Role and predictive strength of transglutaminase type 2 expression in premalignant lesions of the cervix

Abstract

The demonstration that type 2 transglutaminase (TG2) can incorporate polyamine into the E7 oncoprotein of human papillomavirus (HPV) type 18 has led to the hypothesis that TG2 can have a role in the host cellular response to HPV infection. The aim of this study was to investigate whether HPV-related pathology, in infected human cervical epithelium, was associated with modulation of TG2 expression. Normal controls and HPVinfected cervical biopsies were analyzed for the expression of TG2, and the findings were compared with lesion grade. The correlation between TG2 expression and p16, a marker for HPV-induced dysplasia, and the retinoblastoma protein (Rb), a target of the E7 protein of HPV, was also investigated. Results obtained showed that TG2 was absent in normal squamous mucosa, whereas it was present in 100% CIN I lesions. Low-grade lesions showed significantly higher TG2 expression than high-grade lesions (Po0.0001). In 94% of CIN I more than 50% of the cells were positive for TG2, with a strong staining intensity ( þ 3), whereas a decreased staining intensity and a low number of positive cells were found in CIN II/III. In CIN I cases, both nuclear and cytoplasmic staining were found in cells exhibiting classical morphological features of HPV infection. In addition, during progression from low-grade squamous intraepithelial lesions to severe dysplasia, TG2 expression was inversely correlated with p16 (Pearson: À0.930), whereas a positive correlation was observed between the expression of TG2 and pRb (Pearson: 0.997). TG2 is expressed in HPV infection as an early phenomenon, not restricted to high-risk genotypes. TG2 upregulation is probably part of host cell reaction against HPV-induced tissue modification. It may act as a cellular antioxidant defense factor, playing an important role in counteracting oxidative damage in neoplastic disease.

Expression analysis of transglutaminase 2 in premalignant lesions of the cervix

“…Moreover, this enzyme is currently referred as a phenomenon not restricted to high-risk genotypes [3]. Present results corroborate previously published data [3,7], emphasizing that HSIL patients demonstrated a significant statistical association with low TG2 expression (p <0.05).…”

“…Characterization of TG2 expression in normal cervix is seen in only two studies which investigated TG2 levels in samples such as these, even though this is relevant information. Both studies found negative expression in normal tissues, indicating that TG2 expression is solely related to non-malignant changes or LSIL [3,7].…”

“…TG2 relative quantification was categorized into three different intervals markings: > 50%, ≤50% or negative. This classification was based on a previous study [3]. Uncategorized relative expression were also evaluated.…”

“…This type of cancer is related to human papillomavirus (HPV), which is responsible for the appearance of cancer precursor lesions. The mechanism involved in the appearance of cancer is related to a persistent infection by a large number of HPV types, which depends on the virus type and site of infection, as well as on host factors that regulate the virus persistence, regression, and latency [3][4][5].…”

“…Type 2 transglutaminase (TG2) has been proposed as a cellular-interfering factor in HPV infections [3,7]. TG2 belongs to the transglutaminase (TG) iso-enzyme family, which is related to multiple functions [8].…”