Altered p16INK4a and Fhit expression in carcinogenesis and progression of human oral cancer.

To further characterize the biological and clinical role of molecular alterations involved in oral squamous carcinogenesis, the immunohistochemical expression level of two tumor suppressor genes, fragile histidine triad and p16INK4a, in non-carcinomatous squamous epithelia and head and neck squamous cell carcinoma was determined. In addition, human papillomavirus infection determined by PCR assay and the use of alcohol and cigarettes were evaluated. In this study 28 non-carcinomatous squamous epithelia and 57 head and neck squamous cell carcinoma were considered. The expression levels of fragile histidine triad were lower in head and neck squamous cell carcinoma than in non-carcinomatous squamous epithelia. In contrast, p16INK4a is expressed in malignant lesions (51% of the cases analyzed), but not in non-carcinomatous squamous epithelia. No correlation between gene expression alterations of the two tumor suppressors was observed. PCR analysis showed that HPV DNA was present in 5 of the 57 malignant lesions analyzed (8.8%). None of the factors described above, despite changes in gene expression and HPV infection, appears to be associated with alcohol use and/or tobacco smoking and clinical outcome. Our data showed that fragile histidine triad and p16INK4a expression are altered in malignant lesions. Most likely, the decreasing levels of fragile histidine triad is directly involved in cancer development, while the accumulation of p16INK4a in head and neck squamous cell carcinoma may be the consequence of loss of functional tumor suppressor retinoblastoma pathway.