Glioblastoma (GBM) is the most frequent adult malignant brain tumour and despite different therapeutic efforts, the median overall survival still ranges from 14 to 18 months. Thus, new therapeutic strategies are urgently needed. However, the identification of cancer-specific targets is particularly challenging in GBM, due to the high heterogeneity of this tumour in terms of histopathological, molecular, genetic and epigenetic features. Telomerase reactivation is a hallmark of malignant glioma. An activating mutation of the hTERT gene, encoding for the active subunit of telomerase, is one of the molecular criteria to establish a diagnosis of GBM, IDH-wildtype, in the 2021 WHO classification of central nervous system tumours. Telomerase inhibition therefore represents, at least theoretically, a promising strategy for GBM therapy: pharmacological compounds, as well as direct gene expression modulation therapies, have been successfully employed in in vitro and in vivo settings. Unfortunately, the clinical applications of telomerase inhibition in GBM are currently scarce. The aim of the present systematic review is to provide an up-to-date report on the studies investigating telomerase inhibition as a therapeutic strategy for malignant glioma in order to foster the future translational and clinical research on this topic.

Ageing is characterised by the accumulation of molecular and cellular damage through time, leading to a decline in physical and mental abilities. Currently, society has experienced a rapid increase in life expectancy, which has led to an increase in age-associated diseases. Therefore, it is crucial to study the process of ageing to guarantee the best conditions in the final stages of life. In recent years, interest has increased in a myokine known as irisin, which is secreted during physical exercise. This polypeptide hormone is produced by various organs, mainly muscle, and once it is released into the blood, it performs a wide variety of functions that are involved in metabolic control and may be relevant during some of the diseases associated with ageing. The aim of this review is to highlight the recent studies of irisin, such as its mechanism of expression, blood release, distribution, tissue target and participation in various cellular metabolic reactions and the relationship with key anti-ageing pathways such as adenosine monophosphate-activated protein kinase, silent information regulator T 1, autophagy and telomerase. In conclusion, irisin is a key player during the ageing process and it could be a novel target molecule for the therapeutic approach to boost longevity pathways. However, more research will be necessary to use this promising hormone for this gain.

Des mécanismes moléculaires liant le cancer à la sénescence cellulaire sont présentement explorés. Les télomères (l'extrémité des chromosomes) raccourcissent à chaque division cellulaire et il a été proposé que ce raccourcissement soit l'horloge moléculaire qui déclenche le processus de la sénescence cellulaire. La re-expression de la télomérase, une enzyme qui aide à maintenir la longueur des télomères et à prévenir leur raccourcissement, est un événement fréquemment observé dans les cellules tumorales. Cette re-expression est probablement essentielle à la formation et à la croissance soutenue de la majorité des cancers.

Objective: Analysis of the correlation between telomerase and the expression of its related proteins may provide insight into the molecular mechanism of nasopharyngeal carcinogenesis. We investigated the effect of short hair pin ribonucleic acid (RNA) specific for human telomerase reverse transcriptase messenger RNA on the expression of the proteins c-myc (the transcription factor c-myc is a shortlived nuclear phospho-protein involved in cell proliferation and differentiation, belongs to the myc family), proliferating cell nuclear antigen and Caspase-3 in nasopharyngeal carcinoma cells.

Methods: Short hairpin RNA expression vectors targeting the messenger RNA of human telomerase reverse transcriptase were constructed. Cells were treated with the short hairpin RNA expression vectors targeting human telomerase reverse transcriptase or vectors that included mismatched short hairpin RNA, and telomerase activity was measured by telomeric repeat amplification enzyme-linked immunosorbent assay. Cell viability was examined using the 3-(4,5-dimethyl thizol-2-yl) 2,5-diphenyl tetrazolium bromide assay. The expression of the three proteins (c-myc, proliferating cell nuclear antigen and Caspase-3) was determined by Western blotting.

Results: Short hairpin RNA specific for human telomerase reverse transcriptase messenger RNA significantly inhibited telomerase activity. In addition, the expression of and proliferating cell nuclear antigen were both inhibited, while the expression of Caspase-3 was up-regulated.

Conclusions: Our results suggest that short hairpin RNA directed against human telomerase reverse transcriptase inhibits cell viability by regulating telomerase activity and its related proteins expression in nasopharyngeal carcinoma cells. Therefore, RNA interference technology may be a promising strategy for the treatment of nasopharyngeal cancer.

Aims: to determine correlations between relative quantities of telomerase catalytic subunit m-ribonucleic acid (hTERT mRNA) and conventional clinicopathological parameters (such as site, size and grade of tumour, the presence of regional lymph node metastases, and, in particular, survival) in patients with laryngeal and hypopharyngeal squamous cell carcinomas (SCCs).

Material and methods: The relative quantity of hTERT mRNA was analysed by a commercially available LightCycler Telo TAGGG hTERT Quantification Kit in 56 cases of SCC (40 laryngeal and 16 hypopharyngeal). The association with cancer-specific survival was evaluated by univariate and multivariate analysis.

Results: Location of the tumour in the hypopharynx was the only significant negative predictive factor for survival, as determined by univariate analysis (p = 0.028). Although a tendency towards a better overall survival was observed for female patients younger than 50 years, for lower tumour grades and sizes, and for the absence of regional lymph node metastases, the prognostic significance of these factors could not be confirmed. No differences existed in hTERT mRNA expression between laryngeal and hypopharyngeal SCCs. Furthermore, no correlation was found between the relative quantities of hTERT mRNA and the tumour size, regional lymph node metastases or survival of patients with laryngeal or hypopharyngeal SCCs.

Conclusions: The results of the present study suggest that genetic abnormalities other than telomerase reactivation are responsible for progression of laryngeal and hypopharyngeal SCCs.

A number of different approaches have been developed to inhibit telomerase activity in human cancer cells. In this study, the effect of antisense oligonucleotides (ODNs) by targeting human telomerase reverse transcriptase (hTERT) mRNA in a laryngeal cancer cell line (Hep-2) was investigated. A 20mer antisense oligodeoxynucleotide targeting the most open part of hTERT mRNA (anti-hTERT) and a mismatched control sequence were synthesized. Cells were treated daily with oligonucleotides for up to 72 hours. hTERT mRNA expression was measured by the reverse transcription polymerase chain reaction (RT-PCR) assay; telomerase activity by the telomerase PCR ELISA assay kit (TRAP; Boehringer Mannheim, GmbH, Mannheim, Germany). Cell viability after administration of ODNs was determined using the MTT assay. Morphological changes were examined by haematoxylin and eosin staining. The cell cycle was analyzed using flow cytometry.

It was found that antisense treatment induced a decrease in hTERT mRNA expression, telomerase activity, cell growth rate, cell viability, and an increase in apoptosis. The results suggest that inhibition of telomerase activity in Hep-2 cells by short-term antisense treatment against the mRNA of hTERT results in apoptotic cell death. The treatment with anti-hTERT may be useful as a treatment modality for laryngeal squamous carcinoma.

Dyskeratosis congenita (DC) is a severe, inherited, bone marrow failure syndrome, with associated cutaneous and noncutaneous abnormalities. DC patients also show signs of premature ageing and have an increased occurrence of cancer. DC can originate through: (1) mutations in DKC1, which result in X-linked recessive DC; (2) mutations in the RNA component of telomerase (TERC), which result in autosomal dominant DC (AD-DC); and (3) mutations in other, currently uncharacterised, genes, which result in autosomal recessive DC (AR-DC). As DKC1 encodes dyskerin, a protein component of small nucleolar ribonucleoprotein (snoRNP) particles, which are important in ribosomal RNA processing, DC was initially described as a disorder of defective ribosomal biogenesis. Subsequently, dyskerin and TERC were shown to closely associate with each other in the telomerase complex, and DC has since come to be regarded as a telomerase deficiency disorder characterised by shorter telomeres. These findings demonstrate the importance of telomerase in humans and highlight how its deficiency (through DKC1 and TERC mutations) results in multiple abnormalities including premature ageing, bone marrow failure and cancer. Identification of the gene(s) involved in AR-DC will help to define the pathophysiology of DC further, as well as expand our insights into telomere function, ageing and cancer.

The management of malignant disease remains one of the most challenging areas of modern medicine. The lifetime risk of developing cancer in the western world is estimated to be as high as 1 in 3. Traditionally, surgery, chemotherapy and radiotherapy have been the primary choice of treatment for patients with malignant tumours. Despite advances in the use and development of conventional cytotoxic agents, the cure rate remains disappointing in most patients with advanced disease of the common solid tumours. Consequently, the development of novel anti-cancer therapies is a high priority in cancer medicine. In recent years, a new generation of cancer therapies has emerged, based on a growing understanding of the molecular events that contribute to malignant transformation. A major difference between normal and cancer cells is the ability of cancer cells to multiply in an unrestricted and ungoverned fashion. In this context, there is considerable interest in elucidating the mechanisms that allow this unrestricted proliferation and that ultimately result in immortal cancer cells. It is now clear that the enzyme telomerase confers immortality on cells in most types of cancer. With the cancer cell reliant on telomerase for its survival, telomerase represents an extremely attractive mechanism-based target for the development of new cancer therapeutics.

Telomerase maintains the length of telomeres in immortal cells and is also often associated with cell proliferation. Cholesteatoma epithelium is characterized by a dysregulation with hyperproliferative growth. The study evaluated the telomerase activity in cholesteatoma and normal retro-auricular skin to discover the relationship between telomerase expression and clinical findings. Twenty-two samples of cholesteatoma and 15 samples of retro-auricular skin were obtained from patients undergoing middle-ear surgery. The telomerase activity was detected by the telomerase repeat amplification protocol (TRAP) assay method. Seventeen of the 22 (77.3 per cent) cholesteatoma cases expressed telomerase activity, whereas none of the 15 retro-auricular normal skin (0 per cent) detected telomerase activity. There was no significant difference between telomerase expressions and clinical findings, including hearing level, duration of disease, and the degree of extension (p>0.05). The high expression of telomerase in cholesteatoma suggests that the activation of telomerase may be related to the proliferative nature of cholesteatoma.