13 Additionally, Smad proteins that play a pivotal role in intracellular signaling of the TGF superfamily were observed, in an ascending order, in normal oral mucosa, mild dysplasia, moderate to severe oral epithelial dysplasia, and OSCC.16 These selleckbio data support a role of TGF-�� expression in the progression to oral cancer. Alteration of the receptors for growth signals Exogenous growth signal action is transmitted into the cell by binding to a specific transmembrane tyrosine kinase receptor that subsequently activates multiple intracellular signaling pathways, leading to cell proliferation.11 Many studies have shown early over-expression of epidermal growth factor receptors (EGFRs) in OED14,17�C21 and a positive correlation with the severity of dysplasia.

14,22 EGFR family members include c-erbB1 (Her1), c-erbB2 (Her2-neu), c-erbB3 (Her3), and c-erbB4 (Her4). These subclasses have been studied in OED.20,23 Several reports demonstrate that c-erbB-2 expression increased progressively from non-dysplasia to dysplasia and OSCC.24�C27 In addition, a positive association between cytoplasmic c-erbB2 and the Ki-67 proliferation index was found in OED.28 Although a non-significant difference in c-erbB-2 expression between normal, OED, and OSCC was observed in one study,29 dysregulation of EGFR expression may be important in the development of oral cancer, and its evaluation in OED may assist in the diagnosis of these lesions. Ror2 is a member of the Ror family of receptor tyrosine kinases which bind with a member of the Wnt family (Wnt5a), activating a planar cell polarity pathway (Wnt/JNK pathway) to regulate cell polarity and cell movement.

Kobayashi Brefeldin_A et al30 examined the expression of this receptor in OED and OSCC and found that the number of cells expressing Ror2 increased with the progression from dysplasia to malignancy. Dysregulation of intracellular pathways that translate growth signals into mitosis In addition to the dysregulation of growth factor receptors and their ligands, direct activation of the intracellular signalling pathways may also occur in carcinogenesis, allowing cells to proliferate without exogenous stimulation.11 Cyclins and cyclin-dependant kinase The cell cycle is divided into four phases: G1 (first gap), S (DNA synthesis), G2 (second gap), and M (mitosis). Near the end of G1, cells reach a key restriction point at which they either enter S phase and complete the cycle or exit and become quiescent.31 Progression of mammalian cells from quiescence to mitosis is tightly controlled by regulatory proteins such as cyclin and cyclin-dependent kinase (CDK).32 These two molecules form a complex which is responsible for the phosphorylation and inactivation of retinoblastoma protein (pRb).