Prognostic value of human telomerase reverse transcriptase gene expression in oral carcinogenesis

Department of Surgical Sciences, University of Foggia, Foggia, Italy.
International Journal of Oncology (Impact Factor: 3.03). 07/2007; 30(6):1349-57. DOI: 10.3892/ijo.30.6.1349
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Human telomerase reverse transcriptase (hTERT) gene expression in resected specimens of oral squamous cell carcinoma (OSCC) and their surrounding tissue, either apparently normal or clearly histologically dysplastic, was evaluated by both real-time RT-PCR and immunohisto-chemical protein analyses. The expression level of hTERT in oral dysplasia and in OSCC was markedly higher than in normal tissues. The correlation between hTERT expression in OSCC and clinico-pathological parameters or survival of OSCC patients was statistically analyzed. Our study demonstrates that there is no significant relationship between hTERT expression and classical clinico-pathological parameters. Interestingly, survival analysis showed both overexpressing cases and lower survival rate in the early stage of OSCC (p=0.03 for immunohistochemistry; p=0.04 for RT real-time PCR). The histological location of hTERT in these tumors has been discussed in the context of the cancer stem cell theory.

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    • "Kumar et al110 and Chen et al111 found that the expression of hTERT increased significantly from normal through OED to OSCC. At both the mRNA and protein levels, the expression of hTERT in OED and in OSCC was markedly higher than in normal tissues.109,112 Thus overexpression of immortalization marker may occur early in oral carcinogenesis and may be used as a diagnostic indicator in OED; however, its prognostic value remains unknown. "
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    ABSTRACT: Many attempts have been made to identify objective molecular biomarkers to diagnose and prognosticate oral epithelial dysplasia (OED) because histopathological interpretation is subjective and lacks sensitivity. The majority of these efforts describe changes in gene expression at protein level in OED as determined by immunohistochemistry (IHC). However, the literature on these putative markers of oral cancer progression is vast and varied. The main purpose of this article is to review current knowledge on biomarkers of protein expression for OED by IHC approaches. We further discuss these findings in terms of the proposed essential hallmarks of cancer cells to better understand their role in oral oncogenesis.
    10/2013; 5:49-60. DOI:10.4137/BIC.S12951
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    • "region, which was commonly present among the ODFs/OPMLs. This gene was reported to play a crucial role in telomere maintenance, chromosomal instability, DNA repair, negative regulation of apoptosis and was found to be amplified in several human cancers [39–42]. "
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    ABSTRACT: Oral fields of visually normal and non-dysplastic mucosa (ODFs) may represent the precursors of oral potentially malignant lesions (OPMLs). Aim of the study was to provide new evidence for the concept of the "field carcinogenesis" model by comparing the ODF and OPML genomic aberration profiles obtained by high resolution DNA flow cytometry (hr DNA-FCM) and array-Comparative Genomic Hybridization (a-CGH). A second aim was to investigate if specific CGH aberrations were associated with DNA aneuploidy. Nineteen patients with single OPMLs were recruited for the study. In parallel with obtaining samples of OPML tissue from 11 leukoplakias without dysplasia (nd-OPMLs) and 8 with dysplasia (d-OPMLs), we also obtained samples from distant ODFs. DNA aneuploid nuclei detected by hr DNA-FCM were physically separated, based on DNA content, from the DNA diploid components with a DNA-FCM-Sorter. These relatively pure subpopulations of epithelial nuclei were then submitted to DNA extraction and a-CGH for a genome-wide analysis of DNA copy number aberrations (CNAs). The frequencies of DNA aneuploidy (DI ≠ 1) among ODFs and OPMLs were respectively 5.3% and 32%. The DI aneuploid values of ODFs and nd-OPMLs were all near-diploid (DI ≠ 1 and DI ≤ 1.4), while for d-OPMLs were high-aneuploid (DI > 1.4) in 40% of the cases. CNA averages were 1.9 in ODFs and 6.5 in OPMLs. The gain of the chromosomal region 20q13.33-qter was observed in 37% of both ODFs and corresponding OPMLs. Additional common regions included 7p22.2-pter, 11p15.5-pter and 16p13.3-pter where gains were observed. Furthermore, gains of 20q13.31-q13.33 and of 5p13.33-pter and loss of 9p21.3 were detected at high frequency (respectively, at 62.5%, 50% and 50%) only in d-OPMLs. In particular, loss at 9p21.3, gain at 5p13.33-pter and gain of 20q13.31-q13.33 were associated with DNA aneuploidy (p = 0.00004; p = 0.0005; p = 0.01). ODFs and OPMLs showed common CNAs in specific chromosomal regions suggesting that they may represent early events of the natural history of oral carcinogenesis according to the field effect cancerization and may contribute to the ODF-OPML transition. In addition, loss at 9p21.3 and gains at 5p13.33-pter and 20q13.31-q13.33 may contribute to DNA aneuploidization.
    12/2011; 35(1):43-52. DOI:10.1007/s13402-011-0064-2
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    • "and/or abnormal expression of CDK4/cyclinD1 [18] [20] [36] [37]. OSCCs, like many other carcinomas , maintain telomere length with telomerase activation [21] [22]. Immortality is one of the important characteristics of malignancy and ectopic expression of these genes thus could mimic the events that occur during development of OSCCs. "
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    ABSTRACT: Oral squamous cell carcinomas (OSCCs) are considered to arise from human oral keratinocytes. DNAs of human papillomaviruses (HPVs), predominantly types 16 and 18, etiological agents of cervical cancer, have been detected in approximately 25% of OSCCs. In accordance with the established role of E6 and E7 in inactivating p53 and pRB, respectively, mutations of p53 and inactivation of p16(INK4a) are frequently observed in HPV-negative OSCCs. In addition, other alterations such as overexpression of epidermal growth factor receptor (EGFR) are often observed in both HPV-positive and -negative OSCCs. However, causal-relationships between accumulation of these abnormalities and multi-step carcinogenesis are not fully understood. To elucidate underlying processes, we transduced either HPV16 E6/E7 or mutant CDK4 (CDK4(R24C)), cyclin D1 and human telomerase reverse transcriptase (TERT) into primary human tongue keratinocytes (HTK), and obtained immortal cell populations, HTK-16E6E7 and HTK-K4DT. Additional transduction of oncogenic HRAS or EGFR together with MYC into the HTK-16E6E7 and dominant-negative p53 expressing HTK-K4DT resulted in anchorage-independent growth and subcutaneous tumor formation in nude mice. These results indicate that either HRAS mutation or activation of EGFR in cooperation with MYC overexpression play critical roles in transformation of HTKs on a background of inactivation of the pRB and p53 pathways and telomerase activation. This in vitro model system recapitulating the development of OSCCs should facilitate further studies of mechanisms of carcinogenesis in the oral cavity.
    American Journal of Cancer Research 01/2011; 1(7):869-81. · 4.17 Impact Factor
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