 3].
Table 3: Comparison between basal-cell carcinoma and control groups regarding immunohistochemical expression of discoidin domain receptor 1

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None of the control groups showed cytoplasmic epithelial localization DDR1 whereas (90.9%) cytoplasmic epithelial localization was significantly demonstrated in BCC (P < 0.001) [Figure 1], [Figure 2], [Figure 3], and there was a significant difference between BCC and control group regarding DDR1 expression in stroma (P < 0.002) [Figure 4].
Figure 1: Section of apparently normal skin showing discoidin domain receptor 1 diffuse membranocytoplasmic localization in the epidermis (discoidin domain receptor 1 immunohistochemical, ×400).

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Figure 2: Basal-cell carcinoma. (a) Tumor cells showed diffuse discoidin domain receptor 1 cytoplasmic localization; (b) higher magnification of (a). Discoidin domain receptor 1 immunohistochemical, ×100 for a and ×200 for b.

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Figure 3: Discoidin domain receptor 1: Localization vs control group.

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Figure 4: Stromal status of discoidin domain receptor 1 in basal-cell carcinoma vs control group.

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Relation between discoidin domain receptor 1 localization in tumor and clinical data of basal-cell carcinoma.

There was a significant association between cytoplasmic localization of DDR1 and head and neck localization (P > 0.001) [Table 4] and [Figure 5]; whereas a significant association between membrano-cytoplasmic localization of DDR1 and nodular clinical presentation was noted as membranocytoplasmic (100%) whereas (55.7%) of cytoplasmic localization were presented with ulcer (P = 0.005) [Table 4] and [Figure 6].
Table 4: Relation between discoidin domain receptor1 localization in tumor and clinical data of basal-cell carcinoma

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Figure 5: Discoidin domain receptor 1: Cellular localization regarding clinical site of basal-cell carcinoma.

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Figure 6: Discoidin domain receptor 1: Cellular localization regarding clinical presentation of basal-cell carcinoma.

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  Discussion Top


There is scarce information about the role of DDR1 in NMSC especially BCC; therefore, the aim of this study was to investigate the role of DDR1 in the pathogenesis of BCC though its IHC expression and to correlate its expression with clinicopathological parameters.

In the current study all control group showed positive DDR1 IHC expression.

DDR1 is expressed by keratinocytes but its role has not yet been explored [11],[12]. Di Marco et al. [13] hypothesized that DDR1 represents the nerve growth factor receptor and acts solely as a growth-mediating RTK and not as a potential adhesion molecule. However, the exact role of DDR1 in normal skin is not thoroughly assessed. Therefore, other studies are recommended.

All BCC cases were positive in tumor cells while 96.1% were positive in the surrounding stroma in this study. To the best our knowledge, this is the first study trying to demonstrate the role of DDR1 in BCC through IHC expression.

A unique set of RTKs known as the DDRs play a key role in cancer progression by regulating the interactions of tumor cells with their surrounding collagen matrix [6].

DDR1 is mostly activated by type I and type IV collagens. In contrast with classical growth factor RTKs which display a rapid and transient activation, DDR1 and DDR2 are unique in that they exhibit delayed and sustained receptor phosphorylation on binding to the collagen. Studies that show expression and mutations of DDR1 in several cancer types also indicate clearly that these receptors must be considered as new players in the different aspects of tumor progression, from nonmalignant to malignant and invasive stages [14].

In our study, DDR1 cytoplasmic localization was demonstrated in BCC; however, none of the control cases showed cytoplasmic topographic localization.

Signaling pathways activated by DDRs ligand binding to RTKs lead to phosphorylation of distinct cytoplasmic tyrosine residues, which serve as docking sites for the assembly of downstream signaling molecules that are recruited to the receptor [15].

The observation of cytoplasmic expression of DDR1 in BCC and significant association with ulcer clinical presentation suggest that this receptor might be involved in the development and progression of cancer.

In cancer, DDRs are hijacked by tumor cells to disrupt normal cell-matrix communication and initiate promigratory and proinvasive programs. Importantly, several cancer types exhibit DDR mutations, which are thought to alter receptor function and contribute to cancer progression [6]. DDR1 has many functions such as migration and proliferation to cytokine secretion and extracellular matrix homeostasis/remodeling [5]. Other evidence suggests that the actions of DDRs in cancer are complex, either promoting or suppressing tumor cell behavior in a DDR type/isoform specific- and context-dependent manner [6].


  Conclusion Top


To conclude, cytoplasmic localization of DDR1 could be incriminated in the development and progression of BCC. DDR1 is the potential target therapy in cancer.

We recommend further studies to determine the exact role of DDR1 in the pathogenesis of BCC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Rogers HW, Weinstock MA, Feldman SR, Coldiron BM. Incidence estimate of nonmelanoma skin cancer (keratinocyte carcinomas) in the US Population, 2012. JAMA Dermatol 2015; 151:1081–1086.  Back to cited text no. 1
    
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Samarasinghe V, Madan V. Nonmelanoma skin cancer. J Cutan Aesthet Surg 2012; 5:3–10.  Back to cited text no. 2
    
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P Erb, J Ji, E Kump, A Mielgo, M Wernli. Apoptosis and pathogenesis of melanoma and nonmelanoma skin cancer. Adv Exp Med Biol 2008; 624:283–295.  Back to cited text no. 4
    
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Carafoli F, Hohenester E. Collagen recognition and transmembrane signalling by discoidin domain receptors. Biochim Biophys Acta 2013; 1834:2187–2194.  Back to cited text no. 5
    
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Perez JL, Shen X, Finkernagel S, Sciorra L, Jenkins NA, Gilbert DJ, et al. Identification and chromosomal mapping of a receptor tyrosine kinase with a putative phospholipid binding sequence in its ectodomain. Oncogene 1994; 9:211–219.  Back to cited text no. 7
    
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Alves F, Vogel W, Mossie K, Millauer B, Höfler H, Ullrich A. Distinct structural characteristics of discoidin I subfamily receptor tyrosine kinases and complementary expression in human cancer. Oncogene 1995; 10:609–618.  Back to cited text no. 8
    
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Duraiyan J, Govindarajan R, Kaliyappan K, Palanisamy M. Applications of immunohistochemistry. J Pharm Bioallied Sci 2012; 4 (Suppl 2):S307–S309.  Back to cited text no. 9
    
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Abourbih S, Sircar K, Tanguay S, Kassouf W, Aprikian A, Mansure J, et al. Aldehyde dehydrogenase 1 expression in primary and metastatic renal cell carcinoma: an immunohistochemistry study. World J Surg Oncol 2013; 11:298.  Back to cited text no. 10
    
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Reichert-Faria A, Jung JE, Moreschi Neto V, Silva de Castro CC, Mira MT, Noronha L. Reduced immunohistochemical expression of discoidin domain receptor 1 (DDR1) in vitiligo skin. J Eur Acad Dermatol Venereol 2013; 27:1057–1059.  Back to cited text no. 11
    
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Ricard AS, Pain C, Daubos A, Ezzedine K, Lamrissi-Garcia I, Bibeyran A, et al. Study of CCN3 (NOV) and DDR1 in normal melanocytes and vitiligo skin. Exp Dermatol 2012; 21:411–416.  Back to cited text no. 12
    
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Di Marco E, Cutuli N, Guerra L, Cancedda R, De Luca M. Molecular cloning of trkE, a novel trk-related putative tyrosine kinase receptor isolated from normal human keratinocytes and widely expressed by normal human tissues. J Biol Chem 1993; 268:24290–24295.  Back to cited text no. 13
    
14.
Rammal H, Saby C, Magnien K, Van-Gulick L, Garnotel R, Buache E, et al. Discoidin domain receptors: potential actors and targets in cancer. Front Pharmacol 2016; 7:55.  Back to cited text no. 14
    
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Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2010; 141:1117–1134.  Back to cited text no. 15
    


    Figures

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

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



 

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