Figure 5.

Proposed model for downregulation of the ataxia telangiectasia mutated (ATM)–Chk2 pathway by loss of fragile histidine triad (Fhit) during oral carcinogenesis. DNA damage increases the incidence of loss of Fhit expression and loss of heterozygosity and allelic imbalance at the FHIT locus, simultaneously upregulating phosphorylated (p) Chk2 levels in the initial step of carcinogenesis. Loss of Fhit expression decreases pChk2 levels, resulting in a defect of the ATM–Chk2 DNA‐response mechanism and accumulation of genetic alterations in oncogenes and tumor suppressor genes in the development and progression of oral squamous cell carcinoma (OSCC).