|Year : 2008 | Volume
| Issue : 2 | Page : 91-92
Renjith George, Vikrama Simha Reddy, G Sriram
Department of Oral and Maxillofacial Pathology, Meenakshi Ammal Dental College, Chennai, India
Department of Oral and Maxillofacial Pathology, Meenakshi Ammal Dental College, Chennai
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
George R, Reddy VS, Sriram G. Journal Reviews. J Oral Maxillofac Pathol 2008;12:91-2
CK17 in oral submucous fibrosis
Lalli A, Tilakaratne WM, Ariyawardana A, Fitchett C, Leigh IM, Hagi-Pavli E, et al.,
J Oral Pathol Med 2008, 37(4), 211-220
This paper highlights the pathogenesis of oral submucous fibrosis (OSF) and its predisposition to malignancy based on alterations in various keratin expressions at different layers of epithelium by immunohistochemical analysis of OSF tissues. Connective tissue changes in OSF can induce alterations in the epithelium which can alter the expression of cytokeratins (CK). Epithelial mesenchymal interactions play a vital role in keratinocyte differentiation, proliferation, migration and invasion. Alterations in keratin expression as a result of changes in the mesenchyme may have a role in pathogenesis of OSF and their predisposition to malignancy.
In this study, the authors found an increased suprabasal expression of CK1/ CK10 which is a feature of hyperkeratotic lesions. But they also found that expression of CK2 was not upregulated similar to that seen in oral lichen planus. Based on these findings they have hypothesized the possibility of an immunological pathogenesis of OSF. But the keratinisation observed in OSF could be due to direct mechanical trauma from the course fibres of areca nut. Additionally, they have hypothesized that dense fibrosis and reduced vascularity may lead to a long-term build-up of inflammatory cytokines in the epithelium which could induce abnormal keratinocyte differentiation.
In this study, they also found an increased CK6 expression and a decreased expression of CK19 and CK17 in the basal layer of OSF epithelium. The significance of increases CK6 expression needs to be elucidated. Absence of CK17 expression in basal layers had no correlation with disease severity, but CK17 expression in the suprabasal layers was fond to correlate with disease severity i.e., with increase in disease severity, there was an increase in expression of CK17. In conclusion, the authors have stated that OSF results inan altered keratinocyte phenotype, which indicates a potential mechanism for the chronic connective tissue pathology via perturbed epithelial mesenchymal interactions as well as the malignant conversion to oral squamous cell carcinoma.
Genomic instability in oral submucous fibrosis
Teh MT, Tilakaratne WM, Chaplin T, Young BD, Ariyawardana, Pitiyage G, et al.
J Oral Pathol Med 2008,37(7):430-436
This paper concentrates on the genomic instability detected in oral submucous fibrosis (OSF) which may play an important role in malignant transformation. Genomic instability is present in many cancers including oral squamous cell carcinoma (OSCC) were loss of heterozygosity (LOH) is the hallmark of genomic instability found in all the cancers, and many regions of the LOH harbor putative oncogenes and tumour suppressor genes.
In this pioneer study, the authors have reported the presence of genomic instability in the form of LOH in OSF using a high-resolution single nucleotide polymorphism (SNP) mapping technique. They found an increased frequency of LOH with increase in the disease severity. They identified 14 chromosomes containing 23 hot-spot LOH foci which harbour putative oncogenes and tumour suppressor genes known to be involved in the regulation of hypoxia, cellular adhesion/ migration, matrix remodeling, cell cycle/ apoptosis, DNA repair, inflammation etc. Among the 23 hot spot LOH loci, chromosome 13 (13q14-q33) was found to be the largest. So, they have hypothesized that genes within the 13q14-q33 LOH region may play a role in the initiation of oral carcinogenesis in OSF.
They have also found LOH to commonly involve regions at 20p12-p11, 3q21-29, and 19q13.12. This study is the first study to demonstrate the evidence of high frequency of genomic instability in OSF. But further functional association and follow-up studies are required to validate the role of various genes in relation to OSF and cancer
Upregulation of HIF-1α and malignant transformation of oral submucous fibrosis
Tilakaratne WM, Iqbal Z, Teh MT, Ariyawardana A, Pitiyage G, Cruchley A, et al.
J Oral Pathol Med 2008, 37(6):372-377
In oral submucous fibrosis (OSF) various molecules involved in the biological pathways of the fibrotic process appear to be either down- or upregulated at different stages of the disease. HIF-1α is a known transcription factor that is induced by hypoxia. In this study, they the authors have investigate the relationship of HYF-1α and epithelial dysplasia in OSF using immunohistochemistry and RT-PCR.
They have found that HIF-1α was upregulated at both protein and mRNA levels in OSF. They propose that HIF-1α may play a role in malignant transformation of OSF. Further, overexpression of HIF-1α may indicate a role of hypoxia in malignant transformation of OSF. But the present study needs to be correlated with VEGF expression.
Increased plasminogen activator inhibitor-1/tissue type plasminogen activator ratio in oral submucous fibrosis
Yang SF, Hsieh YS, Tsai CH, Chen YJ, Chang, YC
J Oral Pathol Med 2007, 13(2):234-238.
Plasminogen activators and their inhibitors are thought to be key participants in the balance of proteolytic and antiproteolytic activities that regulate extracellular matrix (ECM) turnover. However, little is known about the expression of plasminogen/ plasmin system at the site of oral submucous fibrosis (OSF).
In this study, authors compared the activities of tissue type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) between fibroblasts derived from normal buccal mucosa (BMF) and OSF by using an enzyme-linked immunosorbent assay. Furthermore, arecoline, a major areca nut alkaloid, was challenged with normal buccal mucosal fibroblasts (BMFs) to elucidate whether the activities of t-PA and PAI-1 could be affected by arecoline.
Both t-PA and PAI-1 were found to be increased in OSF than in BMFs. In addition, they found a statistically significant difference in PAI-1/t-PA ratio between OSF and BMF. The addition of arecoline upregulated not only PAI-1, but also t-PA in BMFs. In addition, the ratio between PAI-1 and t-PA was found to be significantly increased by a linear regression assay. These results suggest that OSF caused by areca quid chewing may be the result of an imbalance in the plasminogen/ plasmin system, the net result of which is increased deposition of ECM.
Basic fibroblast growth factor and oral submucous fibrosis
Bishen KA, Radhakrishnan R, Satyamoorthy K
J Oral Pathol Med 2008,37(7):42-411.
The local and systemic upregulation of inflammatory and fibrogenic cytokines and downregulation of antifibrotic cytokines are described to be central to pathogenesis of oral submucous fibrosis (OSF). Fibroblast growth factor (FGF-2) that binds heparin and heparin sulphate modulate function of cell types from mesoderm, mesoectoderm, and endothelial cells.
Immunohistochemical analysis for basic fibroblast growth factor (bFGF) using steptavidin-biotin-peroxidase technique. This gives BFGF Expression weakly positive in fibroblasts and endothelial cells and strongly positive in stroma of moderately advanced and advanced OSF. In early and very early OSF it is strongly positive for fibroblasts and endothelial cells.
Upon staining with Verhoeff's hematoxylin stain which stains normal buccal mucosa, black colour define fibres uniformly distributed in early OSF increase in the coarse fibres in the deeper tissues. These coarse fibers become thicker in moderately and advanced OSF. Their distribution tends to involve the superficial lamina propria. In advanced OSF the thickened coarse fibres are diffused.
On staining with aldehyde fuschin, broad bands arranged in a concentric manner in deeper layers is seen in early OSF.As the OSF progress, it involve the entire connective tissue.
The reduced expression of the cellular FGF established OSF is due to bFGF being released out from differentiated cells into ECM. Mast cells which are present in early OSF which are primary source of heparin serve as significant source for heparin growth factor and bFGF.
The increase in bFGF in early OSF was explainable to an initial injury phase because of areca congestion, followed by cellular activation by chemotactic cytokines and other growth factors with fibrosis as a result of molecular alteration at cellular level.
Heat shock protein 47 expression in human buccal fibroblasts stimulated with arecoline
Yang SF, Tsai CH, Chang TC
J Oral Pathol Med 2008,37(4):206-210.
Heat shock protein 47 (HSP 47) is a collagen specific molecular chaperone, which is involved in the processing and secretion of procollagen. It is expressed in endoplasmic reticulum of cells producing type-1 collagen and actively involved in type-1 collagen biosynthesis. In this study, the HSP 47 mRNA expression in cultured human buccal mucosal fibroblasts (BMF) was studied using RT-PCR.
The RT-PCR assay was used to compare HSP 47 mRNA gene expression on the fibroblasts cultured from BMF and OSF. OSF specimens exhibited higher HSP 47 mRNA expression than BMFs. To examine the effect of arecoline on the HSP 47 expression, human BMFs were treated with arecoline and the levels of mRNA measured. Arecoline was found to elevate HSP 47 mRNA gene expression in a dose dependent manner. This suggests that one of the pathogenic mechanisms of OSF may be the synthesis of HSP 47 expression by resident cells in response to arecanut challenge.
In this study, COX-2 inhibitor NS-398 was found to inhibit arecoline stimulated HSP47 expression. This indicates that COX-2 signal transduction pathway may be involved in the arecoline stimulated HSP-47 expression. These findings suggest that one of the pathologic mechanisms of OSF in vivo may be the synthesis of HSP 47 by resident cells in response to arecanut challenge and this may pave way as a potential target for developing anti-fibrotic therapy.