Abstract
Background:
Oral submucous fibrosis (OSMF) is a potentially premalignant disorder involving oral mucosa presented with 7–13% rate of malignant transformation. Galectin-3 is a chimeric protein presented in the human body which plays an important role in certain physiologic conditions as well as pathologic conditions.
Aim:
This study aims to assess the impact of Gal-3 on connective tissue remodelling in both normal oral mucosa and OSMF.
Materials and Methods:
The study sample included 40 individuals who visited the outpatient department of Manubhai Patel Dental College and a private dental clinic. The study samples were divided into two groups: Group I consisted of 20 patients with clinically diagnosed OSMF, and group II consisted of 20 patients with healthy oral mucosa. A punch biopsy was conducted to obtain the mucosal tissue from the appropriate site in each case of group 1. Tissues from healthy buccal mucosa were obtained during minor oral surgical procedures in group 2 cases. The statistical analysis was conducted using the SPSS software, version 20.0, developed by IBM in USA.
Results:
Based on the examination done according to TFM staging system, most of the cases belonged to stage 3. The majority of the OSMF cases were belonging to the grade III OSMF. Gal-3 immunoreactivity in epithelial cells in OSMF and in normal oral mucosa (NOM) was observed as membranous and cytoplasmic expression.
Conclusion:
The immuno-expression of Gal-3 was observed to be significantly elevated in the connective tissue near the epithelium in OSMF when compared to NOM.
Keywords: Epithelial cells, galectin-3, oral mucosa, oral submucous fibrosis
INTRODUCTION
Oral submucous fibrosis (OSMF) is a collagen metabolic disorder. The alkaloid components of areca nut stimulate fibroblast production, while the flavonoids of areca nut inhibit collagenase. Therefore, there is a decrease in collagen degradation caused by an increase in cross-linking of the fibres and a decrease in collagenase activity observed in OSMF mucosal tissue when compared to normal oral mucosa (NOM). Several biological pathways are involved in the regulation of collagen metabolism, which can be either upregulated or downregulated at different stages of the disease.[1,2,3]
The process of collagen deposition in oral tissue leading to fibrosis is a result of an overall increase in collagen production and a decrease in collagen degradation. OSMF is a complex disease with a fascinating molecular pathogenesis. Certain molecules, such as transforming growth factor β (TGF β), epithelial mesenchymal transition (EMT), reactive oxygen species (ROS), and matrix metalloproteins (MMP), have been found to play a significant role in its development.[4,5]
Several studies have investigated the development of cancer in relation to fibrosis in order to gain insight into the processes that lead to the malignant transformation of the most common oral potentially malignant disorder in South Asia. It has been observed that a small percentage of OSMF cases progress to oral squamous cell carcinoma. It is widely established that areca nut, even without tobacco, is highly carcinogenic. Multiple studies have found that areca nut plays a significant role in the development and progression of OSMF.[6,7,8]
Recently, Galectin-3 (Gal-3), a versatile lectin, has been discovered to have a significant impact on the development of fibrotic diseases in various organs. Gal-3 has a physio-chemical and biological profile that sets it apart from the rest of the galectin family. It is the only chimeric protein in this group. It has generated a great deal of interest due to its potential as a biotarget. Gal-3 exhibits unique patterns of manifestation based on the type of tissue, but its expression can be triggered in response to tissue injury or stress. Excessive expression and release of certain substances have been linked to a range of health conditions, including organ fibrosis, heart failure, atherosclerosis, diabetes mellitus, and different types of cancer.[9,10]
Some patients do not experience malignant transformation as it is believed to be linked to genetic susceptibility in cases of OSMF. Individuals affected by this disease often experience long-term difficulties, including trismus, stomatopyrosis, and recurrent stomatitis. Studies on animals have demonstrated that animals lacking Gal-3 are less likely to develop fibrosis in different organs. Therefore, blocking Gal-3 could be a crucial approach in treating tissue fibrosis. In addition, studies have demonstrated that Gal-3 antagonists can enhance the effectiveness of chemotherapy and immunotherapy in treating malignancies.[11,12] This study aims to assess the impact of Gal-3 on connective tissue remodelling in both NOM and OSMF. The findings suggest that Gal-3 could potentially be a valuable target for treating OSMF and squamous cell carcinoma in the future.
MATERIALS AND METHODS
The study was conducted at M. P. Dental College and Hospital in Vadodara, Gujarat, following the necessary research and ethical clearance. The study’s purpose and procedure were clearly explained to the patient in a language they could understand, and written consent was obtained.
The study sample included 40 individuals who visited the outpatient department of Manubhai Patel Dental College and a private dental clinic.
The study samples were divided into two groups: Group I consisted of 20 patients with clinically diagnosed OSMF (subjects), and group II consisted of 20 patients with healthy oral mucosa (controls). The sample size was calculated by using the following formula by keeping the power of study at 80%.
As per the equation, the minimum sample size calculated was 21 for each group.
Inclusion Criteria: Cases of OSMF diagnosed clinically, with or without malignant transformation.
Exclusion Criteria: Patients who have previously received invasive treatment for OSMF and patients with systemic and infectious diseases.
The patients with OSMF underwent staging for trismus fibrosis malignant transformation (TFM) of OSMF. A punch biopsy was conducted to obtain the mucosal tissue from the appropriate site in each case of group 1. Tissues from healthy buccal mucosa were obtained during minor oral surgical procedures in group 2 cases.
The biopsy tissues were promptly fixed in 10% neutral buffered formalin (NBF) and underwent tissue processing for paraffin embedding. Soft tissue microtome was used to create thin tissue sections from the paraffin embedded tissue blocks. Every specimen had at least one section stained with H&E stain. The other sections underwent an immunohistochemistry (IHC) procedure for Galactin-3.
The IHC procedure was used for the detection of Gal-3 using the monoclonal mouse galectin 3 antibody (9C4) (PM211-6 mL RTU). Poly Excel Poly horseradish peroxidase (HRP) (pre-diluted, PEH002, 6 mL) was used as the secondary antibody. The immunohistochemistry results were evaluated using a Lawrence and Mayo research microscope. The tissue sections were carefully examined at a low-power (10×) objective magnification to identify the stained structures. Several representative hotspots were chosen and captured using a high-power (40×) objective magnification. The assessment was conducted by a knowledgeable observer. The tissues were evaluated based on qualitative staining.
IN EPITHELIUM: (according to Fabio Orlandi 1998)
Upper 1/3rd – Cytoplasmic staining
Middle 1/3rd – Nuclear staining
Lower 1/3rd – Membrane staining.
IN CONNECTIVE TISSUE: (according to Saggirato 2001)
No reactivity
+ - Focal which is <30% of cells are stained (cytoplasm, membrane, or both)
++ - 30–60% of cells are stained (cytoplasm, membrane, or both)
+++ - >60% of cells are stained (cytoplasmic, nuclear, or both).
The staining index (SI) was determined by multiplying the staining intensity score. The scoring was conducted with the observer being unaware of all the clinic-pathological parameters. The scoring was repeated to ensure consistency in the observations.
The statistical analysis was conducted using the SPSS software, version 20.0, developed by IBM in USA.
RESULTS
This study aimed to assess the immuno-expression of gal-3 in the epithelium and connective tissue of OSMF cases. The goal was to determine if gal-3 plays a role in the pathogenesis or malignant transformation of OSMF. The study included two groups: Group 1, which consisted of cases of OSMF, and Group 2, which consisted of cases of NOM. Each group consisted of 20 subjects. We collected tissue biopsies from each case. Every instance in group 1 underwent TFM staging and histopathological grading of OSMF. We evaluated the immuno-expression of Gal-3 antibody in tissue sections from both groups. In group 1 cases, the expression of Gal-3 was examined in both the epithelium and connective tissue. This was then compared to the TFM stage and OSMF grade.
A significant number of individuals in group I fell within the age range of 31 to 50 years. Out of the individuals in group I, only 2 were between the ages of 51 and 60, while 3 individuals were above the age of 60. A significant portion of individuals in group II fell within the age range of 31 to 50 years. In group II, there were only 2 individuals aged between 51 and 60 years, while 3 individuals were below 30 years old. There were 5 female patients and 15 male patients in group I. In group II, there were 9 female patients and 11 male patients.
TFM staging of OSMF was performed on all cases in group I. Out of the total of 20 cases, 9 displayed clear indications of malignant transformation both clinically and histologically. Therefore, they were classified as stage 3. Some individuals were categorised into stage 1 (8 cases) and stage 2 (3 cases) based on their clinical and histological characteristics. In each case of group I, the histological grade of OSMF was assessed using the Khanna and Andrade scale. It was observed that the majority of cases (8 cases) exhibited grade III of OSMF, while a smaller number (5 cases) showed grade II. Seven cases were found to be displaying grade IV OSMF. It is worth noting that no cases of grade I were observed.
Gal-3 immunoreactivity in the epithelium among different groups [Table 1]
Table 1.
Descriptive analysis showing distribution of Gal-3 immuno-expression in epithelium between two groups in high and low ranges
| Group |
Total | ||||
|---|---|---|---|---|---|
| Group 1 | Group II | ||||
| Gal-3 immuno-expression epithelium | No reactivity | Count | 11 | 17 | 28 |
| % within group | 55.0% | 85.0% | 70.0% | ||
| Full thickness | Count | 5 | 0 | 5 | |
| % within group | 25% | 0 | 12.5% | ||
| Lower 1/3rd | Count | 3 | 1 | 4 | |
| % within group | 15% | 5% | 10% | ||
| Middle/upper 1/3rd | Count | 1 | 2 | 3 | |
| % within group | 5% | 10% | 7.5% | ||
| Total | 20 | 20 | 20 | 20 | |
| 100% | 100% | 100% | 100% | ||
| Pearson Chi-square | Value | df | Asymp. Sig (2-sided) | ||
| 7.619 | 3 | 0.055 | |||
The expression of gal-3 was evaluated in the epithelium of all cases in group I and group II. It was noted that 11 cases of OSMF did not show any reactivity in the epithelium, while 5 cases exhibited gal-3 immuno-expression throughout the entire thickness of the epithelium. In cases of OSMF, the immuno-expression was observed in the lower 1/3rd of the epithelium in 3 cases, while only 1 case showed immuno-expression in the middle 1/3rd of the epithelium [Figures 1 and 2]. In contrast, 17 cases from NOM did not show any reactivity, while only 1 case exhibited immuno-expression in the lower 1/3rd of the epithelium. Two cases from NOM displayed reactivity in the middle and upper 1/3rd of the epithelium. A Chi-square test was conducted to analyse the difference in Gal-3 expression in connective tissue between two given groups. The Chi-square test result indicates that the observed difference is not statistically significant (P = 0.055).
Figure 1.
Photomicrograph showing Gal-3 immuno-expression in lower 1/3rd (basal layer) of the epithelium
Figure 2.
Photomicrograph showing Gal-3 immuno-expression in middle 1/3rd of the epithelium
Correlation between Gal-3 immuno-expression in epithelium and TFM stage [Table 2]
Table 2.
Descriptive analysis showing distribution of Gal-3 immuno-expression in epithelium in correlation with TFM stage in high and low ranges
| Gal-3 immuno-expression epithelium |
Total | ||||||
|---|---|---|---|---|---|---|---|
| No reactivity | Full thickness | Lower 1/3rd full thickness | Middle/upper 1/3rd | ||||
| TFM Stage | Count | 6 | 0 | 2 | 0 | 8 | |
| Stage I | % within Gal-3 immuno-expression epithelium | 54.5% | 0 | 66.7% | 0 | 40% | |
| Stage II | Count | 3 | 0 | 0 | 0 | 3 | |
| % within Gal-3 immuno-expression epithelium | 27.3% | 0 | 0 | 0 | 15% | ||
| Stage III | Count | 2 | 5 | 1 | 1 | 9 | |
| % within Gal-3 immuno-expression epithelium | 18.2% | 100 | 33.3% | 100% | 45% | ||
| Total | Count | 11 | 5 | 3 | 1 | 20 | |
| % within Gal-3 immuno-expression epithelium | 100% | 100% | 100% | 100% | 100% | ||
|
| |||||||
|
Chi-square test
|
|||||||
| Value | df | P (<0.05 significant) | |||||
|
| |||||||
| Pearson Chi-square | 11.85 | 6 | 0.065 | ||||
In the study, it was noted that among the 8 cases of stage I, 6 cases did not exhibit any reactivity of Gal-3 in the epithelium. Two cases exhibited reactivity in the lower third of the epithelium. All three cases with stage II showed no reactivity in the epithelium. Among the 9 cases displaying stage III, only 2 cases did not show any reactivity, while 5 cases exhibited reactivity throughout the thickness of the epithelium. Three cases exhibited reactivity in the lower third, while one case showed reactivity in the middle third of the epithelium. The Chi-square test results indicate that the observed difference is not statistically significant (P = 0.065).
Gal-3 immuno-expression in epithelium correlation with OSMF grade [Table 3]
Table 3.
Descriptive analysis showing distribution of Gal-3 immuno-expression in epithelium in correlation with OSMF grade in high and low ranges
| Group |
Total | ||||
|---|---|---|---|---|---|
| Group I | Group II | ||||
| Gal-3 immuno-expression connective tissue | No reactivity | Count | 4 | 18 | 22 |
| % within group | 20% | 90% | 55% | ||
| Focal | Count | 16 | 2 | 18 | |
| % within group | 80% | 10% | 45% | ||
| Total | 20 | 20 | 20 | 40 | |
| 100% | 100% | 100% | 100% | ||
|
| |||||
|
Chi-square test
| |||||
| Value | df | P (<0.05 significant) | |||
|
| |||||
| Pearson Chi-square | 19.79 | 1 | <0.01 | ||
The study examined the relationship between the expression of gal-3 and the severity of OSMF in all cases of group I. Out of 5 cases of grade II OSMF, 2 cases did not show any reactivity, while 3 cases showed reactivity throughout the thickness of the epithelium. For grade III of OSMF, 5 out of 8 cases did not show any reactivity. Three cases exhibited reactivity in the lower 1/3rd of the epithelium. Among the 7 cases of grade IV, it was observed that 4 cases did not show any reactivity, 2 cases showed immuno-expression throughout the thickness, and only 1 case showed reactivity in the middle 1/3rd of the epithelium. The significance of the difference was evaluated using a Chi-square test. The Chi-square test result indicates that there is no significant difference (P = 0.084) [Figure 3].
Figure 3.
Photomicrograph showing Gal-3 immuno-expression in the entire thickness of epithelium
Gal-3 immunoreactivity in connective tissue among different groups [Table 4]
Table 4.
Descriptive analysis showing distribution of Gal-3 expression in connective tissue with TFM stage in high and low ranges
| TFM stage |
Total | |||||
|---|---|---|---|---|---|---|
| Stage I | Stage II | Stage III | ||||
| Gal-3 immuno-expression connective tissue | No reactivity | Count | 1 | 1 | 2 | 4 |
| % within TFM group | 12.5% | 33.3% | 22.2% | 20% | ||
| Focal | Count | 7 | 2 | 7 | 16 | |
| % within TFM group | 87.5% | 66.7% | 77.8% | 80% | ||
| Total | Count | 8 | 3 | 9 | 20 | |
| % within TFM group | 100% | 100% | 100% | 100% | ||
|
| ||||||
|
Chi-square test
| ||||||
| Value | df | P (<0.05 significant) | ||||
|
| ||||||
| Pearson Chi-square | 0.64 | 2 | 0.72 | |||
The immuno-expression of gal-3 was evaluated in all cases of group I and group II. Four cases of OSMF did not show any reactivity in the connective tissue, while 16 cases showed focal positivity. In a similar vein, 18 cases of controls did not exhibit any reactivity, while 2 cases displayed focal positivity [Figure 4]. A Chi-square test was conducted to analyse the variation in Gal-3 expression in connective tissue between two specified groups. The Chi-square test revealed a highly significant difference (P < 0.001). It appears that the expression of gal-3 in connective tissue is distinct in cases of OSMF compared to NOM.
Figure 4.
Photomicrograph showing focal positivity of Gal-3 immuno-expression in connective tissue
Gal-3 immunoreactivity in connective tissue with TFM phase [Table 5]
Table 5.
Descriptive analysis showing distribution of Gal-3 expression in connective tissue with OSMF grade in high and low ranges
| Grade |
Total | |||||
|---|---|---|---|---|---|---|
| II | III | IV | ||||
| Gal-3 immuno-expression connective tissue | No reactivity | Count | 1 | 0 | 3 | 4 |
| % within grade | 20% | 0 | 42.9% | 20% | ||
| Focal | Count | 4 | 8 | 4 | 16 | |
| % within grade | 80% | 100 | 57.1% | 80% | ||
| Total | Count | 5 | 8 | 7 | 20 | |
| % within TFM group | 100% | 100% | 100% | 100% | ||
|
| ||||||
|
Chi-square test
| ||||||
| Value | df | P (<0.05 significant) | ||||
|
| ||||||
| Pearson Chi-square | 4.28 | 2 | 0.11 | |||
It was noted that among the 8 cases of stage I, only 1 case did not exhibit any reactivity of Gla3 in the connective tissue, while 7 cases exhibited focal positivity. Among the three cases with stage II, one case did not show any reactivity, while the other two cases exhibited focal positivity. Among the 9 cases displaying stage III, only 2 cases did not show reactivity, while 7 cases exhibited focal positivity. The Chi-square test result indicates that there is no statistically significant difference (P = 0.725).
Gal-3 immunoreactivity in connective tissue with OSMF grade
The relationship between the expression of gal-3 and the histological grade of OSMF was evaluated in all cases of group I. Out of 5 cases of grade II OSMF, one case did not show any reactivity, while the remaining four cases exhibited focal positivity. All 8 cases of grade III OSMF exhibited focal positivity. Among the 7 cases of grade IV, 3 cases did not show any reactivity, while the remaining 4 cases exhibited focal positivity. An analysis was conducted to examine the distribution of Gal-3 expression in connective tissue among different groups with high and low ranges. The significance of difference was evaluated using a Chi-square test. The Chi-square test results indicate that there is no significant difference (P = 0.117).
DISCUSSION
Various studies have indicated that OSMF is the result of an imbalance in the body’s ability to maintain a stable state between the production and breakdown of the extracellular matrix (ECM), with collagen playing a significant role in this process. So, it was classified as a collagen metabolic disorder. There are common mechanisms that have been suggested to play a role in both OSMF and OSCC. These mechanisms involve collagen maturation and its interaction with myofibroblast and mast cells. The constriction of blood vessels caused by fibrosis can lead to a lack of oxygen in the epithelial cells, which is a significant factor in the development of malignant transformation in OSMF. According to various studies, the malignant transformation rate of OSMF is around 7–13%. This means that it affects a significant percentage, ranging from 2% to 8%, of all individuals with the condition.[13,14]
The pathogenesis of OSMF highlights the significant role of TGF β in the fibrosis of the connective tissue. Galectins are crucial molecules that play a regulatory role in the activity of TGF β pleotropic lectins proteins. These molecules have a significant impact on various biological processes. Out of the 15 members of the galectin family, the unique chimeric protein Gal-3 has the ability to control the activation and inhibition of TGF β. Gal-3 plays a role in various inflammatory and immunomodulatory processes. Gal-3 has been shown to affect different processes related to inflammation by interacting with different types of cells, such as neutrophils, monocytes, and macrophages. Gal-3 has also been linked to various roles in fibrosis, a process that, similar to chronic wound healing, involves excessive inflammation at the beginning. During this phase, inflammation subsides and myofibroblast differentiation occurs, leading to the excessive synthesis of extracellular matrix and the formation of fibrotic tissue.[15,16]
In our study, the average age of all the individuals affected by OSMF was 42.83+/– 10.9 based on a sample size of 40 patients. In contrast, Hazare et al. conducted a study with a sample size of 1000 OSMF patients and found that the average age was 28.8+/– 10.4 years. In the current study, the expression of Gal-3 was found to be higher in the epithelium of OSMF cases compared to NOM cases. It was interesting to observe that gal-3 was expressed in multiple layers of epithelium, spanning the entire thickness. A study conducted in 2012 by Crvalloh found that gal-3 was expressed in the middle/lower third of the least high-risk cases. In their study, they found that 4 cases of NOM exhibited gal-3 immuno-expression in the middle/lower third region of the epithelium.[17] In a study conducted by Weber in 2017, the expression of gal-3 in primary oral squamous cell carcinoma was examined. The findings indicated that a high level of gal-3 expression in OSCC was linked to tumour size and other indicators of malignancy.[18] Additionally, it was discovered that gal-3 may play a role in promoting local immune tolerance in M2 macrophages.
The study found that the expression of Gal-3 was noticeably higher in the connective tissue of OSMF cases compared to normal oral mucosa. TGF β plays a crucial role in tissue fibrosis. Based on multiple studies, it seems that gal-3 plays a role in promoting the activation of TGF β and its activity, resulting in a positive feedback loop between these two molecules. Research has indicated that TGF beta plays a significant role in the development of OSMF. Negative twelve. In addition, gal-3 also plays a role in activating myofibroblasts through both TGF beta-dependent and TGF beta-independent pathways. Based on the findings of the latest study, it appears that gal-3, a molecule associated with promoting fibrosis, may enhance the activity of TGF beta and the growth of myofibroblasts. This could potentially contribute to the development of widespread tissue fibrosis.
Nevertheless, the expression of gal-3 did not show any significant correlation with the progression of OSMF grade or the severity of clinical symptoms, such as TFM stage. Gal-3 may only play a role in the early stages of the disease. Once the fibrotic process begins, its role becomes obsolete.
CONCLUSION
Tumour cells in OSMF with malignant transformation showed strong expression of gal-3. There was no significant difference in Gal-3 immuno-expression in the epithelium between the two groups. Gal-3 immunoreactivity in connective tissue in OSMF was observed in connective tissue cells in juxta epithelial regions, appearing as membranous and cytoplasmic expression. The immuno-expression of Gal-3 was observed to be significantly elevated in the connective tissue near the epithelium in OSMF when compared to NOM.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
Nil.
REFERENCES
- 1.Arakeri G, Brennan PA. Oral submucous fibrosis: An overview of the aetiology, pathogenesis, classification, and principles of management. Br J Oral Maxillofac Surg. 2013;51:587–93. doi: 10.1016/j.bjoms.2012.08.014. [DOI] [PubMed] [Google Scholar]
- 2.Shieh TY, Yang JF. Collagenase activity in oral submucous fibrosis. Proc Natl Sci Counc Repub China B. 1992;16:106–10. [PubMed] [Google Scholar]
- 3.Rai A, Siddiqui M, Parveen S, Parveen S, Rasheed A, Ali S. Molecular pathogenesis of oral submucous fibrosis: A critical appraisal. Biomed Pharmacol J. 2019;12:2027–36. [Google Scholar]
- 4.Zhao R, Li N, Xu J, Li W, Fang X. Quantitative single-molecule study of TGF-β/Smad signaling. Acta Biochim Biophys Sin (Shanghai) 2018;50:51–9. doi: 10.1093/abbs/gmx121. [DOI] [PubMed] [Google Scholar]
- 5.Antar SA, Ashour NA, Marawan ME, Al-Karmalawy AA. Fibrosis: Types, effects, markers, mechanisms for disease progression, and its relation with oxidative stress, immunity, and inflammation. Int J Mol Sci. 2023;24:4004. doi: 10.3390/ijms24044004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Nabi IR, Shankar J, Dennis JW. The galectin lattice at a glance. J Cell Sci. 2015;128:2213–9. doi: 10.1242/jcs.151159. [DOI] [PubMed] [Google Scholar]
- 7.Suthahar N, Meijers WC, Silljé HHW, Ho JE, Liu FT, de Boer RA. Galectin-3 Activation and inhibition in heart failure and cardiovascular disease: An update. Theranostics. 2018;8:593–609. doi: 10.7150/thno.22196. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Kendrick Y, Crawshaw A, Lockstone H, Giannoulatou E, Argoud K, Taylor S, et al. S77 transcriptomic studies reveal monocyte-related genes as major contributor to disease activity in pulmonary sarcoidosis. Thorax. 72(Suppl 3):A1–278. [Google Scholar]
- 9.Li LC, Li J, Gao J. Functions of galectin-3 and its role in fibrotic diseases. J Pharmacol Exp Ther. 2014;351:336–43. doi: 10.1124/jpet.114.218370. [DOI] [PubMed] [Google Scholar]
- 10.Yang RY, Hsu DK, Liu FT. Expression of galectin-3 modulates T-cell growth and apoptosis. Proc Natl Acad Sci USA. 1996;93:6737–42. doi: 10.1073/pnas.93.13.6737. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Hossaka TA, Ribeiro DA, Focchi G, André S, Fernandes M, Lopes Carapeto FC, et al. Expression of Galectins 1, 3 and 9 in normal oral epithelium, oral squamous papilloma, and oral squamous cell carcinoma. Dent Res J (Isfahan) 2014;11:508–12. [PMC free article] [PubMed] [Google Scholar]
- 12.Dings R, Miller M, Griffin R, Mayo K. Galectins as molecular targets for therapeutic intervention. Int J Mol Sci. 2018;19:905. doi: 10.3390/ijms19030905. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Rajalalitha P, Vali S. Molecular pathogenesis of oral submucous fibrosis--A collagen metabolic disorder. J Oral Pathol Med. 2005;34:321–8. doi: 10.1111/j.1600-0714.2005.00325.x. [DOI] [PubMed] [Google Scholar]
- 14.Pakshir P, Hinz B. The big five in fibrosis: Macrophages, myofibroblasts, matrix, mechanics, and miscommunication. Matrix Biol. 2018:68–9. doi: 10.1016/j.matbio.2018.01.019. 81-93. [DOI] [PubMed] [Google Scholar]
- 15.Liu FT, Stowell SR. The role of galectins in immunity and infection. Nat Rev Immunol. 2023;23:479–94. doi: 10.1038/s41577-022-00829-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Ray JG, Ranganathan K, Chattopadhyay A. Malignant transformation of oral submucous fibrosis: Overview of histopathological aspects. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016;122:200–9. doi: 10.1016/j.oooo.2015.11.024. [DOI] [PubMed] [Google Scholar]
- 17.de Vasconcelos Carvalho M, Pereira Jdos S, Alves PM, Silveira EJ, de Souza LB, Queiroz LM. Alterations in the immunoexpression of galectins-1, -3 and -7 between different grades of oral epithelial dysplasia. J Oral Pathol Med. 2013;42:174–9. doi: 10.1111/j.1600-0714.2012.01199.x. [DOI] [PubMed] [Google Scholar]
- 18.Weber M, Büttner-Herold M, Distel L, Ries J, Moebius P, Preidl R, et al. Galectin 3 expression in primary oral squamous cell carcinomas. BMC Cancer. 2017;17:906. doi: 10.1186/s12885-017-3920-2. [DOI] [PMC free article] [PubMed] [Google Scholar]