Telomere attrition predominantly occurs in precursor lesions during in vivo carcinogenic process of the uterine cervix.
Although human papillomavirus (HPV) has been defined as the pathogen for cervical carcinomas, molecular events underlying the oncogenic process are unclear. As telomere dysfunction-mediated chromosomal instability and telomerase activation have been suggested as key events in carcinogenesis, we dissected the dynamic changes in telomere length, checkpoint response, and temporal profile of telomerase expression during the evolution from precursor lesions (cervical intraepithelial neoplasia, CINs) to invasive cancers of the uterine cervix in sequential samples from 16 patients. Telomeres were significantly shortened in all CIN samples and no further substantial attritions occurred in most cases with the acquisition of malignant phenotype. Very short telomeres were coupled with constitutive activation of the DNA damage response pathway (Chk2 phosphorylation) and increased cellular proliferation in those cervical specimens. Telomerase reverse transcriptase (hTERT) expression was preferably induced at advanced CINs or invasive cancers. The present finding demonstrates that excessive telomere shortening predominantly occurs in the early carcinogenesis of the uterine cervix largely prior to telomerase activation. Widespread over-erosion of telomeres or telomere dysfunction in very early stages of cervical tumorigenesis might fuel transformation processes by driving chromosomal instability.
Department of Molecular Medicine, Karolinska Institute, Karolinska University Hospital, CMM, SE-171 76, Stockholm, Sweden.
Anju
A
Zhang
Jianliu
J
Wang
Biying
B
Zheng
Xiaolei
X
Fang
Tord
T
Angström
Cheng
C
Liu
Xidan
X
Li
Fredrik
F
Erlandsson
Magnus
M
Björkholm
Magnus
M
Nordenskjörd
Astrid
A
Gruber
Keng-Ling
KL
Wallin
Dawei
D
Xu
D004249:DNA Damage; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D009361:Neoplasm Invasiveness; D011230:Precancerous Conditions / Q000235:genetics*; D019098:Telomerase / Q000235:genetics; D016615:Telomere / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology; D002578:Uterine Cervical Dysplasia / Q000235:genetics
D004268:DNA-Binding Proteins; D019098:Telomerase