Combined evaluation of expression of telomerase, survivin, and anti-apoptotic Bcl-2 family members in relation to loss of differentiation and apoptosis in human head and neck cancers.
BACKGROUND
Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers, and it accounts for 5% of all adult cancers worldwide. Loss of growth control and a marked resistance to apoptosis are considered major mechanisms driving tumor progression. Little is known about the distribution of inhibitors of apoptosis in HNSCC or how they correlate with other biomarkers of malignancy, such as telomerase, an enzyme that plays a critical role in cellular immortalization. The objective of this study was to assess the protein expression of anti-apoptotic members of Bcl-2 family and survivin and correlate them with telomerase activity.


METHODS
We compared anti-apoptotic protein expression in tumor tissue sections of 50 HNSCC patients and 19 histopathologically normal tissues by immunohistochemistry and Western blotting. Apoptotic index was studied by TUNEL assay. Telomerase activity was determined by polymerase chain reaction (PCR)-enzyme-linked immunosorbent assay (ELISA).


RESULTS
Bcl-2, Bcl-XL, and survivin were found to be significantly upregulated in tumor tissues as compared with the normal tissue. Protein expression of Bcl-2 and survivin was significantly associated with the loss of differentiation in tumors and that of Bcl-XL with nodal metastasis. Telomerase activity was found to be upregulated in tumors as compared with the normal tissue (p <.001) and was found to be significantly associated with the loss of differentiation in tumors.


CONCLUSIONS
Mechanisms that promote both cell proliferation (telomerase activity) and cell survival (expression of inhibitors of apoptosis protein [IAPs]) appear to be activated in HNSCC. This is the first study of its kind to look into the correlation of the apoptotic pathway and proliferation promoting enzyme activity simultaneously in relation to loss of apoptosis and differentiation in HNSCCs. Telomerase activity in these tumors was found to be correlated with Bcl-2, Bcl-XL, and survivin overexpression and with reduced apoptosis, thereby suggesting that novel strategies can be developed to control cancer cell growth by co-targeting telomerase and apoptotic pathways.
Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India 110029.
Himani
H
Sharma
Sudip
S
Sen
Meera
M
Mathur
Sudhir
S
Bahadur
Neeta
N
Singh
D017209:Apoptosis / Q000502:physiology*; D044963:Biopsy, Fine-Needle; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000473:pathology* / Q000503:physiopathology; D016022:Case-Control Studies; D002455:Cell Division / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D008875:Middle Aged; D009363:Neoplasm Proteins; D016133:Polymerase Chain Reaction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D000077022:Survivin; D019098:Telomerase / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; D051020:bcl-X Protein; D019098:Telomerase