50,58 Insensitivity to antigrowth signals Progression of the cell cycle is typically restricted by cell-cycle ARQ197 NSCLC inhibitory signals. Disruption of inhibitory molecules can lead to uncontrolled cell proliferation and tumor formation.31 The multistep process of oral carcinogenesis likely involves the functional loss of these proteins through various mechanisms, including mutation, loss of heterozygosity, or hypermethylation.60 Alteration of the tumor suppressor gene TP53 is one of the most common genetic abnormalities in human malignancy including oral cancer,61 and it is considered one of the strongest predictors for cancer development.62 Based on the fundamental assumption that mutant p53 protein has a prolonged half-life, it can be detected by IHC; the half-life of wild-type p53 protein is too short to permit detection.

61,63,64 Using IHC, p53 protein expression has been detected in 10�C80% of OED.64�C70 Some investigations revealed that the TP53 mutation is an early event in oral carcinogenesis,65,66 while others have shown that it is a late event.61,64 Several studies linked p53 detection with greater risk for malignant progression,61,64,65 particularly when it was detected in basal or parabasal layers.62,71�C74 Although most previous investigations revealed a direct correlation between p53 accumulation and histologic grade of dysplasia,66,68,73,75 no such relation was found in one study.67 The limitation of using this molecular marker as the only evidence of risk assessment is that IHC can detect the overexpression of both mutant and wild-type p53 proteins.

p63 and p73 are members of the p53 family It has been found that p63 and p73 expression was higher in oral cancer and dysplasia than in normal tissue.76�C78 A gradual increase in the extent of p63 staining was observed as the lesions advanced from hyperplasia to dysplasia and ultimately to carcinoma. An association between tumor suppressor protein mammary serine protease inhibitor (maspin) was also observed.79 However, Bortoluzzi et al80 found that p63 and Ki-67 showed different patterns of staining in OED, suggesting that p63 may not be associated with proliferation. In a 5-year follow-up study, a subset of OED showing p63-positive staining underwent malignant transformation.77 Another key regulator of p53 protein is mouse double minute 2 (MDM2). Increased expression of this protein has been observed as OED progressed to cancer.

58,81,82 p16 proteins normally act to block cell cycle progression at the G1 to S transition; therefore, inactivation of the p16 gene enables unregulated cell growth.60 Several studies have investigated hypermethylation of p16 in OED,83,84 but few studies have examined IHC expression of this protein. Shintani et al32 showed that p16 immunostaining was detectable in normal epithelium, but Carfilzomib its expression decreased in dysplasia and was almost absent in OSCC.