NF‑κB (p65) protein expression in head and neck tumors and its association with clinicopathological parameters
- Authors:
- Published online on: February 28, 2025 https://doi.org/10.3892/wasj.2025.330
- Article Number: 42
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Copyright : © Barnes et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].
Abstract
Introduction
Head and neck tumors (HNTs) are a diverse group of tumors that develop due to a variety of genetic and environmental risk factors (1). HNTs commonly occur in the larynx, oral cavity, sinonasal tract and nasopharynx (2). Risk factors, such as smoking, excessive alcohol consumption, and long-term exposure to ultraviolet radiation, viral infections and asbestos have been documented to lead to the development of HNTs (1). In developing countries, tobacco and alcohol, which contribute to inflammation, are responsible for >90% of HNT cases. Moreover, in developed countries, human papillomavirus infection with oncogenic features accounts for >70% of cases (3,4). Although recent progress has been made in the diagnosis and treatment of head and neck cancer (HNC), there have been minimal improvements in life expectancy over the past few decades (5). Surgery, radiation therapy and chemotherapy are the currently available treatment options (6). However, local recurrence and metastasis occur in approximately half of patients with HNC (7).
According to Owusu-Afriyie et al (8), the incidence of HNC varies greatly across sub-Saharan Africa, with the incidence in Ghana being 0.8 per 100,000 individuals, compared to 11.1 per 100,000 individuals in South Africa. Biomarkers including p53, epidermal growth factor receptor, p16 and cyclin-D1 have been studied in Ghana to assess their prognostic significance (8-10). However, alternative therapeutic markers remain unexplored.
Nuclear factor κB (NF-κB), a transcription factor with five family members, namely p105/p50 (NF-κB1), p100/p52 (NF-κB2), p65 (RELA), c-REL and RELB, has been linked to chronic inflammation and malignancies, including HNC. The increased expression of NF-κB target genes has been shown to be associated with tumorigenesis (11,12). NF-κB is normally inactive in the cytosol, bound to the inhibitor of κB (IκB). The IκB kinase (IKK) stimuli-mediated phosphorylation degrades IκB, freeing NF-κB to translocate to the nucleus to perform transcriptional functions and modulate biological roles (13). Studies have shown that NF-κB activation is a key phenomenon that contributes to tumorigenesis and the survival of cancer cells, as observed in pancreatic nd breast cancer (14,15). While typically regulated by negative feedback loops, there is a malfunction in NF-κB activity in cancer cells due to mutations or chronic exposure to activating stimuli, leading to its overexpression (13,16). TNF-α, IL-1 and IL-17 produced by immune cells infiltrating the gastrointestinal mucosa can increase NF-κB activity, thereby increasing risk of colon cancer (17). The activation of the NF-κB pathway also promotes metastasis by regulating epithelial-mesenchymal transition (18) and matrix metalloproteinases-9(19). The increased expression of NF-κB (p65) has been demonstrated to be associated with tumor grade in breast cancer (20). Currently, the clinical value of NF-κB (p65) in tumor specimens is unclear and remains underexplored. Despite advancements being made in cancer research in Africa, including Ghana, to the best of our knowledge, no study available to date has explored the prognostic value of NF-κB (p65) in HNTs. The present study thus aimed to fill this gap by evaluating the prognostic relevance of NF-κB (p65) in patients with HNTs at the Cape Coast Teaching Hospital (CCTH) in Cape Coast, Ghana.
Patients and methods
Study design, ethical approval and sample collection
The present cross-sectional study was approved by the Institutional Review Board of CCTH (Approval no. CCTHERC/EC/2023/183). Laboratory analyses were conducted at the Kumasi Center for Collaborative Research (KCCR), Kumasi, Ghana. The inclusion criteria were patients with histologically confirmed HNTs, available archived formalin-fixed paraffin-embedded (FFPE) tissues and complete medical records. The exclusion criteria were patients with a history of no preoperative chemotherapy and no concurrent cancers from 2017 to 2022. The patients who qualified were purposively sampled at the ACT Pathology Consult, the consulting pathology firm of CCTH. Clinicopathological data including age, sex, tumor location, type of biopsy, type of tumor, perineural invasion, tumor node metastasis (TNM), laterality, tumor grade and lymphovascular invasion were collected from the laboratory request forms of the patients. Hematoxylin and eosin staining was used to confirm the pathological classification of the HNTs prior to the selection of the tissues. A total of 112 tumor tissues were selected for analysis.
Immunohistochemistry
FFPE sections (4-µm-thick) were attached to positively charged slides. These portions underwent several preparatory procedures, such as deparaffinization and rehydration with xylene (two changes for 10 min each and various ethanol concentrations (100, 90 and 70% for 3 min each), respectively. A Biocare decloaking chamber (Biocare Medical System, Inc.) set at 95˚ for 30 min was used for antigen retrieval using Novocastra buffer (pH 9.0) (lot no. 6093858, Leica Microsystems, Ltd.), followed by a 35-min cooling phase in the same buffer and washing with reaction buffer from Ventana (lot no. H18324, Ventana Medical Systems, Inc.).
A protein blocker (Biocare Medical System, Inc.) and 3% hydrogen peroxide were used to inhibit non-specific protein binding and hydrogen peroxidase in the tissues. The tissues were then exposed to appropriately diluted (1:400) NF-κB (p65) rabbit polyclonal antibody IgG (cat. no. 10745-1-AP, Proteintech Group, Inc.) for 2 h at room temperature. The tissues were then rinsed and treated with MACH 1 Universal horse radish peroxidase (HRP) polymer, as a secondary antibody (lot no. 092822A, Biocare Medical System, Inc.) at room temperature for 45 min (no dilution was done). 3,3-Diaminobenzidine (DAB) chromogen (lot no. 010722A-4, Biocare Medical System, Inc.) and substrate (lot no. 071422A-2, Biocare Medical System, Inc.) were added following a second round of washing, and Mayer's hematoxylin (Abcam) was employed for counterstaining at room temperature for 1-2 min. Before mounting the dyed tissues with coverslips using para-mount, the tissues were dehydrated and cleared. Of note, two pathologists then used an Opto-Edu brand [Opto-Edu (Beijing) Co., Ltd.] digital microscope to analyze the slides and read the protein expression of NF-κB (p65) in the HNTs. A brownish-yellow colour observed in the cytoplasm was regarded as positive staining. The semi-quantitative approach, which combines the staining intensity (0, no staining; 1, mild staining; 2, moderate staining; and 3, strong staining) and the percentage of the tumors stained (0, negative; 1, <25%; 2, 25-50%; 3, 51-75%; 4, 76-100%), were used to calculate the final cytoplasmic stain of NF-κB (p65), as previously described (21). Tissues with the product of staining intensity and percentage scores of 0-6 were considered as having a low expression and those with scores of 7-12 were considered as having a high expression. At a magnification of x400, three to four images were obtained.
Statistical analysis
Categorical variables are expressed as frequencies and percentages. Pearson's Chi-square test and Fisher's exact test were used to determine the associations between clinicopathological variables using SPSS version 25 software (IBM Corp.). P-values <0.05 were considered to indicate statistically significant differences. Logistic regression analysis was conducted for the associated variables and diagnostic performance was assessed using receiver operation characteristic analysis with Xlstat (https://www.xlstat.com/en/).
Results
Characteristics of patients with HNTs
The present study utilized FFPE tissue blocks from 112 patients with various HNTs, aged between 1 and 86 years. The average age of the patients was 42.71±18.85 years. There was an equal distribution of male [56 (50%)] and female [56 (50%)] participants. The analysis of the age distribution revealed that 30 patients (26.8%) were of 1-29 years of age, 55 patients (49.1%) of 30-57 years of age and 27 (24.1) of 58-86 years of age. As regards biopsy types, 54 cases (48.2%) were excisional biopsies, 46 cases (41.1%) were incisional biopsies, 8 cases (7.1%) were punch biopsies and 2 cases (1.8%) were free needle core biopsies. Additionally, there was an equal representation of curettage and ultrasound-guided core biopsies (n=1; 0.9%). Of the 112 tumors analyzed, 62 (55.4%) were benign and 50 (44.6%) were malignant. The majority of the tumors were located in the nasal cavity 24 (21.4%) and the larynx 16 (14.3%). Other tumor sites included the ear [6 (5.4%)], oral cavity [10 (8.9)], salivary gland [7 (6.3%)], eye [5 (4.5%)], face [7 (6.3%)], mandible [9 (8.0%)], maxillary region [7 (6.3%)], nasopharynx [13 (11.6%)] and neck [8 (7.1%)]. Laterality data revealed that 52 cases (46.4%) had no specific side designation, while 32 cases (28.6%) were from the left side and 28 cases (25.0%) were from the right side. The detailed patient characteristics are presented in Table I.
 | Table IAssociation between NF-κB (p65) status and characteristics of patients with head and neck tumors. |
NF-κB (p65) protein expression in HNTs, as demonstrated using immunohistochemistry
NF-κB (p65) protein expression was observed exclusively in the cytoplasm, as depicted in Fig. 1. In the benign tumors, NF-κB (p65) expression analysis revealed that 18 (29%) of the tumors exhibited a high expression, while 44 (71%) exhibited a low expression. Conversely, immunostaining in the malignant tumors demonstrated that 30 (60%) of the tissues exhibited a high NF-κB (p65) expression, whereas 20 cases (40%) exhibited a low expression, as detailed in Table I.
Association of NF-κB (p65) expression with clinicopathological characteristics of patients with HNTs
Despite the equal number of males and females, there was a significant association between NF-κB (p65) expression and sex (P=0.013), with males exhibiting higher levels of NF-κB (p65) protein expression compared to females (n=31, 55.4% vs. n=17, 30.4%). Conversely, a low expression of NF-κB (p65) was more prevalent in female tumors (n=39; 69.6%) compared to male tumors 25 (44.6%). Additionally, a significant association (P=0.001) was observed between tumor type (benign or malignant) and NF-κB (p65) expression. A high protein expression of NF-κB (p65) was twice as common in malignant tumors compared to benign tumors (n=30, 60.0% vs. n=18, 29.0%). However, NF-κB (p65) protein expression in HNTs was not significantly associated with age, type of biopsy, location of tumor and laterality (Table I).
Logistic regression analysis revealed a significant decrease in odds for NF-κB (p65) expression when comparing sex [odds ratio (OR), 0.352; 95% confidence interval (CI), 0.162-0.764; P-value=0:008] and tumor type (OR, 0.273, 95% CI, 0.124-0.600; P-value=0.001) (Table II). When the data were stratified to examine the associations between benign tumors and NF-κB (p65) expression (Table III), no significant associations were observed with any of the clinicopathological variables. When examining malignant tumors and NF-κB (p65) expression, tumor grade, perineural invasion, lymphovascular invasion, laterality, type of biopsy and tumor location, no significant associations were observed. Notably, sex and TNM stage were significantly associated with NF-κB (p65) expression (Table IV).
Diagnostic performance of NF-κB (p65) as a marker in HNTs in CCTH
The diagnostic performance of NF-κB (p65) protein expression in HNTs was determined by drawing receiver operating characteristic curves with Xlstat. Sensitivity, specificity, positive predictive (PPV) and negative predictive (NPV) values were determined and the results are presented in Fig. 2 and Table V. The overall sensitivity was 62.5%, with a specificity of 68.8%. The PPV and NPV were 60.0 and 71.1% respectively. Using a cut-off value ≥0.600, the area under the curve was calculated as 0.656 (P<0.0001).
Discussion
A number of inflammatory mediators and signaling pathways have been linked to the development of HNCs (22). However, NF-κB, a key driver and inducer of inflammatory mediators that promote cell survival and therapeutic resistance (23), has not been extensively investigated in numerous African countries, including Ghana. Additionally, there is a global paucity of data on this topic. Therefore, the present study was designed to provide pertinent information on NF-κB (p65) expression and its association with the clinicopathological characteristics of patients with HNTs.
In the present study, only cytoplasmic immunostaining was observed in all the HNTs examined. Consistent with the findings of the present study, cytoplasmic NF-κB (p65) has been reported as a good prognostic marker in triple-negative breast cancer (24). Moreover, Al-Mutairi and Habashy (25) demonstrated that cytoplasmic NF-κB (p65) expression was associated with tumor size and high grade. Furthermore, Barnes et al (20) demonstrated that cytoplasmic NF-κB (p65) was linked to tumor grade. Conversely, NF-κB (p65) expression has been found in the nucleus (26). The findings of the present study suggest that NF-κB (p65) may be restrained in the cytosol, preventing its nuclear translocation and subsequent transcriptional regulation through DNA binding. This finding indicates the dysfunction of NF-κB (p65) signaling in HNTs, which may provide insight into the pathophysiology of these cancers and may highlight its potential for use as a prognostic biomarker and therapeutic target.
One of the main findings of the present study was the substantial association between sex and NF-κB (p65) expression in HNC. According to Pasquali et al (27), the tumor microenvironment involving NF-κB is influenced by hormonal and inflammatory dynamics, which may vary by sex. This suggests that sex hormones have the potential to modulate NF-κB (p65) events. Moreover, the data of the present study revealed that males expressed higher levels of NF-κB (p65) than females, with a statistically significant difference (P=0.013). This notable sex difference in NF-κB (p65) expression levels may have significant clinical ramifications, influencing tumor behavior and therapeutic responses. It also indicates that NF-κB (p65) regulation in these tumors may be influenced by sex-specific differences in the immune response and inflammation. Generally, it is well-established that females mount stronger immune responses and have chronic inflammation at lower levels compared to males (28). The exact mechanism(s) underpinning this link is unknown; thus, further investigations are required to clarify the pathogenesis and hormonal elements causing this sex-based difference. The analysis of malignant tumors revealed that sex and TNM stage were significantly associated with NF-κB (p65) protein expression. This is consistent with the findings of other studies on other types of cancer, where NF-κB (p65) was shown to be significantly associated with TNM stage (29,30). The sex-specific association observed in malignant tumors underscores the importance of considering sex-related factors, such as hormonal receptor expressions in future studies, on NF-κB (p65) and HNC. These findings also suggest that sex-specific therapeutic approaches should be explored when targeting NF-κB (p65)-related pathways in the treatment of HNC. Furthermore, the association between NF-κB (p65) protein expression and TNM stage in malignant tumors highlights the critical role of NF-κB (p65) signaling in cancer progression and metastasis. Elevated NF-κB (p65) levels are typically linked to more advanced disease stages and poorer clinical outcomes.
Another main result of the present study was the association between NF-κB (p65) protein expression and tumor types (benign vs. malignant). Malignant tumors expressed significantly high NF-κB (p65) similar to previous studies (20,25). This finding raises the possibility that the NF-κB (p65) may be involved in the pathophysiology of malignant transformation in head and neck cancer. Numerous pro-tumorigenic mechanisms, such as inflammation, cell survival and proliferation, have been connected to NF-κB (p65) activation. Therefore, its increased expression in malignant tumors may indicate a role in promoting tumor growth.
The present study found no significant links between NF-κB (p65) protein expression and age, biopsy type, tumor site, laterality (in both benign and malignant tumors), tumor grade, perinueral invasion and lymphovascular invasion in malignant tumors. However, while age and declining immunity has been shown to be associated with NF-κB (31), similarly, the present study found a higher expression of NF-κB (p65) among older populations. However, the results of the present study may have been influenced by its retrospective design, limited clinicopathological variables analyzed and immunohistochemistry scoring methods.
The overall diagnostic performance of NF-κB (p65) in distinguishing between benign and malignant HNTs was moderate. The moderate sensitivity and specificity indicates that while NF-κB (p65) may not be sufficient as a stand-alone prognostic tool, it could be combined with other markers or clinical data to enhance predictive value and improve patient prognosis. To establish NF-κB (p65) as a reliable prognostic marker for HNTs, additional studies with larger and more diverse patient populations are required. Further studies are required to better determine the factors influencing NF-κB (p65) expression and refine its utility as a diagnostic and a prognostic tool.
In conclusion, the present study emphasizes that NF-κB (p65) expression levels may indeed be controlled by sex and TNM stage, with males usually exhibiting a higher NF-kB (p65) activity than females in HNC. These results highlight the need for further studies to elucidate the molecular mechanisms regulating NF-κB (p65) expression, advanced disease stages and sex disparities, which may involve genetic, hormonal and environmental factors. Investigating its potential as a prognostic biomarker and therapeutic target is crucial to improving the outcomes and wellbeing of patients.
Acknowledgements
The authors would like to thank Mr. Samuel Mingyigilougu Apewe Ka-Chungu of the Department of Pathology at Komfo Anokye Teaching Hospital, Kumasi, Ghana for assisting with tissue sectioning.
Funding
Funding: The Directorate of Research, Innovation and Consultancy (RSG/GRP/CoHAS/2022/104), University of Cape Coast (Cape Coast, Ghana) funded this study with additional support from Samuel and Emelia Brew-Butler/Graduate Studies research grant, University of Cape Coast.
Availability of data and materials
The data generated in the present study may be requested from the corresponding author.
Authors' contributions
PB and ROS were involved in the conceptualization and design of the study, as well as in data collection, data analysis, project administration, manuscript writing and funding acquisition. AM, LDK, EAd, EAg, ESY, BA, EGI, GA, PKA, FHL, KD, SVN, DOY were involved in the laboratory investigation, literature review, data analysis and the drafting of the manuscript. All authors have read, edited and approved the final manuscript. PB and EAd confirm the authenticity of the raw data.
Ethics approval and consent to participate
The present study was approved by the Institutional Review Board of Cape Coast Teaching Hospital (reference no. CCTHERC/EC/2023/183). Consent to participate was waived as it was a retrospective study which did not violate patient privacy.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Use of artificial intelligence tools
During the preparation of this work, AI tools were used to improve the readability and language of the manuscript or to generate images, and subsequently, the authors revised and edited the content produced by the AI tools as necessary, taking full responsibility for the ultimate content of the present manuscript.
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