Expression of Human Papillomavirus 16/18 E6/E7 , p53 and Rb Proteins according to Progression of Cancerous Lesions of the Uterine Cervix

Jang, K H; Lee, K W; Yeom, B W

Abstract

Human papillomavirus (HPV) infection in women is known to be a causative factor in the initiation and progression of uterine cervical cancer by producing proteins in host cells to effect transformation and immortalization at the cellular level resulting in cancerous tumor growth. Among the types of the HPV, type 16 and type 18 are classified as high risk types because they are frequently found in cervical lesions with high grade dysplasias and invasive carcinomas. However, it is impossible to ascertain by host histologic or cellular changes which type of HPV is infected. The HPV genome is composed of six open reading frames (ORF`s) named as E1, E2, E4, E5, E6, and E7 in the early region, of which the E6 and E7 ORF`s interact with tumor suppressor proteins p53 and retinoblastoma (Rb) gene products repectively, and stimulate the cell cycle. In this study, immunohistochemical staining of E6, E7, p53, and Rb proteins was conducted to determine the rate of expression of HPV oncoproteins, correlation with the tumor supressor proteins, and relationship in dysplasia and invasive uterine cervical cancer. Sixty cases of carcinoma in situ (CIS) and invasive cacinoma were immunohistochemically stained, and the results obtained were as follows: 1) p53 was positive in 5 of 17 cases (29.4%) of CIS, in 6 of 8 cases of microinvasive carcinoma (75.0%), and in 17 of 25 cases of invasive carcinoma (68.0%), showing significantly different p53 protein expression between the dysplasia and invasive cancer groups (p=0.007). 2) Rb protein was positive in 12 of 17 cases (70.6%) of CIS, in 4 of 8 cases of microinvasive carcinoma (50.0%), and in only 5 of 25 cases of invasive carcinoma (20.0%), showing that there was significantly different Rb protein expression between the CIS and invasive cancer groups (p=0.003). 3) E6 protein of HPV type 16/18 was expressed in 6 of 17 cases (35.3%) of CIS, in 4 of 8 cases of microinvasive carcinoma (50.0%), and in 15 of 25 cases of invasive carcinoma (60.0%), but there was no significant difference in expression between the CIS and invasive cancer groups (p=0.136). 4) E7 protein of HPV type 16/18 was expressed in 12 of 17 cases (70.6%) of CIS, in 7 of 8 cases of microinvasive carcinoma (87.5%), and in 23 of 25 cases of invasive carcinoma (92.0%), but there was no significant difference in expression between the CIS and invasive cancer groups (p=0.063). 5) There was no statistical significance between HPV type 16/18 E6 protein and p53 protein expression (p=0.07). 6) There was also no statistical significance between HPV type 16/18 E7 protein and Rb protein expression (p=0.19). The above results suggest that limited action by mutation of the tumor suppressor genes p53 and Rb seems to play a role in the progression of uterine cervical cancer, and E6 and E7 proteins may also play a role. However, this study was unable to reveal a significant role of p53 and Rb protiens in adenocarcinoma of the uterine cervix, and it is recommended that further studies should be undertaken.