Oncosuppressor proteins of fragile sites are reduced in cervical cancer

Abstract

FHIT and WWOX are tumor suppressor genes that span the common fragile sites FRA3B and FRA16D, respectively. To analyze possible synergisms among these genes in cervical cancer progression, we considered 159 cervical intraepithelial neoplasias, and 58 invasive squamous cell carcinomas of the uterine cervix. All cases were previously selected as high risk HPV. FHIT and WWOX proteins were examined by immunohistochemistry and their expression was inversely correlated with precancerous vs. invasive lesions. Statistics among biological markers indicated an association between FHIT and WWOX. Protein expression of these two genes was also absent or reduced in cancer cell lines. Thus, WWOX may be considered as a novel important genetic marker in cervical cancer and the association between the altered expression of FHIT and WWOX may be a critical event in the progression of this neoplasia.

Figure 1

Illustration of representative immunohistochemistry in normal epithelium, cervical preneoplastic and invasive lesions. Case 1 (magnification, ×10). Fhit and Wwox positive immunoreactivity in normal ectocervical squamous epithelium. Case 2 (magnification, ×20). Low or undetectable immunoreactivity of Fhit and Wwox in high grade cervical intraepithelial neoplasia (CIN 3) lesion. Case 3 (magnification, ×10). A case with Low or undetectable immunoreactivity of Fhit and Wwox protein expression observed in high grade cervical intraepithelial neoplasia (CIN 3) lesion. Note Wwox positive expression in normal columnar epithelial cells. Case 4 (magnification, ×10). In invasive squamous cell carcinoma, Fhit and Wwox protein expression show negative immunoractivity.

Figure 2

Western blot showing the reduced protein expression in vitro of Fhit and Wwox in five cervical carcinoma cell lines, in comparison with a carcinoma cell line positive for both proteins. Actin is shown to demonstrate the same amount of proteins loaded on the gel.