Relationship between telomerase activation and HPV 16/18 oncogene expression in squamous intraepithelial lesions and squamous cell carcinomas of the uterine cervix.
SILs (squamous intraepithelial lesions) comprise a wide spectrum of clinically and biologically heterogeneous lesions ranging from benign proliferations to precancerous lesions. Telomerase activation plays a critical role in cellular immortalization and might be important for malignant progression. The viral oncogenes E6 and E7 are the principal transforming genes of high-risk HPVs and are important in HPV-associated immortalization and neoplastic transformation. In this study we investigated the relationship between telomerase activity, telomerase RNA, and HPV 16/18 oncogene expression in low- and high-grade SILs and SCCs (squamous cell carcinomas) of the cervix uteri. Telomerase activity was examined by the TRAP-assay and expression of the telomerase RNA (hTR) and HPV 16/18 E6/E7 oncogenes by RNA/RNA-in situ hybridization (ISH). The associated HPV-type was determined by PCR. Telomerase activity was observed in 25/29 (86%) SCCs, 31/41 (76%) high-grade SILs, 6/14 (43%) low-grade SILs, and 1/28 (3.6%) normal cervical tissues. Expression of hTR and viral oncogenes increased significantly with histopathologic severity of the lesion (p < 0.0001). A correlation was found between telomerase activity and intensity of viral oncogene expression. These findings suggest that telomerase activation occurs early in cervical carcinogenesis and is predominantly found in high-grade SILs and cervical SCCs. Our findings support current experimental data that suggest that telomerase is at least partially activated by viral oncogenes of high-risk HPV types. Telomerase activity with concomitant strong viral oncogene expression might therefore characterize a subset of lesions that are at risk for malignant progression.
Riethdorf
S
S
Institute of Pathology, Department of Gynecopathology, University of Hamburg, Germany.
Riethdorf
L
L
Schulz
G
G
Ikenberg
H
H
Jänicke
F
F
Löning
T
T
Park
T W
TW
D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000821:virology; D004279:DNA, Viral / Q000032:analysis*; D004789:Enzyme Activation; D005260:Female; D015870:Gene Expression; D006801:Humans; D009362:Neoplasm Metastasis; D027383:Papillomaviridae / Q000235:genetics*; D030361:Papillomavirus Infections / Q000175:diagnosis / Q000201:enzymology / Q000821:virology; D012333:RNA, Messenger / Q000032:analysis; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D014412:Tumor Virus Infections / Q000175:diagnosis / Q000201:enzymology / Q000821:virology; D002583:Uterine Cervical Neoplasms / Q000201:enzymology / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000201:enzymology / Q000821:virology
D004279:DNA, Viral; D012333:RNA, Messenger; D019098:Telomerase