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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 30  |  Issue : 4  |  Page : 1155-1161

Expression of nuclear factor-κB1/P105 in Helicobacter pylori-induced gastric lesions


1 Department of Pathology, Theodor Bilharz Research Institute, Giza, Egypt
2 Department of Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt

Date of Submission15-Jan-2017
Date of Acceptance07-May-2017
Date of Web Publication04-Apr-2018

Correspondence Address:
Noha S Helal
Department of Pathology, Theodor Bilharz Research Institute, PO Box 30, El-Nile Street, Warrak El-Hadar, Imbaba, Giza 12411
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_53_17

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  Abstract 


Background and aim
The current study aimed to assess the proliferative activity of gastric epithelium in Helicobacter pylori (H. pylori) associated lesions through immunohistochemical tissue localization of NF-κB1/p105.
Patients and methods
Forty seven gastric specimens were included in this study as follows: 33 chronic gastritis specimens (24 H. pylori associated and nine H. pylori negative); seven gastric cancer (GC) specimens; and seven specimens from areas adjacent to GC. H. pylori intensity, gastric activity, chronicity, intestinal metaplasia, and glandular atrophy were assessed and graded by the Sydney system and correlated with NF-κB1/p105 expression.
Results
Gastric epithelial cells in H. pylori negative specimens expressed NFκB1/p105 as weak heterogeneous cytoplasmic staining without nuclear positivity and served as a control for immunostaining. Nuclear positivity was found in 83.3% of H. pylori gastritis, 71.4% of areas adjacent to cancer lesions and in 100% of GC lesions. The mean values of the NFκB1/p105 nuclear labeling index were significantly increased in H. pylori gastritis (46.83 ± 30.43) (P < 0.01), premalignant gastric lesions (82.0 ± 5.44) (P < 0.01), and GC (95.0 ± 3.55) (P < 0.01) compared with H. pylori-negative controls (0 ± 0).
Conclusion
It is concluded that aberrant activation of NF-κB1 plays an important role in H. pylori associated gastritis, precancerous, and cancerous lesions. Hence, methods of inhibiting NF-κB signaling may have potential therapeutic application in cancer and inflammatory diseases. A better understanding of the molecular mechanisms would contribute toward both prevention and treatment of gastric carcinoma.

Keywords: gastric cancer, gastritis, Helicobacter pylori, nuclear factor-κB1


How to cite this article:
Badawy AA, Moussa MM, Omran ZS, Helal NS, El-Hindawi AA, Mosaad MM, Hammam OA, Mohammed MM. Expression of nuclear factor-κB1/P105 in Helicobacter pylori-induced gastric lesions. Menoufia Med J 2017;30:1155-61

How to cite this URL:
Badawy AA, Moussa MM, Omran ZS, Helal NS, El-Hindawi AA, Mosaad MM, Hammam OA, Mohammed MM. Expression of nuclear factor-κB1/P105 in Helicobacter pylori-induced gastric lesions. Menoufia Med J [serial online] 2017 [cited 2018 Aug 18];30:1155-61. Available from: http://www.mmj.eg.net/text.asp?2017/30/4/1155/229230




  Introduction Top


Many factors are known to contribute toward the development of cancer, and gastric cancer (GC) development is no different[1]. Slightly more than 20% of the global cancer burden can be linked to infectious agents[2].

Gastritis is a major characteristic of the disease process initiated by the bacterial pathogen Helicobacter pylori (H. pylori)that colonize the external surfaces of the gastric mucosa. Epithelial cells lining the mucosa are the major sources of the proinflammatory factors produced during infection[3]. H. pylori colonization occurs in 50% of the human population and is a key factor in the development of GC development[4]. H. pylori have been categorized as class I carcinogen by the WHO in 1994, and this categorization has been reiterated by the International Agency for Research on Cancer in 2010[5].

H. pylori bacterium is responsible for 5.5% of all infection-associated cancers and specifically with 80% of stomach cancers[2],[6]. H. pylori- associated GC is an example of an inflammation-associated cancer. Gastric colonization with H. pylori s leads to a stereotypical pathological sequence in which superficial gastritis progresses to atrophic gastritis, intestinal metaplasia (IM), dysplasia, and eventually cancer[7],[8], mainly with incidence of the intestinal type of gastric adenocarcinoma[9]. The oncogenic effects of H. pylori infection have been shown through two major mechanisms: the direct epigenetic effects of H. pylori on gastric epithelial cells and the indirect inflammatory response of H. pylori on the gastric mucosa[10].

Worldwide, GC is the fifth leading cause of cancer[11] and the third leading cause of cancer death[12], making up 7% of cases and 9% of deaths[11]. It is a tumor with a high recurrence rate tumor, which is represented in about 90% cases by adenocarcinomas[13].

The transcription factor NF-κB was discovered in 1986 as a nuclear factor that binds to the enhancer element of the immunoglobulin κ light-chain of activated B cells[14]. Members of this transcription factor family have been identified, designated as p65 (RelA), RelB, c-Rel, NF-κB1, and NF-κB2[15]. In contrast to the other family members, NF-κB1 and NF-κB2 are synthesized as pro-forms (p105 and p100) and are proteolytically processed to p50 and p52, respectively[16].

This transcription factor is ubiquitously present in all types of eukaryotic cells. It plays a crucial role in various biological processes, including immune response, inflammation, cell growth, survival, and development[17]. It exists in an inactive form; its activation occurs by proinflammatory stimuli, such as live microorganisms or their products[18]. Once activated, it believed to trigger the onset of inflammation[19]. Furthermore, NF-κB also governs the expression of genes encoding proteins essential in the control of stress response, cell growth and development, maintenance of intercellular communications, promoting cancer cell proliferation, preventing apoptosis, and generating chemotherapeutic resistance[20]. Therefore, it provides a mechanistic link between inflammation and cancer, and is a major factor controlling the ability of both preneoplastic and malignant cells to resist apoptosis-based tumor-surveillance mechanisms[21]. In addition, it is associated with lymphatic invasion, advanced stage, and poor clinical outcomes[22]. However, other investigators have reported conflicting data with respect to the relationship of NF-κB protein with patient survival[23].

It is clear that H. pylori infection activates NF-κB, causing chronic atrophic gastritis accompanied by IM, dysplasia (DYS), and GC[24], but the precise mechanics of the H. pylori–NF-κB pathway interface have been difficult to resolve and appear to be numerous[25].

Recent data have expanded the concept of inflammation as a critical component in carcinogenesis, suggesting new anti-inflammatory therapies for a complementary approach in treating a variety of tumor types. Thus, NF-κB signaling pathways that mediate NF-κB activation provide attractive targets for new chemopreventive and chemotherapeutic approaches among pharmaceutical companies[20].

The aim of this study was to assess immunoexpression of the proliferative marker NF-κB1 in H. pylori gastritis-associated lesions aiming to clarify its input in inflammatory process, tumor initiation and promotion.


  Patients and Methods Top


Groups

This study was carried out on 47 archival gastric paraffin blocks obtained from patients at the Pathology Department, Theodor Bilharz Research Institute, Giza, Egypt. The study protocol was approved by the Ethics committee of Theodor Bilharz Research Institute for the protection of human participants and adopted by the 18th world medical assembly, Helsinki, Finland.

The specimens were histopathologically classified as follows:

  • Group I: nine endoscopic biopsies with chronic gastritis negative for H. pylori
  • Group II: 24 endoscopic biopsies with H. pylori-associated gastritis including five gastric polyps
  • Group III: seven specimens from areas adjacent to gastric carcinomas with preneoplastic changes
  • Group IV: seven gastrectomy specimens diagnosed as gastric carcinoma: five intestinal type-adenocarcinoma and two signet ring carcinoma (3/7 associated with H. pylori).


Histological study

Five microns serial sections from paraffin blocks were stained with hematoxylin/eosin for routine examination, modified Giemsa for the detection of H. pylori, and others processed for immunohistochemistry. All nonmalignant gastric sections were evaluated and graded according to the Sydney system[26] for the following parameters: H. pylori colonization, chronic inflammation (a score of the number of mononuclear cells), inflammatory activity (a measure of neutrophil influx), atrophy, and IM.

Immunohistochemical technique

Formalin-fixed paraffin sections (5 μm in thickness) were cut. Sections were incubated at 60°C overnight, and deparaffinization and rehydration were performed. Endogenous peroxidase was blocked with methanol containing 3% hydrogen peroxide. Antigen retrieval was performed by microwaving the sections in citrate buffer, pH of 6.0. Sections were incubated overnight at 4°C in a humid chamber with the primary antibody NF-kB1 (NCL-p105 mouse monoclonal antibody, class IgM clone 2B3; Leica Biosystems, Nova Castra, UK), at an optimal dilution of 1: 20, with application of the ultravision detection system horseradish peroxidase polymer. The antigen was localized by the addition of DAB (3, 3′ diaminobenzidine) substrate chromogen solution. Finally, slides were counterstained with hematoxylin, dehydrated in alcohol, and mounted.

For each setting, negative controls were carried out in which phosphate buffered saline was used instead of the primary antibody. Sections of high-grade invasive gastric adenocarcinoma were used as positive controls.

Interpretation of immunostaining

All immunostained slides were assessed and scored. The sections were examined using a light microscope (Oberkochen, Zeiss, Germany). Immunopositivity was indicated by brownish nuclear ± cytoplasmic staining. The nuclear labeling index was scored as the percentage of positive cells evaluated in 10 microscopic fields at power ×400 in each section and the mean values were obtained.

Statistical analysis

Data were summarized as percentage and means ± SD, and were analyzed using SPSS version 20 (IBM Corporation, Armonk, New York, USA). t-Test and analysis of variance tests were used for quantitative variables. P value less than 0.05 was considered significant.


  Results Top


Fifteen out of 33 (45.5%) chronic gastritis cases and four out of seven (57.14%) of malignant cases were men. In terms of age, the highest frequency of chronic gastritis was in the fourth decade (29.54 ± 17.92), whereas most of the malignant cases were in the seventh decade (63.57 ± 11.43).

Gastritis cases were considered H. pylori positive when bacteria (irrespective of their density) were histologically detected. A 24/33 gastritis cases were H. pylori associated and 9/33 were H. pylori negative (served as controls for immunohistochemistry withNF-κB1/p105). Total of 3/7 (42.8%) of cases from areas adjacent to GC were H. pylori associated. Chronicity was detected – with moderate, or severe mononuclear cells density – more frequently in group II (H. pylori gastritis cases) (70.8%) compared with group III (areas adjacent to GC) (14.2%). However, activity was detected – with moderate or severe influx of neutrophils – more frequently in group III (85.8%) compared with group II cases (58%). IM was diagnosed in 70.8% of the cases in group III compared with in 41.7% of the cases in group II. Mucosal atrophy was sparsely found as it was detected in 12.5% of the cases in group II and in 14.2% of the cases in group III cases [Table 1].
Table 1: Parameters of chronic gastritis cases according to Sydney system[24]

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Dysplastic changes were diagnosed in 4/7 (57.1%) of the cases in group III compared with 2/24 (8.3%) of the cases in group II cases [Table 2].
Table 2: Frequency of dysplasia in chronic gastritis cases

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In our different groups studied, immunohistochemical expression of NF-κB1 was identified mainly in the nuclei of gastric epithelial cells and inflammatory cells [Figure 1] infiltrating lamina propria of H. pylori-positive mucosa. H. pylori-negative biopsy specimens showed occasional weak cytoplasmic staining in some gastric epithelial cells without nuclear staining that was considered negative.
Figure 1: Immunohistochemical staining of NF-kB1/p105 showing nuclear/cytoplasmic expression mainly in gastric epithelial cells and some inflammatory cells in a case of H. pylori gastritis (moderate score of chronicity and severe score of activity) (×400).

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Nuclear positivity was absent in H. pylori-negative gastritis cases (group I) [Figure 2] and detected in 83.3% of H. pylori gastritis (group II), 71.4% of areas adjacent to cancer lesions (group III) and in 100% of GC lesions (group IV) [Table 3] and [Figure 3].
Table 3: Expression of NF-κB1/p105 in the studied groups

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Figure 2: Gastric mucosa of an area adjacent to gastric carcinoma. (A) Chronic gastritis with dysplastic changes, exhibits NF-kB1/p105 cytoplasmic expression. (B) Chronic gastritis with intestinal metaplasia, exhibits NF-kB1/p105 nuclear expression (IHCX400).

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Figure 3: Marked nuclear expression of NF-kB1/p105 in cases of: (A) Adenocarcinoma, grade II. (B) Poorly differentiated adenocarcinoma, grade III. (C) Signet ring adenocarcinoma (IHCX400).

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The mean values of the NF-κB1/p105 nuclear labeling index were significantly increasing in an ascending pattern among the studied groups from group I (controls) to group II to group III up to group IV [Table 3] and [Figure 3].

As shown in [Table 4], nuclear expression of NF-κB1/p105 showed a significant increase in cases with severe degree of chronicity, activity, and IM in comparison with those with mild or absent scores (P< 0.05) [Figure 1]. Cases with dysplastic changes showed significantly higher nuclear expression of NF-κB1/p105 compared with negative ones (P< 0.05) [Table 5] and [Figure 2].
Table 4: Nuclear labeling index of NF-κB1/p105 (mean % of positive cells±SD) in different scores of gastritis

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Table 5: Nuclear labeling index of NF-κB1/p105 (mean % of positive cells±SD) in relation to dysplasia-associated gastritis

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  Discussion Top


In the stomach, chronic inflammation is the initial step toward atrophy, metaplasia, and dysplasia, and a potent promoter of cancer development. H. pylori-induced inflammation becomes cancer-induced inflammation, where damaged tumor cells and their products modulate the immune response[27]. NF-κB provides a mechanistic link between inflammation and cancer, including gastrointestinal malignancies[28].

Increased scores of chronicity and activity of chronic gastritis were observed mostly in specimens obtained from areas adjacent to gastric carcinoma. This can be explained as, in chronic gastritis, the degree of chronicity is often associated with degree of activity. This finding is in agreement with van den Brink et al.[29].

IM was found more frequently in areas adjacent to gastric carcinoma; in addition we observed the presence of H. pylori in scattered areas of these specimens. This can be explained by the fact that H. pylori infection can provide a proper environment for the development of IM in some stages of inflammation[30] and, later, IM becomes an inhospitable environment for H. pylori colonization, and is associated with a reduction or disappearance of the organisms[31]; however, further proliferation in IM and development of gastric adenocarcinoma does not depend on H. pylori status[32]. Moreover, dysplasia is more frequently found in areas adjacent to gastric carcinoma; which reflects high epithelial proliferation. It is found more frequently where IM is present. This is in agreement with the Correa model of gastric carcinogenesis with the following sequential stages: chronic gastritis; atrophy; IM; and dysplasia[1],[33].

Transcription factor NF-κB1 is detected in various types of cells involved in the expression of growth factors, cell adhesion molecules, cytokines, and chemokines[9]. It is a master regulator of immune and inflammatory responses and regulates many cellular processes important in carcinogenesis, including transformation, proliferation, angiogenesis and metastasis[6],[18]. Moreover, NF-κB signaling was shown to contribute toward cancer progression by controlling epithelial to mesenchymal transition[34].

H. pylori infection activates NF-κB1 through both the canonical and the noncanonical pathways in a cell type-specific manner. Three bacterial products are currently considered to be particularly important for the activation of NF-κB1 by H. pylori: lipopolysaccharides, peptidoglycan, and cytotoxin-associated gene A[25],[35]. The inflammation and influx of neutrophils that release reactive oxygen species to kill invading pathogens might cause DNA damage and thus genetic mutations as side effects, thereby triggering tumor initiation[36]. Furthermore, H. pylori infection has been shown to stimulate epithelial to mesenchymal transition to provide transdifferentiable cells from which adenocarcinomas may arise[34].

In this work, NF-κB1/p105 expression was observed occasionally in the cytoplasm of the 9 cases of H. pylori negative gastritis (controls). This could be explained by the fact that active NF-κB1/p105 is primarily expressed in the G cells of gastric pits, which are the sites of normal production of NF-κB1/p105 in H. pylori negative gastritis[29]. In unstimulated cells, NF-κB1/p105 is found in the cytoplasm in an inactive form associated with regulatory proteins called inhibitors of κB (IκB), which prevents it from entering nuclei. When cells are stimulated, specific kinase phosphorylate IκB results in the rapid degradation of IκB's rapid degradation by proteasomes. The release of NF-κB from IκB would result in passage of NF-κB into nuclei, where it binds to specific sequences in promoter regions of target genes with further activation[24]. Therefore, our study focused on scoring of only the nuclear pattern of NF-κB1/p105, with calculation of its nuclear labeling index.

Our data showed that H. pylori infection markedly increased the number of cells positive for NF-κB1/p105; this activation was detected within the nuclei of epithelial cells of gastric mucosa, and little activation was detected in neutrophils and macrophages. In addition, a strong relation was found between epithelial NF-κB1/p105 expression and the amount of neutrophil attacking the glands (gastritis activity) especially in moderate and severe scores of H. pylori-associated gastritis, which is considered a clear indication of the importance of NF-κB1/p105 activation in chemokine production. This is in agreement with the findings of Isomoto et al.[37] and van den Brink et al.[29] in patients infected with H. pylori and consistent with the work presented by Rogler et al.[38] in patients with inflammatory bowel disease; they reported that NF-κB1was mainly activated in epithelial cells and macrophages. These authors also reported a correlation between the activity of NF-κB1/p105 and an endoscopic score of inflammation.

In our study, there was a significantly positive correlation between the NF-κB1/p105 labeling index and scores of chronic inflammation, with significantly higher values in moderate and severe scores of chronicity compared with mild and absent scores. This is in agreement with study of Isomoto et al.[37]. On the contrary, van den Brink et al.[29] did not find a correlation between the NF-κB1/p105 labeling index and the chronicity of gastritis.

Upregulated expression of NF-κB1/p105 was detected in the present study in the tissues of H. pylori group associated with IM, dysplasia and in gastric adenocarcinoma cases relative to non-tumor cases (compared with areas adjacent to GC and to H. pylori associated gastritis cases). This finding is consistent with the data reported by Ebrahimi-Askari et al.[39] and Yin et al.[40].

In addition, weak to moderate staining of NF-κB1 in stromal inflammatory cells of gastric lesions was observed, which is in agreement with the findings of Isomoto et al.[37]. This can be as attributed to the fact that H. pylori cytotoxin-associated gene A infection led to gastritis and activated NF-κB1, promoting inflammatory cells and epithelium of gastritis to produce large amounts of cyclooxygenase-2, reaction oxygen species, interlukin-6, and interlukin-8[41].

Some investigations showed that NF-κB has been linked to radiotherapy and chemotherapy resistance in carcinoma cells; thus, inhibition of NF-κB activity could enhance the radiosensitivity and chemosensitivity of cancer treatment[42].


  Conclusion and Recommendations Top


NF-κB1 is a key player in the inflammatory response. Aberrant activation of NF - κ B1 is observed in H. pylori-associated gastric precancerous and cancerous lesions. Thus, NF-κB1 inhibition is expected to have positive effects in the chronic inflammatory phase of tumor progression. A better understanding of the molecular pathways for H. pylori-mediated NF-κB activation and inflammation may provide further insights into chronic inflammation-induced carcinogenesis and enable the identification of agents that could contribute toward the prevention and treatment of gastric carcinoma.

Acknowledgements

Study concept and design was done by Professor Dr Afkar A. Badawy, Professor Dr Ali El-Hindawi; acquisition of data done by Dr Mona M. Mohammed, Dr Noha S. Helal; analysis and interpretation of data done by Professor Dr Olfat Hammam, Dr Mona M. Mohammed, Dr Noha S. Helal; drafting of the manuscript was done by Professor Dr Mona Moussa, Zeinab S. Omran, Dr Noha S. Helal; critical revision of the manuscript for important intellectual content done by Professor Dr Afkar A. Badawy, Professor Dr Mona Moussa; statistical analysis done by Professor Dr Olfat Hammam; obtained funding by Professor Dr. Afkar A. Badawy; technical and material support by Professor Dr Afkar A. Badawy; study supervision by Professor Dr Afkar A. Badawy, Professor Dr Ali El-Hindawi, Professor Dr Maha M. Mosaad.

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]
 
 
    Tables

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



 

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