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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 34  |  Issue : 1  |  Page : 321-327

Does Beclin 1 have a role in basal cell carcinoma?


1 Department of Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Dermatology, Venereology and STDs, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of General Surgery, Faculty of Medicine, Menoufia University, Menoufia, Egypt
4 Department of Dermatology, Venereology and STDs Department, Birket Alsabae Central Hospital, Menoufia, Egypt

Date of Submission26-Aug-2019
Date of Decision23-Sep-2019
Date of Acceptance29-Sep-2019
Date of Web Publication27-Mar-2021

Correspondence Address:
Dania N Abo Elros
Birket Alsabae, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_252_19

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  Abstract 


Objective
To evaluate the role of Beclin 1 in basal cell carcinoma (BCC).
Background
BCC is the most common kind of skin cancer with increased incidence. Autophagy is considered an intracellular homeostatic pathway that is related to cancer and other diseases. Beclin 1 is a specific marker for autophagy.
Patients and methods
This An Ambidirectional Cohort Study was conducted on 77 cases with BCC and 20 age-matched and sex-matched apparently healthy participants. All sections were immunohistochemical stained for Beclin 1 antibody.
Results
Significant absolute Beclin 1 cytoplasmic localization in epidermis and dermis of control group was noted, whereas in BCC, most cases showed nucleocytoplasmic Beclin 1 expression in epithelial cells and surrounding stroma (P > 0.001 for both). High Beclin 1 H score and H score category of epithelium and stroma were significantly noted in BCC in comparison with control groups (P > 0.001 for both). There were significant associations between higher Beclin 1 stromal H score and noduloulcerative clinical presentation and adenoid variant of BCC (P = 0.001 and 0.02, respectively). Moreover, there was a positive correlation between Beclin 1 stromal H score and size of BCC.
Conclusion
Overexpression and nuclear localization of Beclin 1 could play a tumor-promoting role in pathogenesis of BCC.

Keywords: autophagy, basal cell carcinoma, Beclin 1, immunohistochemistry, marker


How to cite this article:
Samaka RM, Marey AH, Rageh TM, Abo Elros DN. Does Beclin 1 have a role in basal cell carcinoma?. Menoufia Med J 2021;34:321-7

How to cite this URL:
Samaka RM, Marey AH, Rageh TM, Abo Elros DN. Does Beclin 1 have a role in basal cell carcinoma?. Menoufia Med J [serial online] 2021 [cited 2021 Dec 7];34:321-7. Available from: http://www.mmj.eg.net/text.asp?2021/34/1/321/312034




  Introduction Top


Basal cell carcinoma (BCC) mainly affects people older than 40 years and is most commonly found on the face, neck, or other parts of the head, which are frequently exposed to sunlight [1]. It usually grows slowly and stays in the area where it first develops. So, it is generally discovered at a stage where it can be completely removed with surgery [2]. However, it is still not totally harmless: if it is only treated at a later stage, or not treated at all, it can enter deeper layers of tissue. Only approximately one of 1000 people who have BCC die owing to it [3]. The gold standard of treatment is surgery, particularly for the H region of the face and infiltrative lesions [4]. Surgical techniques include excision, curettage, and electrodessication and Mohs micrographic surgery [5]. The skin is a self-regulating protective barrier organ designed to maintain cutaneous and bodily homeostasis against environmental stressors, including ultraviolet (UV), thermal, or chemical energy. The skin's immune, pigmentary, epidermal, and adnexal systems function and communicate with the systemic immune and neuroendocrine systems in response to these environmental stressors [6]. UV electromagnetic energy is transduced into chemical, hormonal, and neural signals affecting skin integrity and the cutaneous neuroendocrine system, which finally induces skin pathology [7]. Extensive studies have reported that overexposure to UV radiation is responsible for the development and progression of many skin cancers, and ultraviolet B (UVB) (280–320 nm UV spectrum) is the major carcinogen for nonmelanoma skin cancer owing to the higher sensitivity of DNA and protein to its damage [8]. UVB exposure causes damage to skin and represents the primary etiological agent for skin cancer formation. UVB induces DNA damage and apoptosis in epidermal cells. The increase in Beclin 1 expression, induced by UVB, activated autophagy in JB6 epidermal cells. Autophagy appeared to be a protective response to UVB-induced damage because inhibition of autophagy exacerbated UVB-induced cell death, and stimulation of autophagy offered protection [9]. Autophagy is considered to play a crucial role in tumorigenesis [10]. Although the involvement of the autophagy machinery and several autophagy-related genes (ATGs) has been revealed in skin cancers, the exact mechanism requires further clarification [11]. Beclin 1 is implicated in numerous biological processes, including adaptation to stress, development, endocytosis, cytokinesis, immunity, tumorigenesis, ageing, and cell death; the role of Beclin 1 in all of these processes can be probably brought back to a crucial function in membrane dynamics [11]. Beclin 1, the mammalian ortholog of the yeast Atg6/Vps30 gene, is an essential mediator of autophagy and also has a role as a tumor suppressor. Beclin 1 forms a multimeric complex with Atg14, Vps34/class 3 phosphatidylinositol-3-kinase (PI3k), and Vps15; the formation of this complex is necessary for the formation of the autophagosome and contributes to the regulation of autophagy [12]. Despite these possible autophagy-independent functions of Beclin 1, the best-characterized function of Beclin 1 is its role in autophagy. The autophagy function of Atg6/Beclin 1 is highly conserved throughout eukaryotic evolution and is presumed to be important in mediating many of its biological effects. Genetic knockdown or knockout studies of Beclin 1, or its orthologs, in lower eukaryotes have revealed several important phenotypes, many of which are likely related to autophagy, as the loss-of-function mutations of ATG6/Beclin 1 are photocopied by null mutations in other ATG genes [12]. The aim of this work was to evaluate the role of Beclin 1 in BCC.


  Patients and methods Top


This retrospective and prospective case–controlled study included 77 cases with BCC and 20 age-matched and sex-matched healthy participants as a control group. The protocol was approved by the ethical committee in Menoufia University. A written informed consent was obtained from old participants. Newly diagnosed BCC cases were selected from Dermatology Outpatient Clinic and Surgery Department, Menoufia University Hospital during the period from January 2016 to December 2017. For BCC cases, they were selected, based on the availability of paraffin-embedded blocks for serial cutting and examination. Tissue blocks were retrieved from archives of Pathology Department, Faculty of Medicine, Menoufia University Hospital. The prospectively collected case specimens that had been surgically biopsied were fixed in 10% formalin solution and then sent to Pathology Department, Faculty of Medicine, Menoufia University, where they were subjected to routine tissue processing and preparation of hematoxylin and eosin-stained slides to assess the pathological changes. Normal skin samples were obtained from patients attending General Surgery Department.

Ethical consideration

The study was approved by the ethical committee of Menoufia Faculty of Medicine, and an informed consent was obtained from all participants before the study was commenced.

Skin examination

Ethara cutaneous assessments for suspicious area and the rest of body were done. Regarding skin biopsy, the type of skin biopsy will depend on the type and the size of the lesion.

Incisional skin biopsy was done for histopathological assessment.

For tissue microarray, all formalin-fixed, paraffin-embedded tissues included were carefully assessed by hematoxylin and eosin staining to choose the most proper sections. Then tissue microarray was done on more representative parts of the section.

For immunohistochemistry, sections were cut at 3 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 peroxidase block for 5 min. The nonspecific binding was blocked by preincubation with protein block for 5 min at room temperature (Dako Laboratories, Santa Clara, California , USA). Slides were then incubated 1 h at room temperature with the primary diluted antibodies rabbit polyclonal antibodies raised against Beclin 1 (Cat. No. YPA1333; Abgent Biotechnology, San Diego, California, US) with dilution 1/200 for Beclin 1 antibody. The slides were washed with PBS (2–5 min) and then incubated with secondary antibody (Dako Laboratories) for 30 min. The color reaction was developed in diaminobenzidine for 5 min. The sections were then counterstained with hematoxylin, dehydrated, and mounted.

Clinicohistopathological parameters

The following clinicopathological data were collected from pathology reports: age, sex, tumor size, site, and gross pattern of tumor. Histopathological parameters including lymph node status, whether positive or negative. Moreover, lymph node staging, either N0, N1, or N2, was assessed. Pathologic staging of the tumor was performed.

Statistical analysis

The statistical analysis was conducted using statistical package for the social sciences program for Windows, version 20 (SPSS Inc., Chicago, Illinois, USA). All factors were used as dichotomous covariates in the statistical analysis. To test whether or not these variables differed according to clinicopathological parameters and biological markers, the Fisher's exact and Mann–Whitney test were used. All P values were two sided. P value less than or equal to 0.05 was considered statistically significant.


  Results Top


The most frequent location was head and neck [nine (84.4%)], most frequent presentation was in the form of ulcer (39%), and 57.1% did not involve margin. Mean size was 3.2 ± 2.4. Overall, 51.9% had nodular clinical types and adenoid histopathological type. Moreover, 98.7% had clefting. Lymphatic invasion, perinural invasion, external staining, stromal Angiogenesis, recurrence, calcification, and lymph node status were absent among the studied BCC cases (not showing in table). Significant absolute Beclin 1 cytoplasmic localization in epidermis and dermis of control group was noted, whereas in BCC, most cases showed nucleocytoplasmic Beclin 1 expression in epithelial cells and surrounding stroma (P > 0.001 for both). High Beclin 1 H score and H score category of epithelium and stroma were significantly noted in BCC in comparison with control groups (P > 0.001 for both) (not showing in table). There was no significant association between Beclin 1 expression in both epithelium and stromal and clinicopathological parameters [Table 1]. There were significant association between higher of Beclin 1 stromal H score and noduloulcerative clinical presentation and adenoid variant of BCC (P = 0.001 and 0.02, respectively). Moreover, there was a positive correlation between Beclin 1 stromal H score and size of BCC (r = 0.27 and P = 0.017) [Table 2]. [Figure 1] shows the following: (a) preoperative BCC in the nose, (b) postoperative flap closure, (c) preoperative BCC of scalp, and (d) postoperative with primary closure. [Figure 2] (a) shows normal skin with diffused moderate cytoplasmic Beclin 1 expression in epidermis and (b) high-power view demonstrating cytoplasmic epithelium and nucleocytoplasmic stroma expression of Beclin 1 (Beclin 1, IHC ×200 for a and ×400 for b); (c) a case of BCC shows strong diffused nucleocytoplasmic Beclin 1 expression in both epithelium and surrounding stroma, and under (d) high-power view (Beclin 1 IHC ×200 for c and ×400 for d).
Table 1: Relationship of Beclin 1 epithelial and stromal localization and clinicopathological parameters in basal cell carcinoma

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Table 2: Relation between Beclin 1 H score of epithelium and stroma in basal cell carcinoma regarding clinical data

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Figure 1: (a) Preoperative BCC in the nose, (b) postoperative flap closure, (c) preoperative BCC of scalp, and (d) postoperative with primary closure. BCC, basal cell carcinoma.

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Figure 2: Control skin: (a) normal skin showed diffused moderate cytoplasmic Beclin 1 expression in epidermis. (b) High-power view demonstrating cytoplasmic epithelium and nucleocytoplasmic stroma expression of Beclin 1 (Beclin 1, IHC ×200 for a and ×400 for b). A case of BCC shows (c) strong diffused nucleocytoplasmic Beclin 1 expression both in epithelium and surrounding stroma and under (d) high-power view (Beclin 1, IHC ×200 for c and ×400 for d). BCC, basal cell carcinoma.

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  Discussion Top


BCC is the most common skin cancer. The cancer arises in sun-exposed areas of the skin. The incidence of morbidity is high, and it is still growing. The metastatic rate is low, but the enlarging tumor may cause severe tissue disfigurement and a poor cosmetic outcome [2]. The treatment of choice for BCC is surgical excision, which can be accomplished in various ways, such as curettage where no margins are identified, surgical excision with predetermined margins of clinically normal tissue, excision under frozen section control, or Mohs' micrographic surgery. Costs, availability, and curative effectiveness of these methods vary. The ideal treatment should provide total tumor eradication with the lowest recurrence risk and use the most cost-effective method with acceptable cosmetic outcomes. Mohs' micrographic surgery offers the smallest overall defect size with the lowest recurrence rate for BCC and is the standard against which other treatments are compared [13]. Autophagy is present at a basal level in all mammals and is regulated by some conditions, such as oxidative stress, starvation, or hypoxia [14]. Autophagy plays a significant role in cancer cells as well as in normal cells [15]. Chen et al. [16] found that Beclin 1 is one of the hallmarks of autophagy and plays an important role in autophagy, which is considered a dynamic indicator of autophagy activity. Beclin 1 is a protein that can form complexes with a variety of cellular proteins to control different steps in the autophagic pathway [17]. Koneri et al. [18] concluded that Beclin 1 could play a role in tumor biology. Therefore, the aim of current study was to evaluate the role of Beclin 1 in BCC. In the current study, all cases of BCC and control group were positive for Beclin 1 in epithelium and stroma; moreover, high Beclin 1 H score and H score category of epithelium and stroma were significantly noted in BCC in comparison with control groups. Beclin 1 is a key regulator of autophagy and endocytosis. However, its autophagy-independent functions remain poorly understood. Here, Noguchi et al. [19] report that Beclin 1 regulates recycling endosome and is required for skin development in vivo. To the best our knowledge, this is the first study concerned to demonstrate the role of Beclin 1 in BCC in English literation. Li et al. [20] found that Beclin 1 is elevated in colon and gastric cancers compared with adjacent normal tissue [21]. In the present study, a significant overexpression of Beclin 1 in epithelial and stromal BCC was demonstrated. These results agreed with Li et al. [20] who showed high expression in human pancreatic ductal adenocarcinoma, colon, and gastric cancers. Wirawan et al. [12] found that Beclin 1 is the mammalian homolog of yeast vacuolar protein sorting-associated protein Vps30/autophagy-related protein 6 (Atg6) and functions within a core complex that includes class III phosphatidylinositol (PI)-3-kinase (PI3KC3)/Vps34 and PI3-kinase p150 subunit p150]/Vps15. Beclin 1 stimulates the activity of PI3KC3/Vps34 to generate phosphatidylinositol-3 phosphate (PI3P), which is necessary for the recruitment of FYVE (Fab1p YOTBVac1p, EEA1) or PX (Phox homology) domain containing effector proteins that facilitate membrane fusion and trafficking events. Beclin 1 has been implicated in multiple membrane trafficking pathways that require PI3P including autophagy, vacuolar protein sorting, cytokinesis phagocytosis, and endocytosis [12]. This promiscuous activity raises an important question regarding which of this Beclin 1-regulated pathway is important for its tumor suppressor function. To date, the contribution of Beclin 1 to cancer has been ascribed primarily to its role in the regulation of the degradative process of autophagy. In contrast, alternative functions of Beclin 1 have been relatively understudy in the context of cancer. This is important given that disruption of other essential autophagy pathway genes has not recapitulated the results from the Becn1+/− mice with regard to tumor development. It is this discrepancy that supports the potential role for autophagy-independent Beclin 1 functions in cancer. A recent study by Rohatgi et al. [22] had identified the role for Beclin 1 in the control of growth factor receptor signaling. Beclin 1 regulation of epidermal growth factor receptor degradation had been reported previously, but the functional consequences of this regulation were not known [23]. Beclin 1 is required for the growth factor-stimulated production of PI3P by PI3KC3, and in the absence of Beclin 1, the transition of PI3P-negative (PI3P−) endosomes to PI3P-positive (PI3P+) endosomes is delayed. The extended residency time of growth factor receptors in the PI3P-negative compartment sustains the longevity of downstream signals. Beclin 1 recruits distinct binding partners to regulate autophagy initiation [ATG14L/Beclin 1-associated autophagy-related key regulator (Barkor)/Atg14 Complex I] or endocytic receptor trafficking [UV radiation resistance-associated gene (UVRAG)/Vps38; Complex II] [10]. Thoresen et al. [23] found that suppression of UVRAG, but not ATG14L expression, delays epidermal growth factor receptor degradation. In contrast, White et al. [10] found that low expression of Beclin 1 was noted as in human breast cancer cell lines and tissue, as well as low Beclin 1 mRNA and protein in human melanoma, colonic carcinomas, lymphomas, hepatocellular cancers, ovarian cancers, breast cancers, and prostatic cancer [16],[20],[24],[25]. There is dual effect of Beclin 1 loss on cancer. Rohatgi and Shaw [26] found that decreased Beclin 1 expression inhibits autophagy, which can promote tumor initiation by increasing oxidative stress that promotes DNA damage and genomic instability. Escalatine et al. [27] found that regulators that induce autophagy include tumor suppressors, such as PTEN, tuberous sclerosis comple × 1 and tuberous sclerosis comple × 2 complexes, and DAPk; stress-activated signaling molecules, such as c-Jun N-terminal kinase 1 (JNK1) and those that respond to low energy or endoplasmic reticulum (ER) stress [e.g. PKR-like ER kinase (PERK), eIF2a-kinase and inositol-requiring enzyme 1 (IRE1)], and molecules involved in innate immune signaling, such as toll-like receptors and immunity-related GTPases [27]. The current study showed significant absolute Beclin 1 cytoplasmic localization in epidermis and dermis of control group was noted, whereas in BCC, most cases showed nucleocytoplasmic Beclin 1 expression in epithelial cells and surrounding stroma. Liang et al. [28] has been found that Beclin 1 associates with intracytoplasmic organelles such as the ER, mitochondria, and perinuclear membrane. Given that the double membranes of autophagic vacuoles are primarily derived from invaginations of the ER membrane [29], it is possible that Beclin 1 must be present in the ER for autophagy to proceed. According to this model, the nuclear compartmentalization of Beclin 1 would represent a mechanism for blocking autophagy from occurring in the cytoplasm. An alternative explanation is that the nuclear export of Beclin 1 is required to facilitate the degradation of another autophagy-inhibitory protein. Moreover, Li et al. [20] found that there was a positive correlation between Beclin 1 stromal H score and size of BCC. There was bad prognosis associated with overexpression, as in human pancreatic ductal adenocarcinoma, colon, and gastric cancers. In contrast to the current study, decreased expression of Beclin 1 has been correlated with tumor progression in breast, ovarian, and brain cancer and with a lower survival rate in esophageal, colorectal, hepatocellular, and brain cancer [30]. Our study showed a significant association between higher of Beclin 1 stromal H score and noduloulcerative clinical presentation and adenoid variant of BCC. To the best our knowledge, this is the first study concerned to demonstrate the association between higher of Beclin 1 stromal H score and noduloulcerative clinical presentation and adenoid variant of BCC. Further studies are recommended to elicit the exact relationship between Beclin 1 expression and clinicopathological types of BCC.


  Conclusion Top


Overexpression and nuclear localization of Beclin 1 could play a tumor-promoting role in pathogenesis of BCC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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