Telomere Length and Telomerase Activation in Carcinoma of the Cervix related to Human papilloma Virus(HPV) Infection

Park, Jong Ha; Lee, Tae Sung; Cha, Soon Do; Cho, Chi Heum; Choo, Young Ae; Suh, Seong Il; Baek, Won Ki; Suh, Min Ho

Abstract

E6 and E7 proteins produced by oncogenic HPV bind to the protein products of cellular tumor suppressor genes p53 and Rb, respectively. This mechanism has been suggested to contribute to the oncogenesis of HPV-infected carcinoma. The cells which are blocked the function of p53 and pub protein continue to divide by bypassing Ml stage known as antiproliferative mechanism but telomeres, the genetic elements at the ends of chromosomes, continue to shorten until the telomeres are so short that further replication is prevented(M2 stage). But telomeres can be maintained if telomerase is derepressed, giving rise to a immortal cell. The present study has been investigated the presence of HPV, telomere length and telomerase activation in cervical carcinomas. HPV DNA were detected by polymerase chain reaction in 17 of 19 precancerous lesions and cervical carcinoma specimens; HPV16 was detected in 12 cases, HPV18 in one case, HPV33 in two cases, and HPV58 in two cases. Overall, the prevalence of HPV was 89.5%. To study the difference of telomere length in cervical carcinomas and each normal counterpart, DNAs were digested with Hinf III and Rsa I to liberate the terminal restriction fragments(TRF). TRFs were resolved on agarose gels and detected by hybridization to the telomeric probe. This result indicated that there were no significant difference of TRF length in samples tested except two cases. TRF length of one carcinoma specimen was found to be significantly increased as compared with normal counterpart, but the other was found to be significantly decreased. Telomerase activity was detected in 4 of dysplasia specimens(5 cases), all of carcinoma in situ(CIS), and 6 of 8 invasive carcinoma. Overall, telomerase activity was detected in 84%. The degree of telomerase activity was high in 2 of dysplasia, 3 of CIS, and 3 of invasive carcinoma. And then there was no apparent association between HPV types and levels of telomerase activity. However, telomerase activity was depressed in invasive carcinoma as compared to dysplasia and CIS. These results suggest that HPV may be a possible causative agent in cervical carcinoma. In addition, telomerase activation may be necessary for the immortalization of cells and the progression of malignancy in cervical carcinoma.