Tissue transglutaminase 2 as a biomarker of cervical intraepithelial neoplasia (CIN) and its relationship to p16INK4A and nuclear factor κB expression

Tissue transglutaminase 2 (TG2) is a recently identified molecule with multifunctional physiological roles. This is the first report of the expression of TG2 in cervical intraepithelial neoplasia (CIN) and invasive squamous cell carcinoma (SCC). For comparison, the expression of p16, a known surrogate biomarker of HPV infection, was evaluated. The expression of nuclear factor kappa B (NF-kappa B), a molecule crucial to inflammation and neoplasia, was also determined to explore its possible linkage with TG2 expression. Twenty cases each with normal cervical histology, CIN1, CIN2, CIN3, and invasive SCC were analyzed for TG2, p16, and NF-kappa B expression by immunohistochemistry. Intergroup differences were analyzed by Friedman ANOVA. Cytoplasmic as well as nuclear TG2 expression was observed in the epithelial cells. As compared to normal controls, CIN1 showed markedly increased cytoplasmic TG2 expression (p = 0.006). In CIN2/3, additional nuclear TG2 expression was seen (p = 0.009 and 0.031, respectively). Marked extracellular stromal upregulation of TG2 was noted in CIN3/SCC versus normal controls (p = 0.054; p = 0.003). There was no relationship of TG2 with either p16 of NF-kappa B expression. Combining TG2 immunoreactivity with p16 increased the immunolabeling of dysplasia from 35% to 100% in CIN1, 45% to 60% in CIN2, and 60% to 85% in CIN3. TG2 serves as an additional biomarker for all grades of cervical dysplasia, especially for low-grade dysplasia.