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Year : 2018  |  Volume : 13  |  Issue : 1  |  Page : 38-43

Role of hypoxia in malignant transformation of oral submucous fibrosis

Department of Oral Pathology and Microbiology, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Medical Sciences, Wardha, Maharashtra, India

Date of Web Publication10-Sep-2018

Correspondence Address:
Dr. Alka Harish Hande
Department of Oral Pathology and Microbiology, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Medical Sciences, Sawangi (Meghe), Wardha - 442 001, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jdmimsu.jdmimsu_40_18

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Context: In the Indian subcontinent and Southeast Asia, habit of chewing areca nut has been recognized as one of the most important risk factors leading to a ubiquitous oral potentially malignant disorder (OPMD), oral submucous fibrosis (OSMF).In OSMF, owing to fibrosis in the connective tissue, there is narrowing of blood vessels which further results in compromised blood supply to the local tissue milieu. This tissue hypoxia elicits the activation of the transcription factor Hypoxia-inducible factor 1-alpha (HIF-1 α). In OSMF, its expression shows significant correlation with degree of epithelial dysplasia. Aim: This study aims to evaluate the expression of HIF-1 α in OSMF. Settings and Design: Seventy-five histopathologically proven cases of OSMF were included in the study. The tissue sections were studied for histopathological evaluation and HIF-1α expression. Statistical Analysis Used: Descriptive and inferential statistics using one-way ANOVA and multiple comparison using Kruskal–Wallis test were used. Results: Comparison of HIF-1α expression in different grades of OSMF was done. There were 47 cases without dysplasia, whereas 16 and 12 were of low-risk and high-risk dysplasia, respectively. On comparison of HIF-1α expression in different grades of OSMF, it was found to increase significantly from normal oral mucosa (1.43 ± 0.89) to no dysplasia (3.97 ± 2.75) to low-risk epithelial dysplasia (4.93 ± 1.76) to high-risk epithelial dysplasia (5.66 ± 2.01). Conclusion: The altered expression of HIF-1α can signify the disturbed epithelial-mesenchymal interaction which indicates progression toward the malignant transformation of OSMF. Thus, HIF-1 α expression showed good correlation with increase in grades of epithelial dysplasia and thus can assist for grading/quantifying oral epithelial dysplasia in OSMF.

Keywords: Hypoxia-inducible factor 1-alpha, malignant transformation, oral submucous fibrosis

How to cite this article:
Hande AH, Chaudhary MS, Gadbail AR, Zade PR, Gawande MN, Patil SK. Role of hypoxia in malignant transformation of oral submucous fibrosis. J Datta Meghe Inst Med Sci Univ 2018;13:38-43

How to cite this URL:
Hande AH, Chaudhary MS, Gadbail AR, Zade PR, Gawande MN, Patil SK. Role of hypoxia in malignant transformation of oral submucous fibrosis. J Datta Meghe Inst Med Sci Univ [serial online] 2018 [cited 2022 Aug 17];13:38-43. Available from: http://www.journaldmims.com/text.asp?2018/13/1/38/240896

  Introduction Top

In the Indian subcontinent and Southeast Asia, habit of chewing areca nut and its commercial preparation is widespread. The upsurge in the popularity and increased uptake of this habit by young people [1] is due to easy access, affordable price, and marketing strategy.[2] In India, the areca nut is used in various combinations; pan masala or kharra (powdered areca nut with tobacco and flavoring agents), betel quid (areca nut, slaked lime, and betel leaf) with or without tobacco, and raw areca nut (flakes or granules).[3] The chewing of these arecanut preparations has been recognized as one of the most important risk factors leading to a ubiquitous oral potentially malignant disorder (OPMD), oral submucous fibrosis (OSMF). OSMF is defined as a chronic progressive, scarring disease affecting oral, oropharyngeal, and sometimes, the upper third of esophageal mucosa.[4] It is characterized by the juxta-epithelial inflammatory reaction and progressive fibrosis of the lamina propria and submucosal tissue which leads to stiffness of the oral mucous membrane and restricted mouth opening.[5],[6] Etiopathogenesis of OSMF has been studied over the last two decades, and research on elucidating the etiology and pathogenesis appears to have been focused on changes in the extracellular matrix by arecoline, an ingredient found in areca nut.[7] Most of the alterations in molecules and various pathways which lead to accumulation of collagen are mediated through it.[8] It is obvious that fibrosis of the submucosal tissues is mediated through transforming growth factor (TGF)-b as a result of arecoline [7] and it accounts for most of the manifestations of OSMF. The characteristic histopathological features of OSMF include epithelial atrophy with loss of rete ridges, increased deposition of collagen as a result of a collagen metabolic disorder caused by exposure to the areca nut alkaloids, juxta-epithelial chronic inflammatory cell infiltrate, reduced vascularity, and hyalinization of the submucosal tissue.[5] The morphological features of OSMF especially fibrosis suggests a possibility of hypoxic environment in diseased tissues.[7] The adaptation of cells to hypoxia seems to be facilitated via HIF-1 α. The HIF-1 α is a well-known transcription factor that binds specifically to a5-RCGTG-3 hypoxia response element (HRE) on the promoter region of various hypoxia-inducible genes which are known to be involved in angiogenesis, oxygen transport, iron metabolism, glycolysis, glucose uptake, growth factor signaling, apoptosis, invasion, and metastasis.[7] Recent literature shows that HIF-1 α is associated with the upregulation of various growth factors such as vascular endothelial growth factor (VEGF), TGF-b, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and epidermal growth factor receptor (EGFR).[7]

Malignant transformation of oral submucous fibrosis

Often, oral cancer is preceded by clinically recognizable diseases, potentially malignant disorders (PMDs). In general, the malignant transformation of PMDs begins with single-cell atypia subject to genetic mutation and/or various carcinogenic factors such as tobacco, betelnut, betel quid, virus, and alcohol. Recently, the carcinogenicity of areca nut without tobacco was identified and has been classified as a “group one human carcinogen” as per se cond International Agency for Research on Cancer monograph on betel quid, based on epidemiologic and laboratory studies.[9] OSMF, now globally accepted as an Indian disease, has one of the highest malignant transformation rates among OPMDs.

Hypoxia has been reported to be associated with fibrosis in other organs of the body. Upregulation of matrix production and amplified levels of TGF-b and enhanced accumulation of collagen fibers was demonstrated in renal and lung fibroblasts.[10],[11] In addition, demonstration of hypoxia-inducible factor-1 α (HIF-1 α) at early stages of prostate and cervical carcinogens plays a significant role in malignant transformation of it.[12],[13]

In OSMF, it is traditionally believed that owing to fibrosis in the connective tissue; there is narrowing of blood vessels which further results in compromised blood supply to the local tissue milieu. This tissue hypoxia elicits the activation of transcription factor HIF-1 α. In OSMF, HIF-1 α has been found to be upregulated at both protein and mRNA levels. Its expression shows statistically significant correlation with degree of epithelial dysplasia.[7]

Thus, we hypothesize that fibrosis in OSMF and malignant transformation in the background of fibrosis mediates through HIF-1 α. Adaptation to low oxygen tension that is hypoxia in cells and tissues leads to transcriptional induction of series of genes that participate in angiogenesis, iron metabolism, glucose metabolism, and cell proliferation/survival.[2]

  Subjects and Methods Top

This study was a retrospective appraisal for which the essential Institutional Ethical Committee clearance was obtained. Patients with OSMF were categorized based on the clinical criteria: intolerance to hot and spicy foods, pale-looking oral mucosa, palpable fibrotic bands, and chronic progressive trismus.[14] The extent of involvement of oral mucosa and maximal inter incisor opening was recorded. The clinical staging of the OSMF was performed based on the degree of mouth opening according to Lai et al. 1995,[15] as follows. Stage 1: mouth opening >35 mm; Stage 2: mouth opening between 30 and 35 mm; Stage 3: mouth opening between 20 and 30 mm, and Stage 4: mouth opening <20 mm. The included cases of OSMF were evaluated histologically. Oral epithelial dysplasia (OED) in OSMF was recorded on the basis of its presence or absence. Further, it is categorized as low-risk epithelial dysplasia (LRED, Low-risk: no/mild/questionable) and high-risk epithelial dysplasia (HRED, high-risk: moderate/severe).[16]

The study was carried out on neutral-buffered formalin-fixed paraffin embedded tissue to detect expression of HIF-1α. Paraffin-embedded tissues of 30 normal oral mucosae (NOM) and 75 OSMF were retrieved from the archival tissues of the department Immunohistochemical method for detection of HIF-1α antigen.

For immunohistochemistry (IHC), Universal Immuno-enzyme polymer method was employed. The sections were deparaffinized with xylene and hydrated. The antigen retrieval for HIF-1α was carried out by treating tissue section on slides to 0.01 M sodium citrate buffer (pH 6.0) in microwave oven for 10 min followed by bench-cooled for 20 min, and again, the same cycle was repeated. Endogenous peroxidase activity was blocked by incubating the section with 3% H2O2 in methanol for 30 min. To prevent nonspecific reactions, sections were incubated with 10% serum for 10 min. HIF-1α (Diluted 1:100, polyclonal Rabbit HIF-1α, Product code: NB 100–479, Novus Biologicals) were incubated at room temperature in a humidifying chamber for 60 min. One section from each positive control was used as the negative control by omitting the primary antibody and by incubating with serum. After the primary antibody and antigen reaction, the sections were rinsed in phosphate-buffered saline (PBS) three times for 10 min each. The horseradish peroxidase (HRP) labeled Polymer Antimouse (DakoEnVision System HRP Labelled Polymer Anti mouse, Product Code: K4000, Dako North America Inc.) was incubated at room temperature in humidifying chamber for 30 min. After the PBS washing three times for 10 min each, freshly prepared substrate/chromogen solution of 3, 3' Diaminobenzidine (DAB) in provided buffer (mixing 5 μl of concentrated DAB in 50 ml of substrate buffer) was used to visualize the antigen-antibody reaction. Finally, the sections were counterstained in Mayer's hematoxylin.

Assessment of immunohistochemically stained sections

Sections stained with HIF-1α antibody were examined under Leica DM LB2 (Leica microscope) at × 100 followed by ×400 magnification. The positive control was examined for the presence of a colored end product at the site of the target antigen (DAB chromogen brown end product). The presence of these colors was interpreted as positive staining result, indicating proper performance of kit reagents. The absence of nonspecific staining in the negative control confirmed the specificity of primary antibody.

Assessment of hypoxia-inducible factor 1-alpha-positive cells

The sections stained with HIF-1α were examined under Leica DM LB2 (Leica microscope) at ×100 followed by ×400 magnification. HIF-1α was scored based on percentage of cells showing both nuclear and cytoplasmic staining (0 = 0%; 1 = 1%–25%; 2 = 26%–50%; 3 = 51%–75%; 4 = 76%–100%). Staining intensity was scored as 1, weak; 2, moderate, and 3, intensive. Scores for percentage of positive cells and scores for expression intensities were multiplied to calculate an immunoreactive score. Negative control slides without addition of primary antibody were included for each staining. Known positive specimens were used as positive control for HIF-1α.

Study design

All the histopathology slides and IHC slides were blinded for analysis. Two independent experienced oral pathologists did the grading of OED. The degree of agreement between them was statistically significant. Similarly, two oral pathologists who were unaware of the OED grading status of the cases performed IHC scoring of HIF-1α. The IHC values obtained were then computed with the NOM, LRED, HRED groups of OSMF.

Statistical analysis

The mean score was obtained for HIF-1α expression in all the groups. The obtained data were analyzed statistically using (SPSS 17.0 version software for Windows, SPSS Inc., Chicago, IL). The obtained score was compared in NOM, LRED, and HRED using one-way ANOVA and Multiple comparison by using Tukey HSD test. Spearman's correlation analysis test and Pearson's rank correlation test were used for correlation analysis as and when applicable. Differences among groups were assessed by the, unpaired t-test. Subsequent comparisons between groups were carried by Mann–Whitney U test and independent Student's t-test as and when applicable. The level of statistical significance is at P < 0.05.

  Results Top

In the present study, the clinicopathological analysis of OSMF cases was done. The ages of the patients range from 18 to 56 years with a mean of 32.58 ± 9.16. A males predilection was observed with male: female ratio of 2.84:1. A maximum number of patients were reported in Grade III (40%; 53.33%) followed by Grade II (21%; 28%), Grade I (08%; 10.66%), and Grade VI (06%; 8. 00%). Out of 75 cases of OSMF, 28 (37.3%) cases showed the presence of dysplasia. They were graded as 12 (42.86%) HRED and 16 (57.14%) as LRED [Table 1].
Table 1: Clinicopathological analysis of oral submucous fibrosis cases

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Analysis of biomarker, HIF-1α expression in OSMF was done on comparison of HIF-1α expression in different grades of OSMF (by Kruskal–Wallis test). There were 47 cases without dysplasia whereas 16 and 12 were of low-risk and high-risk dysplasia, respectively. On comparison of HIF-1α expression in different grades of OSMF, it was found to increase significantly from NOM (1.43 ± 0.89) to no dysplasia (ND) (3.97 ± 2.75) to LRED (4.93 ± 1.76) to HRED (5.66 ± 2.01) dysplasia [Graph 1], [Figure 1], [Figure 2], [Figure 3].

Figure 1: Expression of hypoxia-inducible factor 1-alpha in oral submucous fibrosis without epithelial dysplasia (×100)

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Figure 2: Expression of Hypoxia-inducible factor 1-alpha in low-risk epithelial dysplasia (×100)

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Figure 3: Expression of Hypoxia-inducible factor 1-alpha in high-risk epithelial dysplasia (×100)

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  Discussion Top

The malignant potential of OSMF was first described by Paymaster in 1956 on the observation that one-third of the patients of oral squamous cell carcinoma (OSCC) had associated with OSMF.[17] OSCC is commonly preceded by a range of tissue and cellular alterations consistent with carcinoma, which are restricted to the surface epithelial layer and termed OED. The risk of malignant change in OSMF is often assessed by microscopic recognition of epithelial dysplasia since lesions with epithelial dysplasia carried 15 times higher risk of malignant change.[18] The World Health Organization (WHO) divides OED into mild, moderate, and severe dysplasia and carcinoma in situ.[19] Most pathologists grade OED according to a combination of architectural and cytological changes; however, evaluation of these features is subjective and considerable inter- and intra-observer variations in the scoring have been reported. To minimize the subjectivity and disagreements between the pathologists, WHO recently developed a binary grading system (low-risk: no/mild/questionable and high-risk: moderate/severe) reducing the number of choices from three to two.[16]

Epithelial dysplasia has been displayed in 7%–43% cases of OSMF as reported in various studies. However, malignant transformation has been reported in 7%–12% cases of OSMF.[3] The strong association of areca nut with OSF, its dose-dependant effects and the confirmation of OSMF as a potentially malignant disease leading to oral cancer provided further evidence for this affirmation.[20]

Our study results showed presence of dysplasia in 28 (37.3%) cases out of 75 cases of OSMF. They were graded as 12 (42.86%) HRED and 16 (57.14%) as LRED. On evaluation of hypoxia, we reported a significant increase in hypoxia that is expressed by HIF-1 α from NOM to ND to LRED and higher in HRED in OSMF. This is in agreement with the study by Tilakratne et al. and Lin et al. on OED.[7],[21] They concluded that the expression of HIF-1α is an early event in oral carcinogenesis. The reason for this positive correlation of the expression of HIF-1α with increasing grades of epithelial dysplasia is thought to be the activation of HIF-1α which tends to increase the secretion of growth factors such as VEGF, FGF, TGF-β, PDGF, and EGFR that have a direct relationship to carcinogenesis. The association of HIF-1α with increased expression of proliferation markers, growth factors, anti-apoptotic molecules further enhances the evidence for increased survival and possible malignant transformation of oral epithelium. In addition, the cellular response to hypoxic stress is controlled by a family of prolyl hydroxylases (PHD). In the presence of adequate oxygen, PHDs hydroxylate HIF1α at conserved proline residues within the oxygen-dependent degradation domain. Once hydroxylated, HIF1-α becomes a substrate for von Hippel-Lindau–mediated ubiquitination and degradation. Under hypoxic conditions, PHDs are inactive, and HIF1-α is stabilized and translocates to the nucleus where it forms the functional transcription factor HIF-1α. The sustained decrease in PHD activity through genetic or epigenetic mechanisms would serve to preadapt the cells (e.g., increased glycolytic rate) to the hypoxic environment found in many, and perhaps, all tumors and give them a growth advantage on tumor development. It is also possible that this loss of PHD activity and subsequent increased glycolytic activity causes the malignant transformation, as Warburg had proposed.[22] This indicates the role of hypoxia in malignant transformation of OED. Thus, the upregulation of HIF-1 α is an early event in carcinogenesis. Similarly, Chaudhary et al. observed a rise in the expression of HIF1-α in OSMF. Further, they investigated the relationship between the expression of HIF1α in OSMF and OSCC and observed gradual increase of HIF1-α from OSMF to OSCC to OSCC with OSMF.[23] Dalmia et al. in 2016 investigated the relationship between differential HIF-1 α messenger RNA expression level and OED in OSMF as well as grades of OSCC. They observed a sequential upregulation of HIF-1 α from OSMF without dysplasia to OSMF with dysplasia to Grade I to Grade II to Grade III OSCC squamous cell carcinoma suggesting a possible role of HIF-1 α in oral carcinogenesis, a marker for early detection of malignant transformation with prognostic significance. The reason for increase in expression of HIF-1 α with increase in grades of OED and OSCC is HIF-1 α gene regulating around 1% of genome, especially those factors involved in regulating carcinogenesis such as VEGF, TGF-B, FGF, PDGF, and EGFR, even in the background of fibrosis.[2] Semenza suggested that HIF-1 α is an essential component in changing the transcriptional response of tumors under hypoxia, targeting transcription of over 60 genes involved in many aspects of cancer biology including cell survival, glucose metabolism, cell invasion, and angiogenesis.[24] Thus, they concluded that HIF-1 α expression can be used as both diagnostic as well as a prognostic marker.[2] Ho et al. compared the HIF-1 α expression from fibroblasts derived from human normal buccal mucosa and OSMF specimens and further to explore the potential mechanisms that may lead to induce HIF-1 α expression. OSMF buccal mucosal fibroblasts (BMFs) demonstrated significantly higher HIF-1 α mRNA expression than normal BMFs (P < 0.005). Arecoline, the major areca nut alkaloid, was also found to elevate HIF-1 α mRNA expression in a dose-dependent manner (P < 0.05).[25] These results suggest that the altered expression of HIF-1 αbiomarker can signify event in the disturbed epithelial-mesenchymal interaction. It is indicative of progression toward malignant transformation of OSMF. Thus, HIF-1 α expression showed good correlation with increase in epithelial dysplasia (that is in LRED and HRED) and thus can be assist for grading/quantifying OED in OSMF. This could further help the clinician for deciding treatment and follow-up protocol for the OSMF patients on a case to case basis.

  Conclusion Top

The quantitative assessment of HIF-1 α biomarker can be used as a better predictive marker for progression from dysplasia to malignancy and can augment OED grading to improve the identification of patients at increased risk of malignant transformation so that they can be targeted for more aggressive treatment and closer surveillance.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1]

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