7015

TERT

telomerase reverse transcriptase;TERT;telomerase reverse transcriptase

telomerase catalytic subunit|telomerase-associated protein 2

5p15.33

protein-coding

Telomerase was found in cancers and immortalized cell lines, but only occasionally in normal tissues, thus suggesting that measurement of its hTERT subunit might help distinguishing benign from malignant tumors. Data on hTERT expression in adrenocortical tumors are scant and mostly confined to non-functioning tumors. Therefore, we investigated whether hTERT expression may predict malignancy in aldosterone producing adrenocortical tumors. We measured hTERT mRNA with a real-time one-step reverse transcription (RT) polymerase chain reaction (PCR) method, based on the use of hTERT-specific fluorescence resonance energy transfer (FRET) probes, in 19 adrenalectomized patients with aldosterone-producing adenomas (APAs), in whom long-term follow-up (median 7 years, range 5-14 years) data were available. We also studied two rare aldosterone-producing carcinomas (APCs), eight adrenocortical carcinomas (ACs), twelve normal adrenal cortexes, and two malignant cell lines (NCI-295H and SW-13). Telomerase activity and hTERT immunoreactivity were also investigated. Of interest, we detected hTERT mRNA in 58% of APAs at levels similar to those of malignant tumors, which all consistently showed hTERT expression. In hTERT expressing tumors, immunocytochemistry showed the nuclear expression of hTERT. No hTERT expression was found in the normal adrenocortical tissue. No histopathology differences were observed between hTERT-positive and -negative APAs; however, a patient originally held to have an hTERT-positive APA was retrospectively classified as APC because of metastatic spread. In conclusion, RT-PCR measurement of hTERT mRNA is a hallmark of malignant adrenocortical tumors, but identifies also a subset of hTERT-expressing APAs that might show metastatic spread at long-term follow-up.

A comprehensive proteomic study utilizing 2D-DIGE and MALDI-TOF was used to assess the effect of inhibiting two different regulatory mechanisms of telomerase in glioma. RNAi was used to target hTERT and hsp90alpha. Inhibition of telomerase activity resulted in downregulation of various cytoskeletal proteins with correlative evidence of the involvement of telomerase in regulating the expression of vimentin. Inhibition of telomerase via sihTERT resulted in the downregulation of vimentin expression in glioma cell lines in a grade-specific manner. This study identified novel downstream role of telomerase in regulating the expression of vimentin, thereby affecting tumor progression and metastasis.

Stage 4 neuroblastomas have a high rate of local and metastatic relapse and associated disease mortality. The central nervous system (CNS) is currently one of the most common isolated relapse sites, yet the genomic alterations that contribute to these metastases are unknown. This study sought to identify recurrent DNA copy number alterations (CNAs) and target genes relating to neuroblastoma CNS metastases by studying 19 pre-CNS primary tumors and 27 CNS metastases, including 12 matched pairs. SNP microarray analyses revealed that MYCN amplified (MYCNA) tumors had recurrent CNAs different from non-MYCNA cohorts. Several CNAs known to be prevalent among primary neuroblastomas occurred more frequently in CNS metastases, including 4p-, 7q+, 12q+, and 19q- in non-MYCNA metastases, and 9p- and 14q- irrespective of MYCNA status. In addition, novel CNS metastases-related CNAs included 18q22.1 gains in non-MYCNA pre-CNS primaries and 5p15.33 gains and 15q26.1-->tel losses in non-MYCNA CNS metastases. Based on minimal common regions, gene expression, and biological properties, TERT (5p), NR2F2 (15q), ALDH1A3 (15q), CDKN2A (9p), and possibly CDH7 and CDH19 (18q) were candidate genes associated with the CNS metastatic process. Notably, the 5p15 minimal common region contained only TERT, and non-MYCNA CNS metastases with focal 5p15 gains had increased TERT expression, similar to MYCNA tumors. These findings suggest that a specific genomic lesion (18q22.1 gain) predisposes to CNS metastases and that distinct lesions are recurrently acquired during metastatic progression. Among the acquired lesions, increased TERT copy number and expression appears likely to function in lieu of MYCNA to promote CNS metastasis.

Telomerase reactivation, which prevents telomere shortening and maintains cell viability, is crucial for the continued growth or progression of cancer cells. A minisatellite tandem repeat, MNS16A, located in the downstream of the human telomerase reverse transcriptase (hTERT) gene was recently identified and reported to have an effect on hTERT expression and telomerase activity. The aim of this study was to test the hypothesis that the MNS16A variant is associated with risk of breast cancer development and metastasis. We genotyped MNS16A variant in hTERT in a case-control study of 1029 histologically confirmed breast cancer patients and 1107 cancer-free controls in Chinese women. The variant genotypes (302/271, 302/243 and 243/243) of MNS16A were associated with a significantly increased risk of breast cancer [adjusted odds ratio (OR) = 1.50, 95% confidence interval (CI) = 1.15-1.96], compared with the wild-type 302/302 genotype. In stratified analyses, we found that the 302/271 genotype was associated with a significantly increased risk of axillary lymph nodes metastasis (adjusted OR = 2.13, 95%

Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of human telomerase and its rate-limiting component. The purpose of the present study was to investigate the diagnostic value of hTERT in serum of cervical cancer patients. Preoperative values of hTERT, squamous cell carcinoma antigen (SCC-ag) and cancer antigen 125 (CA 125) were measured by enzyme-linked immunosorbent assay (ELISA) in 192 patients with squamous cell carcinoma or adenocarcinoma of the uterine cervix and 38 healthy controls. Elevated pretreatment levels of hTERT were identified in 80.2% of squamous cell carcinoma and 73.8% of adenocarcinoma patients. The expression of serum hTERT was correlated with telomerase activity in cancer tissues of both histological types. Pretreatment serum hTERT levels showed a significant correlation with clinical stage, tumor size and lymph node metastasis, but not with age. Serum hTERT measurement was found to be useful in the diagnosis and assessment of clinical stage of cervical cancer, and to be superior to the conventional tumor markers. Therefore, serum hTERT is a novel and readily available marker for cervical malignancies.

OBJECTIVE: To investigate the effect of hTERT single nucleotide polymorphisms on the development and metastasis of hepatocellular carcinoma. METHODS: A total of 290 male patients were divided into hepatitis-induced primary hepatocellular carcinoma (HCC) group (n%162), metastatic HCC group (n%22), and control group (n%106). hTERT gene was amplified and hTERT single nucleotide polymorphisms (SNPs) were tested in these subjects. RESULTS: Significant differences were found in rs2853690 and rs10069690 distribution, but the difference in rs6554743 remained uncertain. The C and T alleles of rs10069690 and rs6554743 showed significant differences between the 3 groups; the carriers of non-T allele of rs10069690 had higher frequencies in both primary and metastatic HCC groups. CONCLUSION: Some of the polymorphisms of hTERT may increase the risks of development and metastasis of hepatocellular carcinoma.

OBJECTIVE: To study the correlation of the expressions of CD82 and hTERT and HPV infection with the clinical pathological features of penile cancer and identify their prognostic significance in the lymphatic metastasis of the disease. METHODS: A total of 44 patients underwent partial or radical penectomy and lymph node dissection. The expressions of CD82 and hTERT were determined by immunohistochemistry, and HPV infection was detected by PCR. RESULTS: The positive rates of CD82, hTERT, and HPV DNA in penile carcinoma were 47.7%, 38.6% and 25.9%, respectively. The amplified HPV DNA was HPV-16. The pathological stage and hTERT expression were positively correlated with inguinal lymph node metastasis of penile cancer (P = 0.032, P = 0.041), and so was the pathological stage with the expression of CD82 (P = 0.045), but neither the pathological stage, nor the expression of CD82 or the positive rate of HPV DNA showed any correlation with lymph node metastasis (P = 0.627, P = 0.094, P = 0.633). CONCLUSION: The pathological grade and hTERT expression are independent prognostic factors for lymph node metastasis in penile carcinoma. These features help the prognosis and identification of the patient at the risk of nodal metastasis.

Stromal cell-derived factor-1 (SDF-1)/CXCR4 pathway has been shown to play an important role in prostate cancer (PCa) metastasis and siRNA expression using cell-specific promoters has been demonstrated to be a potential tool for targeted gene therapy. Here, we illustrate that human telomerase reverse transcriptase (hTERT) promoter-induced CXCR4 knockdown inhibits PCa bone metastasis. We first investigated CXCR4 expressions and interactions of CXCR4/SDF-1 in PCa cells, developed a retrovirus system that could stably express CXCR4 small hairpin RNA driven by hTERT promoter and then determined the inhibitory effects of cell-specific blockade of CXCR4/SDF-1 pathway on PCa metastasis. It was shown that both PCa tissues and cell lines expressed CXCR4 and the expression in PCa tissue had a positive correlation to clinical stages while not to Gleason scores or serum PSA level. PCa metastases most presenting human tissues expressed high levels of SDF-1. Exogenous SDF-1 enhanced in vitro adhesion, migration and invasion of PCa cells and these bioeffects were repressed by hTERT promoter-induced CXCR4-shRNA expression. This CXCR4 knockdown was also found to significantly inhibit bone metastasis in vivo. We conclude that CXCR4/SDF-1 pathway plays an important role in PCa bone metastasis. hTERT promoter-induced tumor cell-specific CXCR4 gene silencing may prevent in vitro invasiveness and in vivo bone metastasis of PCa. These findings may enable new avenues of prevention and treatment for PCa metastasis.