|Year : 2021 | Volume
| Issue : 2 | Page : 75-81
Cyclin D1 and nuclear factor kappa B expression in oral squamous cell carcinoma, oral submucous fibrosis, and oral squamous cell carcinoma associated with oral submucous fibrosis – An analytical cross-sectional study
Deepali Patekar1, Sachin C Sarode1, Gargi S Sarode1, Pravin More2
1 Department of Oral Pathology and Microbiology, Dr. D.Y. Patil Dental College and Hospital, Dr. D.Y. Patil Vidyapeeth, Hadapsar, Pune, Maharashtra, India
2 Private Practitioner, More Dental Clinic, Hadapsar, Pune, Maharashtra, India
|Date of Submission||01-Nov-2020|
|Date of Acceptance||10-Nov-2020|
|Date of Web Publication||16-Jul-2021|
Department of Oral Pathology and Microbiology, Dr. D.Y. Patil Dental College and Hospital, Dr. D.Y. Patil Vidyapeeth, Maheshnagar, Pimpri, Pune, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: According to statistics, oral squamous cell carcinoma (OSCC) is regarded as commonest cancer of the oral and maxillofacial region, having about 83% prevalence over the recent years. The prognostic accuracy of the cancer is determined by the stage of its detection and the onset of treatment. Expression of certain immunohistochemical markers such as cyclin Dl and nuclear factor kappa B (NF-κB) and their role in prognosis at an early stage would alter the treatment planning of such cases. Aim and Objectives: To assess and determine cyclin D1 and NF-κB expression using immunohistochemistry in OSCC, oral submucous fibrosis (OSMF) and OSCC associated with OSMF. Materials and Methods: An analytical cross-sectional study was conducted using 72 paraffin embedded and formalin fixed blocks of tissue retrieved from oral pathology department archives in a dental college. These bocks were categorized as cases equally divided into three groups. Group I consisted of 24 cases of OSCC; Group II consisted 24 cases of OSMF; and Group III consisted of 24 cases of OSCC-OSMF. Further, the cyclin D1 and NF-κB expression was evaluated and scoring criteria was followed by Soini et al. Statistical analysis was done using Pearson's correlation coefficient and Chi-square test, keeping 95% confidence intervals and having a P ≤ 0.05 statistically significant. Results: A moderate positive correlation was observed among cyclin D1 immune expression and NF-κB with the Dysplasia grades and Clinical stages in patient with OSMF, whereas a weak positive correlation was observed amongst cyclin D1 immune expression with Grades and TNM stages of OSCC patients. Conclusion: Our study concludes that there is significant expression of cyclin D1 and NF-κB amongst OSCC, OSMF, and OSCC-OSMF cases. Therefore, they could be considered important biomarkers, which act synergistically and can be used for the evaluation of the malignant potential of oral lesions.
Keywords: Cyclin D1, nuclear factor kappa B, oral squamous cell carcinoma, oral submucous fibrosis
|How to cite this article:|
Patekar D, Sarode SC, Sarode GS, More P. Cyclin D1 and nuclear factor kappa B expression in oral squamous cell carcinoma, oral submucous fibrosis, and oral squamous cell carcinoma associated with oral submucous fibrosis – An analytical cross-sectional study. J Dent Res Rev 2021;8:75-81
|How to cite this URL:|
Patekar D, Sarode SC, Sarode GS, More P. Cyclin D1 and nuclear factor kappa B expression in oral squamous cell carcinoma, oral submucous fibrosis, and oral squamous cell carcinoma associated with oral submucous fibrosis – An analytical cross-sectional study. J Dent Res Rev [serial online] 2021 [cited 2021 Aug 1];8:75-81. Available from: https://www.jdrr.org/text.asp?2021/8/2/75/321532
| Introduction|| |
Among the overall cancers affecting oral and maxillofacial region, oral squamous cell carcinoma (OSCC) is regarded as most frequent cancer with highest prevalence and incidence rates. Its poor prognosis is due to its metastatic and invasive abilities. The transformation rate of potentially malignant lesions (OPMDs) such as leukoplakia and oral submucous fibrosis (OSMF) into oral cancer is very high. Epithelial dysplasia is considered as an important predictor for malignant transformation, but not all dysplastic lesions progress to OSCC. The mechanisms involved in the transformation and progression of OPMDs to invasive cancer are still unknown. Cyclin D1 is located on chromosome 11q13 of cyclin D1 gene and is encoded by 45 kD protein. It forms a part of the cell cycle regulator and is responsible for G1 to S transition. In G1 phase, it activates CDK4 and cyclinD–CDK4 complex, phosphorylates the Rb protein promoting cell replication after the release of E2F. Soni et al. and Izzo et al. stated that a sequential increase in cyclinD1 expression has been observed from normal oral tissues to dysplastic lesions and OSCC's. In cell biology, cyclin D1 has an efficient role. It is particularly involved in cell proliferation, growth regulation, activity of mitochondrial modulation, repair of DNA, and has control over cell migration. The gene, CCND1 along with its protein cyclin D1 is altered by various molecular mechanisms. These mechanisms include amplification, chromosomal translocations, mutations, and modified activation of the pathways involved in cyclin D1 expression., This pathways and alterations are thought to be significant for the causation and increased severity of human cancers, including oral carcinoma. Cyclin D1's regulation has an important role in the physiological cycle. Furthermore in OSCC, it has an effect on the oncogenic activation of cyclin D1. CCND1/cyclin D1 has an influence on the size of the tumors as well as is correlated with the clinical stage of tumor. Overexpression of cyclin D1 is responsible for shortening the G1 phase. It causes limited dependency on growth factors, thus leading to abnormal and uneven proliferation of cells, which leads to additional genetic lesions. Thus, cyclin Dl is that proto-oncogene which acts as a key protein, regulating the proliferation of cells. It is also responsible for controlling its overexpression, which might cause malignant tumors with complications. Past literature studies have focused on cyclin D1 expression in different form of carcinomas involving the OSCC, however the results have not been consistent.
NF-kB makes numerous cell-autonomous contributions to the development of mature T and B lymphocytes. Given the importance of NF-kB in adaptive immune responses mediated by mature lymphocytes, it seems prudent for developing lymphocytes to have adopted a strategy in which their maturation hinges on a properly functioning NF-kB system. NF-κB is a transcription factor formed by protein dimmers containing the Rel dimerization domain, where Rel-A (p65)/p50 hetero-complex is the best characterized and plays a pivotal role in the reg-ulation of diverse biological processes, including immune response, development, cell growth and survival., NF-κB can be rapidly and transiently activated by a large variety of stimuli, such as DNA damage, cytokines, microbial components and mitogens,andin-duces a variety of genes involved in cell proliferation and survival, including Cyclin D1 (CD1)., Gene transactivation, induced by NF-κB, is regulated by a dynamic balance between the activity of coactivators and corepressors. The deregulated function of NF-κB contributes to the development of a variety of human diseases, particularly immune-related diseases and cancers.
Increased cyclin D1 expression is correlated with increased nuclear factor-jB (NF-jB) activity and maintenance of Bcl-2 and Bcl-xL expression following exposure of cells to either cisplatin or gemcitabine. Overexpression of cyclin D1 in pancreatic cancer cells has been reported to contribute chemo resistance to cisplatin therapy. Abrogation of cyclin D1 expression by the antisense strategy has predisposed human lung cancer cells and various squamous carcinoma cell lines to apoptosis and further indicated the pro-survival function of cyclin D1 in these tumor cells.
Hence, this study was conducted to analyze cyclin D1 and NF-κB expression using immunohistochemistry in OSCC, OSMF, and OSCC-OSMF.
| Materials and Methods|| |
This is a cross-sectional analytical study conducted after obtaining relevant permissions from the institutional review board. The study samples were 72 paraffin embedded and formalin fixed blocks of tissue retrieved from Oral pathology department archives in a dental college. Blanket consent was obtained from the participants at the time of biopsy. The guidelines of Strengthening the Reporting of Observational studies in Epidemiology (STROBE) was followed for our study.
Cases were equally divided into three groups, namely, Group I having 24 cases of OSCC; Group II having 24 cases of OSMF; and Group III having 24 cases of OSCC-OSMF. OSCC cases were histologically graded into three types; poorly differentiated, moderately differentiated, and well differentiated. Only those cases were included which were classified histopathologically as OSCC with adequate epithelial components, OSMF and cases of OSMF-OSCC. The paraffin embedded block having tissue deficient in epithelial components or inadequate tissue component to give a definite histopathological diagnosis of OSMF were excluded from the study. All the 72 blocks were subjected to immunohistochemical staining with cyclin D1 and NF-κB p65. Four μm thick sections were cut from all the blocks for immunostaining. The immunohistochemical kit of cyclin D1 and NF-κB p65 consisted of mouse monoclonal anti-cyclin D1 and anti-NF-κB p65 as the primary antibody respectively (Abcam UK) and the secondary antibody and detection kit used was Super Sensitive Polymer-HRP/DAB system of Biogenex Laboratories, USA. The staining procedure followed was; sectioning, deparaffinization and hydration, antigen retrieval, application of peroxide block and power block, application of primary antibody and negative control reagent, application of Super Enhancer™ reagent, application of Poly-HRP reagent (2° antibody), application of Substrate solution, counterstaining procedure in a bath of Mayer's hematoxylin for 1 min and washing in running tap water for 5 min followed by Dehydration and Mounting with DPX.
For the evaluation of anti-NF-κB p65 and anti-cyclin D1 expression in OSMF, OSCC and OSCC-OSMF the slides were examined under a compound microscope at ×400 magnification by two observers simultaneously using a double-headed microscope. In [Figure 1] the internal positive controls of cyclin D1 and internal positive control of NF-κB p65 are microscopically seen as Photograph 1 and Photograph 2, respectively [Figure 1]. The expression of NF-κB p65 in the salivary gland is seen microscopically as Photograph 3 and Photograph 4, respectively [Figure 1].
|Figure 1: Internal positive control of Cyclin D1, NF kappa Bp65 and Expression of NF kappa Bp65 in salivary gland|
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Scoring was based on the criteria described by Soini et al.; wherein the immune-staining intensity in the malignant cells was categorized as 0 is absent, 1 is weak, 2 is moderate, 3 is strong, and 4 is very strong). The second component was the percentage of positive malignant cells, wherein 0 is 0% positive cells, 1 is <25% positive cells, 2 is 25%–50% positive cells, 3 is 50%–75% positive cells, and 4 is >75% positive cells. The final overall immune-staining score was calculated as the sum of the above two components. Therefore, a score range of 0–8 was followed for final classification of grading; wherein 0 is absent, 1–4 is weak, and 5–8 is strong.
The grading has been depicted as strong and weak for different markers in OSCC and OSMF cases. In [Figure 1] Photograph 5 and Photograph 6 show strong and weak expression of cyclin D1 in OSMF respectively whereas, Photograph 7 and Photograph 8 show strong and weak expression of NF-κB p65 in OSMF, respectively. For OSCC cases [Figure 3], Photograph 9 and Photograph 10 show strong and weak expression of cyclin D1 respectively whereas, Photograph 11 and Photograph 12 show strong and weak expression of NF-κB p65 respectively.
|Figure 2: Strong and week expression of Cyclin D1 and NF kappa Bp65 in OSMF|
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|Figure 3: Strong and weak expression of Cyclin D1 and NF kappa Bp65 in OSCC|
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Data collected was entered into Microsoft Excel (2013) and statistical analysis was carried out by usage of Statistical product and service solutions (v. 21.0). Descriptive and Frequency analysis were performed. Chi-square test was used to find out significant differences amongst groups and correlation coefficient of Pearson's was used to find out a correlation between the expression of the markers with the clinical stages of the disease, keeping 95% confidence intervals and having a P value statistically significant of <0.05.
| Results|| |
This is an analytical cross-sectional study conducted to analyze cyclin D1 and NF-κB expression using immunohistochemistry in OSCC, OSMF, and OSCC-OSMF. The present study included 24 blocks of OSMF, 25 blocks of OSCC and 24 blocks of OSCC-OSMF. In our study, the mean age was 31 (±7.14) years, 54 (±13) years and 43.87 (±9.12) years in in OSMF, OSCC, and OSCC-OSMF cases respectively. All the cases showed male predominance, with a M: F ratio of 7:1, 2.1:1 and 1.6:1 in OSMF, OSCC, and OSCC-OSMF cases, respectively. The site most commonly involved in OSCC and OSCC-OSMF cases was Gingio-buccal sulcus; BM: Buccal mucosa, with a lower prevalence on RMT, Floor of mouth, lip and tongue amongst the clinical stages of the diseases, majority of the cases were in Stage IV of OSMF, OSCC and OSCC-OSMF. In our study, there were maximum number of patients with well-differentiated squamous cell carcinoma (WDSCC). It was noted that a strong immune expression of cyclin D1 and NF-κB (p65) was persistent among all OSMF, OSCC, and OSCC-OSMF cases [Table 1].
|Table 1: Demographic data of oral squamous cell carcinoma, oral submucous fibrosis, and oral squamous cell carcinoma associated with oral submucous fibrosis patients|
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In our study, comparison of expression of cyclin D1 and NF-κB (p65) in OSMF and OSCC was performed using Chi-square test. A significant difference was noted within the immune expression of cyclin D1 and OSMF and OSCC, whereas, for the immune expression of NF-κB, statistically no significant difference was observed [Table 2]. Similarly, when the comparison of cyclin D1 and NF-κB (p65) expression in OSMF and OSCC-OSMF was done, a statistically significant difference was observed within the immune expression of cyclin D1 and OSMF and OSCC, whereas, for the immune expression of NF-κB, statistically no significant difference was noted with a P > 0.05 [Table 3]. Moreover, when the comparison of cyclin D1 and NF-κB (p65) expression in OSMF with all OSCC cases showed significant differences suggesting that in OSMF, OSCC and OSCC-OSMF cases, there is strong cyclin D1 and NF-κB (p65) immune expression [Table 4].
|Table 2: Comparison of Cyclin D1 and Nuclear factor kappa B (p65) expression in Oral Submucous Fibrosis and Oral Squamous Cell Carcinoma|
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|Table 3: Comparison of Cyclin D1 and Nuclear factor kappa B (p65) expression in oral submucous fibrosis and oral squamous cell carcinoma associated with oral submucous fibrosis|
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|Table 4: Comparison of Cyclin D1 and nuclear factor kappa b (p65) expression in oral submucous fibrosis with all oral squamous cell carcinoma associated with oral submucous fibrosis cases|
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In our study, the correlation analysis of the marker with the different parameters the three study groups. A positive moderate correlation was noted among immune expression of cyclin D1 and NF-κB with the dysplasia grades and clinical stages in patient with OSMF, whereas a positive weak correlation was noted amongst immune expression of cyclin D1 with Grades and TNM stages of OSCC patients. A weak negative correlation was seen between immune expression of cyclin D1and NF-κB with Grades and TNM stages of OSCC-OSMF patients [Table 5].
|Table 5: Correlation analysis of the marker with the different parameters the three study groups|
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| Discussion|| |
This is an immunohistochemical study, which was conducted to analyze cyclin D1 and NF-κB expression amongst OSCC, OSMF, and OSCC-OSMF cases. Our study results showed that cyclin D1 expression in OSCC group (Group 1) and OSCC-OSMF (Group 3) was significantly higher than the expression in OSMF group (Group 2). Moreover, the expression of NF-κB p65 in OSCC group (Group 1) and OSCC-OSMF (Group 3) was significantly higher than the expression in OSMF group (Group 2). Similar results were found in the studies conducted by Michael et al., Maria et al. and Chen et al., wherein a correlation was significant amongst cyclin D1 and NF-κB in cases of OSMF and OSCC. This proposes that there is an additional relationship between the expression of these biomarkers in premalignant and malignant lesions.
It was found that there is significant association among IHC expression of cyclin D1 and NF-κB p65 in cases of OSMF and OSCC. This NF-κB p65 is considered responsible for the stimulation of the cyclin D1 transcription, and further regulates the control of G checkpoint. NF-κB binding sites are two in number, playing a crucial role in the promotion of human cyclin D1 whose activation is conferred by NF-κB as well as due to the activation of growth factors. The expression of cyclin D1 at different levels and its kinetics particularly during G phase, are both under the control of NF-κB. Furthermore, failure of activation of NF-κB was responsible for reduced activity of cyclin D1 and its associated kinase which is serum induced. This affects the retinoblastoma protein and results in its delayed phosphorylation. It has been reported by Matos and Jordan that in one way, cyclin D1 can cause inhibition of transcriptional activity of NF-κB mainly by acting as a co repressor. Moreover, NF-κB is also activated by the cyclin D1 gene transcription. This causes an increase in the cyclin D1 protein expression. These findings reported were similar to those of our study, which can be attributed to the immunohistochemical nature of cyclin D1.
Furthermore, Klein et al. found that NF-κB activation by Ral GTPases is mandatory for the regulation of transcription of cyclin D1. This function is carried out through a binding site on cyclin D1, which acts as a promoter of NF-κB. There are differences in cyclic mechanisms, however, it is well noted that NF-κB play a role of strong potent inducers of expression of cyclin D1 gene.
Our study findings resembled those reported by Jiang wherein a positive relationship was found between NF-κB and cyclin D1 mainly in oral leukoplakia cases and OSCC cases. Furthermore, it was reported that in the cancerization of oral leukoplakia the NF-κB/p65 and cyclin D1 expression was predominantly associated. This suggests that both cyclin D1 and NF-κB/p65 play a synergistic role in proliferation of cell and also form a vital part in OSCC carcinogenesis.
Studies conducted by Banerjee et al. and Anto et al. observed that NF-κB activation is mainly by different carcinogens such as DMBA and tumor promoters, such as benzoapyrene diol-epoxide (BaPDE) and PMA. These mechanisms and their way of functioning remains unclear for activation of NF-κB. Nonetheless, they are still thought as important factors in the specific expression of all these biomarkers. Furthermore, PMA is responsible for activation of NF-κB mainly due to phosphorylation of IκBα which was noted in a similar way in lung epithelial cells in humans.
It has been noted that in animal experiments, DMBA–TPA treatment on skin of mouse as topical application also causes activation of NF-κB. There is a nuclear translocation which occurs as a result of increased IκBα phosphorylation. This mainly induces DNA-binding process and transcription of NF-κB.,
Numerous studies,,, have stated that due to the induction of invasion, proliferation, and further tumor cells metastasis, the TNF mediates carcinogenesis. Hence, it is also considered the active and potent initiator of NF-κB transcription.
Our study has thoroughly focused on the important immunohistochemical markers for different oral cancerous and potentially malignant disorders. There is a need of the hour to identify and evaluate the role of these markers and their variability in expression in these cases. Such variabilities and the relationship of the expression of markers have been considered in our study. This will act as a rationale for future research studies. All these contribute to the strengths of this study. This study involved a smaller representative sample size and only a few cases of the potentially malignant disorders were addressed in our study. These were the possible limitations of our study, within the scope of this type of research study.
| Conclusion|| |
Our study findings suggest that there is significant cyclin D1 and NF-κB expression amongst OSCC, OSMF, and OSCC-OSMF cases. Therefore, they could be considered important biomarkers, which act synergistically and can be used for evaluation of the malignant potential of oral lesions. The NF-κB activation should be thought as an upcoming milestone for identification of various types of carcinomas. NF-κB activation occurs in response to tumor promoters, viral proteins, oncogenes, and different inflammatory stimuli. Suppressing the NF-κB activation can further be considered important in early diagnosis of OSCC by various agents. This includes natural compounds and its bioactive components which inhibit the transformed cells from developing into malignant ones. Thus, NF-κB is regarded as a novel therapeutic agent targeted in cancer. Further studies should be conducted with a more comprehensive population and with significant control over other confounding factors thus giving the future research an appropriate direction.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]