94 In contrast, Loro et al91 showed that bcl-2 protein were markedly decreased in the basal layer of moderate and severe OED compared with the basal layer of normal oral epithelium, while Sousa et al95 found over-expression of Bax in OED. Survivin this plays an important role in apoptosis inhibition Lin et al96 reported a high incidence of survivin protein expression in OED and OSCC samples, but not in adjacent normal oral mucosal tissues. A similar pattern was found at the mRNA level.97 In an important follow-up study (13�C292 months), Lo Muzio et al98 showed that survivin expression was seen in 33% of OPMLs that did not progress to cancer, compared to 94% of OPMLs that eventually progressed to OSCC, suggesting the use of this marker for the identification of OPMLs at higher risk of progression.
98 Cyclooxygenases are enzymes that mediate the production of prostaglandins from arachidonic acid, which have been shown to decrease apoptosis rates in oesophageal adenocarcinoma cells.99 Protein expression by IHC in normal oral epithelium and in different stages of oral cancer progression showed a gradient increase of COX-2 staining.44,100,101 However, one study showed that COX-2 expression was not a reliable marker to select OPMLs at risk for development of OSCC after 6�C225 months follow-up.102 Recent evidence suggests that the coordinated function of cytosolic PLA-2 (cPLA-2) and COX-2 in the arachidonic acid pathway may contribute to the process of carcinogenesis in various tissue types.101 Expression of cPLA-2 in normal oral epithelia was significantly lower than in oral dysplasia and OSCC.
101 Heat shock proteins (HSP) are synthesized by cells in response to a variety of stress conditions, including carcinogenesis.90 Experimental evidence suggests that HSPs may be associated with tumor progression by inhibiting apoptosis.103 A study conducted on oral leukoplakia revealed that HSP60 expression increased in moderate dysplasia compared tomild dysplasia. However, no significant difference was found between leukoplakia with severe dysplasia and leukoplakia with moderate dysplasia, or between leukoplakia with severe dysplasia and OSCC.90 Another study found a non-significant difference for HSP27 cytoplasmic expression between oral leukoplakia with and without epithelial dysplasia.103 A significant correlation between HSP70 expression and dysplasia severity has been observed.
103,104 A 5-year follow-up study showed that the median transition time (premalignancy to malignancy) was significantly shorter in cases showing over-expression of HSP70 protein.104 Metallothionein GSK-3 belongs to a group of low-molecular weight proteins characterized by high levels of cystein, which are bound to metal ions. It plays a role in protecting against oxidative damage caused by free radicals, inhibition of cell apoptosis, and carcinogenesis.