Cancer, also known as malignant tumors, is formed due to abnormal mutations and the proliferation of human cells. Cancer cells not only demonstrate accelerated proliferation but also show robust invasive and metastatic potential, disseminating from a primary affected region of the body to multiple areas and potentially culminating in organ dysfunction or failure, thereby jeopardizing the individual's life. The rapid growth of the biopharmaceutical market has given rise to numerous novel medicines, thereby precipitating a paradigm shift in contemporary drug development methodologies. This modification is focused on identifying methodologies that can effectively target cancerous cells while minimizing damage to normal cells. There is an increasing societal movement that supports the utilization of natural ingredients derived from plants. In recent years, traditional herbal medicine has experienced a surge in popularity within the global cancer market. In comparison with the use of more toxic chemotherapy methods, there has been an increasing focus on advanced therapies that exhibit reduced side effects. Ginsenoside compound K (CK) is derived from the natural components in ginseng through biotransformation. The utilization of CK in cancer research is a practice engaged in by numerous scientists. The underlying rationale is that CK exhibits a multitude of effects within the realm of cancer research, including but not limited to the mitigation of inflammation, the suppression of cancerous cell proliferation, and the safeguarding of cardiovascular, hepatic, and renal functions. This review methodically identifies and organizes CK-related journals according to the following key points of cancer treatment: the effects on cancer cells themselves, angiogenesis inhibition, modulation of immune response to identify cancer cells, and inflammation regulation. The intricate interplay between ginsenoside CK and cells is elucidated through a graphical representation. The present review focuses on the results of CK in in vitro tests. It is our hope that the present article will aid future studies on the results of CK in vivo tests, clarify the correlation between cellular mechanisms in vivo and in vitro tests, and assist in the development of drugs.

The telomerase reverse transcriptase (TERT) promoter mutations have been linked to the prognosis and survival of several cancers; however, it is still debatable in case of oral squamous cell carcinoma. The exact reason for it is currently unknown. However, considering its role in cell survival and proliferation it is imperative to evaluate the association between TERT promoter mutations and OSCC. The systematic review and meta-analysis were carried out to gather evidence for TERT promotor mutation in OSCC. Electronic databases along with grey literature were searched for relevant studies. We used fixed- or random-effect models to calculate pooled proportion, estimated odds ratios or standardized mean differences, and corresponding 95% confidence intervals (CIs). We included 13 eligible studies incorporating 816 cases. The average frequency of TERT promotor mutation was 46.1% (0.46, 95% CI, 0.33, 0.60). However, TERT promoter mutations were not associated with gender, habit (smoking and betel nut), nodal involvement, metastases, and TNM stage. C228T (189/287), C250T (73/287), C228A, and other variants of TERT mutation were frequently detected TERT mutation variant in OSCC. TERT promoter mutations could be considered as biomarkers assisting in risk stratification and prognostic prediction.

G-quadruplex (G4) structures are non-canonical nucleic acid conformations that play crucial roles in gene regulation, DNA replication, and telomere maintenance. Recent studies have highlighted G4 ligands as promising anticancer agents due to their ability to modulate oncogene expression and induce DNA damage. By stabilizing G4 structures, these ligands affect tumor progression. Additionally, they have been implicated in tumor immunity modulation, particularly through the activation and immunogenic cell death induction of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. Moreover, their disruption of telomere maintenance and regulation of key oncogenes, such as c-MYC and KRAS, position them as candidates for immune-based therapeutic interventions. Despite their therapeutic potential, challenges remain in optimizing their clinical applications, particularly in patient stratification and elucidating their immunomodulatory effects. This review provides a comprehensive overview of the mechanisms through which G4 ligands influence tumor progression and immune regulation, highlighting their potential role in future cancer immunotherapy strategies.

The relationship of Leukocyte telomere length (LTL) dynamic changes with resectable NSCLC progression remains unclear. This study aims to reveal its clinical utility for prognosis of the resectable NSCLC. LTL was measured in 76 resectable NSCLC patients and 80 healthy controls using peripheral blood samples. Pre-operation LTL (Pre-LTL) and post-operation LTL (Po-LTL) were analyzed in relation to TNM stage, metastasis, and survival outcomes. The prognostic value was evaluated by disease-free survival (DFS) and overall survival (OS). NSCLC patients had significantly shorter LTL compared to controls, with LTL inversely correlated to disease stage. Po-LTL increased significantly and was associated with better OS. Combining Po-LTL with TNM stage improved prognostic prediction for OS and DFS. LTL is a promising biomarker for predicting prognosis in resectable NSCLC. Po-LTL, as well as in combination with TNM stage, enhances predictive accuracy for OS and DFS.

Telomere repeat binding factor 2 (TRF2) is currently a novel tumor marker, yet its clinical implication has not been investigated. The aim of this study was to investigate the prognostic value of circulating TRF2 and leukocyte telomere length in 5-year mortality in breast cancer patients. In this cohort retrospective study, breast cancer patients were included and the length of telomeres and circulating TRF2 were quantified. Receiver operating characteristics and the Youden index were used to determine the optimal cut-off. To analyze the overall survival rate in five years, Kaplan Meier analysis was used, while the prognostic value of both variables was analyzed in Cox proportional hazard regression on both univariate and multivariate models. Our data indicated that the optimal cut-off points for TRF2 and leukocyte telomere length were 598 pg/mL and 0.93 kb, respectively. Based on the optimal cut-off points, the participant's data was grouped, and our data indicated that the high TRF2 group had a poorer overall survival rate in comparison to the low group (91.3% vs 83.87%; log-rank test; p < 0.01). The overall survival between short and long telomeres was comparable (88.24% vs 88.37%; log-rank test; p = 0.64). TRF2 (hazard ratio (HR): 3.66; 95%CI: 1.45-9.29) and molecular subtype (p = 0.04) were identified as independent factors to predict mortality. In conclusion, a high circulating TRF2 in breast cancer participants was associated with lower overall 5-year survival rates in comparison with the low TRF2 group. Moreover, high TRF2 could predict the mortality of the breast cancer population to be 3.66 times higher than the lower group. In contrast, telomere length was not associated with overall survival rate nor predicting mortality in five years.

The expression of the hTERT component of the human telomerase is elevated in different types of malignancies, including skin cancer. Early diagnosis of malignant melanoma is necessary to improve the prognosis of the disease. Although there are many diagnostic biomarkers for malignant melanoma, none is accurate, specific, and sensitive. The aim of the present study is to evaluate the expression rate and patterns of the hTERT component of human telomerase in melanoma and to compare this with squamous cell carcinoma as a common non melanoma skin cancer to investigate the potential of using telomerase as a molecular biomarker for the early diagnosis of this tumor. Additionally, the study compared the telomerase expression in these two tumor types with varying clinicopathological parameters.

In this retrospective observational study, a total of 348 formalin-fixed paraffin-embedded tissue microarrays samples consisting of cutaneous melanoma (n = 189), squamous cell carcinoma (n = 115), and normal human skin samples (n = 44) were analyzed by immunohistochemistry for the expression of the hTERT component of human telomerase.

Out of 189 melanoma cases, 97 (51.3%) showed positive telomerase expression in contrast to detection of telomerase expression only in 3 out of 115 (2.6%) squamous cell carcinoma tissue samples. The telomerase was expressed only in 5 out of 44 normal human skins.

Our data indicate that telomerase expression is significantly more pronounced in melanoma compared to squamous cell carcinoma. These findings may support the potential utilization of telomerase as a biomarker for early diagnosis and monitoring of melanoma which can lead to timely treatment and enhances a better outcome.

The telomerase complex consists of a protein component (TERT), which has reverse transcriptase activity, and an RNA component (TERC), which serves as a template for telomere synthesis. Evidence is rapidly accumulating regarding the non-canonical functions of these components in both normal or diseased cells. An oligonucleotide-based drug, the first telomerase inhibitor, secured FDA approval in June 2024. We recently summarized the non-canonical functions of TERT in viral infections and cancer. In this review, we expand on these non-canonical functions of TERC beyond telomere maintenance. Specifically, we explore TERC's roles in cellular aging and senescence, immune regulation, genetic diseases, human cancer, as well as involvement in viral infections and host interactions. Finally, we discuss a transcription product of telomere repeats, TERRA, and explore strategies for targeting TERC as a therapeutic approach.

Telomere maintenance mechanism significantly impacts the metastasis, progression, and survival of breast cancer (BC) patients. This study aimed to investigate the role of telomere maintenance-related genes (TMRGs) in BC prognosis and to construct a related prognostic model.

Differentially expressed genes were identified from the TCGA-BC cohort, and functional enrichment analysis was conducted. TMRGs were sourced from the literature and intersected with DEGs. Candidate genes were selected using machine learning algorithms, including Lasso Cox, Random Forest, and XGBoost. Multivariate Cox regression analysis was conducted to construct a prognostic model and identify hub genes. Subsequent analyses included survival analysis, gene set enrichment analysis (GSEA), immune infiltration analysis, and drug sensitivity analysis of the hub genes. Finally, in vitro experiments were conducted to validate the expression of the hub genes.

A total of 1329 differentially expressed TMRGs were analyzed, with 128 significantly associated with overall survival. Machine learning identified 7 prognosis-related TMRGs: MECP2, PCMT1, PFKL, PTMA, TAGLN2, TRMT5, and XRCC4. These genes were used to construct a prognostic model, with MECP2, PCMT1, PFKL, TAGLN2, and XRCC4 as harmful factors, while PTMA and TRMT5 were protective. The model demonstrated a significant prognostic value (AUC: 0.81, 0.72, 0.69 for 1-, 3-, and 5-year, respectively). Survival analysis confirmed the prognostic relevance of these genes, and GSEA highlighted their roles in oxidative phosphorylation, glycolysis, and PI3K/AKT/mTOR signaling.

The study identified 7 key TMRGs with significant prognostic value in BC. The constructed model effectively stratifies patient risk, providing a foundation for targeted therapies and personalized treatment strategies.

Telomeres are dynamic complexes at the ends of chromosomes that are made up of protective proteins and tandem repeating DNA sequences. In the large majority of cancer cells, telomere length is maintained by telomerase, an enzyme that elongates telomeres. Telomerase activation is seen in the majority of cancer, which permits uncontrol cell proliferation. About 90% of human malignancies show telomere dysfunction and telomerase reactivation; as a result, telomerase activation plays a special role as a practically universal stage on the way to malignancy. This review understands the structural and functional of telomere and telomerase, mechanisms of telomerase activation in oncogenesis, biomarkers and therapeutic targets. Therapeutic strategies targeting telomerase, including antisense oligonucleotides, G-quadruplex stabilizers, immunotherapy, small-molecule inhibitors, gene therapy, Telomerase-Responsive Drug Release System, have shown promise in preclinical and clinical settings. Advances in telomere biology not only illuminate the complex interplay between telomeres, telomerase, and cancer progression but also open avenues for innovative, targeted cancer therapies.

Telomerase reverse transcriptase (TERT), a critical player in cellular immortalization, has emerged as a focal point of investigation due to its frequent promoter mutations in various human malignancies. TERT promoter mutations exhibit a significant role in tumorigenesis, fostering unbridled cellular proliferation and survival. This comprehensive review delves into the landscape of TERT promoter mutations and their profound implications in cancer, particularly within the context of gliomas. This article meticulously examines the intricate interplay between TERT promoter mutations and the metastatic cascade, shedding light on their capacity to orchestrate invasive behavior in gliomas. Moreover, this review describes the recent trends in therapeutic targeting of the TERT and dissects the evolving landscape of drug resistance associated with TERT mutations, providing insights into potential therapeutic challenges. In addition, the diagnostic and prognostic implications of TERT promoter mutations in gliomas are scrutinized, unraveling their potential as robust biomarkers. It also discusses the recent advancements in molecular diagnostics, illustrating the promise of TERT mutations as diagnostic tools and prognostic indicators. This review collectively aims to contribute to a deeper understanding of TERT promoter mutations in gliomas, offering a foundation for future research endeavors and paving the way for innovative strategies in glioma management.

Gastric cancer (GC) poses a major global health challenge because of its unfavorable prognosis. Elevated telomerase activity has been linked to the rapid growth and invasiveness of GC tumors. Investigating the expression profiles of telomerase could improve our understanding of the mechanisms underlying telomere-related GC advancement and its applicability as potential targets for diverse therapeutic strategies for GC.

The TCGA and GEO databases were utilized to access transcriptome and clinical data related to GC. After assessing differentially expressed genes (DEGs), a prognostic risk model was developed through Cox univariate regression, LASSO-Cox regression. The prognostic risk model was validated using data from the GSE62254 cohort. The significant influence of the risk model on the tumor immune microenvironment (TIME) and its sensitivity to various drugs was assessed.

Differential expression analysis identified 328 significantly telomere-related DEGs in GC, with 35 of them showing a significant association with GC prognosis. A predictive risk model composed of four telomere-related genes (TRGs) was established, enabling the accurate stratification of GC patients into two distinct prognostic groups. The LASSO risk model demonstrated notable variations in immune-cell infiltration and drug sensitivity patterns between high- and low-risk groups.

The study establishes suggestive relationships between four TRGs (LRRN1, SNCG, GAMT, and PDE1B) and the prognosis of GC. The comprehensive characterization of the TRG model reveals their possible roles in the prognosis, TIME, and drug sensitivity in GC.

Telomeres and telomerase play crucial roles in the initiation and progression of cancer. As biomarkers, they aid in distinguishing benign from malignant tissues. Despite the promising therapeutic potential of targeting telomeres and telomerase for therapy, translating this concept from the laboratory to the clinic remains challenging. Many candidate drugs remain in the experimental stage, with only a few advancing to clinical trials. This review explores the relationship between telomeres, telomerase, and cancer, synthesizing their roles as biomarkers and reviewing the outcomes of completed trials. We propose that changes in telomere length and telomerase activity can be used to stratify cancer stages. Furthermore, we suggest that differential expression of telomere and telomerase components at the subcellular level holds promise as a biomarker. From a therapeutic standpoint, combining telomerase-targeted therapies with drugs that mitigate the adverse effects of telomerase inhibition may offer a viable strategy.

This study investigates the interrelationship between human telomerase reverse transcriptase (hTERT) and ferroptosis in precursor-B (pre-B) acute lymphoblastic leukemia (ALL), specifically examining how hTERT modulation affects ferroptotic cell death pathways. Given that hTERT overexpression characterizes various cancer phenotypes and elevated telomerase activity is observed in early-stage and relapsed ALL, we investigated the molecular mechanisms linking hTERT regulation and ferroptosis in leukemia cells. The experimental design employed Nalm-6 and REH cell lines under three distinct conditions: curcumin treatment, hTERT siRNA knockdown, and their combination. Cell viability and proliferation were assessed via MTT and BrdU assays at 24- and 48-hour intervals post-treatment. Ferroptotic and oxidative markers were quantified using commercial assays, while cell death parameters and gene expression were evaluated through flow cytometry and qRT-PCR analyses. Molecular docking studies were performed to evaluate protein-ligand interactions. Results demonstrated that combined curcumin treatment and hTERT knockdown significantly enhanced cytotoxicity in Nalm-6 cells compared to individual interventions. This was characterized by the upregulation of ferroptosis promoters (lipid-ROS, Fe²⁺, ACSL4) and suppression of inhibitors (GSH, GPx, SLC7A11, GPx4). The response showed cell-line specificity, with Nalm-6 cells exhibiting enhanced ferroptotic sensitivity while REH cells underwent apoptotic cell death. Molecular docking revealed strong curcumin-protein interactions (∆G = -34.24 kcal/mol for hTERT). This study establishes hTERT as a critical regulator of ferroptotic cell death in pre-B ALL, operating through redox homeostasis, iron metabolism, and lipid peroxidation pathways. The cell-type-specific responses suggest promising therapeutic strategies through combined hTERT suppression and ferroptosis induction.

Esophageal squamous cell carcinoma (ESCC) is a malignant tumor with high morbidity and mortality, and easy to develop resistance to chemotherapeutic agents. Telomeres are DNA-protein complexes located at the termini of chromosomes in eukaryotic cells, which are unreplaceable in maintaining the stability and integrity of genome. Telomerase, an RNA-dependent DNA polymerase, play vital role in telomere length maintain, targeting telomerase is a promising therapeutic strategy for cancer.

To investigate the efficacy and underlying mechanisms of BIBR1532, a telomerase inhibitor, in ESCC.

KYSE150 and KYSE410 cells were cultured and exposed to various concentrations of BIBR1532. Cell viability was assessed at 48 hours and 72 hours to determine the IC50 values. The effects of BIBR1532 on ESCC cell proliferation, migration, and cellular senescence were evaluated using the cell counting kit-8 assay, plate colony formation assay, scratch assay, transwell assay, and β-galactosidase staining, respectively. Western blotting was performed to detect the expression of proteins in BIBR1532-treated ESCC cells, such as human telomerase reverse transcriptase (hTERT), key molecules involved in DNA damage response (DDR) or cellular senescence, as well as telomere-binding proteins. Additionally, a tumor-bearing nude mouse model was established to evaluate the anti-cancer effect of BIBR1532 in vivo.

The IC50 values for KYSE150 and KYSE410 cells after 48 hours of BIBR1532 exposure were 48.53 μM and 39.59 μM, respectively. These values decreased to 37.22 μM and 22.71 μM, respectively, following a longer exposure of 72 hours. BIBR1532 exhibited dose-dependent effects on KYSE150 and KYSE410 cells, including decreased hTERT expression, inhibition of proliferation and metastasis, and induction of cellular senescence. Mechanistically, BIBR1532 upregulated the expression of the DDR protein, γ-H2AX, and activated the ataxia telangiectasia and Rad3-related protein (ATR)/ check point kinase 1 (CHK-1) and ataxia-telangiectasia mutated gene (ATM)/CHK2 pathways. BIBR1532 downregulated the expression of telomere-binding proteins, including telomeric-repeat binding factor 1 (TRF1), TRF2, protection of telomeres 1, and TIN2-interacting protein 1. In a nude mouse xenograft model, BIBR1532 significantly suppressed tumor growth, reduced hTERT expression, and increased γ-H2AX protein levels. Hematoxylin and eosin staining of various organs, including the heart, liver, spleen, lungs, and kidneys, revealed no apparent adverse effects.

BIBR1532 exerts anti-cancer effects on ESCC by inducing DDR through the ATR/CHK1 and ATM/CHK2 pathways and downregulating the expression of telomere-binding proteins.

High telomerase activity has been detected in over 85 % of tumors, with the activation of hTERT being the most crucial mechanism for re-establishing telomerase activity. Activation of hTERT maintains telomere length in cells, enabling cancer cells to proliferate indefinitely. Nevertheless, the specific mechanism of telomerase activation in non-small cell lung cancer (NSCLC) remains unclear, and post-transcriptional regulation of hTERT could be a potential activation mechanism.

We explored the regulatory impact of CMSS1 on hTERT expression in NSCLC cells using several methods: Yeast three-hybrid system, Reporter gene assay, Western blot, RNA decay assay, and Telomere length measurement. Our analysis revealed significant overexpression of CMSS1 in NSCLC, which correlated with poor prognosis, as determined by bioinformatics and tissue microarray techniques. RNA sequencing analysis showed that CMSS1 knockdown influenced the adhesion capabilities of NSCLC cells. Additionally, potential interacting proteins with CMSS1 were identified through mass spectrometry and co-immunoprecipitation experiments.

We discovered that CMSS1 regulates hTERT expression in NSCLC cells by binding to the 5' UTR of hTERT mRNA, impacting its mRNA stability and thereby influencing NSCLC progression. RNA-Seq results and adhesion experiments indicated that CMSS1 knockdown disrupts cell adhesion. hTERT also affects cell adhesion in NSCLC, underscoring CMSS1's role as an upstream regulator of hTERT. Mass spectrometry and Co-IP studies suggest potential interactions between CMSS1, RBM34, and DDX5 that further modulate hTERT expression.

These findings indicate that CMSS1 plays a crucial role in NSCLC progression through its interaction with hTERT, making it a promising therapeutic target.

Traffic-related particulate matter (PM) and polycyclic aromatic hydrocarbons (PAHs) have been linked to respiratory diseases and cancer risk in humans. Genomic damage, including benzo[a]pyrene diolepoxide (BPDE)-DNA adducts as well as alterations in telomere length (TL) and mitochondrial DNA copy number (mtDNA-CN) are associated with respiratory diseases. This study aimed to investigate the association between exposure to traffic-related particulate pollutants and genomic damage in exhaled breath condensate (EBC) in human subjects and a bronchial epithelial cell line (BEAS-2B). Among the 60 healthy recruited subjects, residents living in high-traffic-congested areas were exposed to higher concentrations of PM2.5 (1.66-fold, p < 0.01), UFPs (1.79-fold, p < 0.01), PM2.5-PAHs (1.50-fold, p < 0.01), and UFPs-PAHs (1.35-fold, p < 0.05), than those in low-traffic-congested areas. In line with increased exposure to particulate air pollution, the high-traffic-exposed group had significantly increased BPDE-DNA adducts (1.40-fold, p < 0.05), TL shortening (1.24-fold, p < 0.05), and lower mtDNA-CN (1.38-fold, p < 0.05) in EBC. The observations in the human study linking exposure to PM2.5, UFPs, PM2.5-PAHs, and UFPs-PAHs with the aforementioned biological effects were confirmed by an in vitro cell-based study, in which BEAS-2B cells were treated with diesel exhaust particulate matter (DEP) containing fine and ultrafine PM and PAHs. Increased BPDE-DNA adducts levels, shortened TL, and decreased mtDNA-CN were also found in treated BEAS-2B cells. The shortened TL and decreased mtDNA-CN were in part mediated by decreased transcript levels of hTERT, and SIRT1, which are involved in telomerase activity and mitochondrial biogenesis, respectively. These results suggest that exposure to traffic-related particulate pollutants can cause genomic instability in respiratory cells, which may increase the health risk of respiratory diseases and the development of cancer.

Telomerase, an enzyme crucial for maintaining telomere length, plays a critical role in cellular immortality and is overexpressed in most cancers. This ubiquitous presence makes telomerase, and specifically its catalytic subunit, human telomerase reverse transcriptase (hTERT), an attractive target for cancer immunotherapy. This review explores the development and application of telomerase-based vaccines, focusing on DNA and peptide-based approaches. While DNA vaccines demonstrate promising immunogenicity, peptide vaccines, such as UV1, UCPVax, and Vx-001, have shown clinical efficacy in certain cancer types. Recent advancements in vaccine design, including multiple peptides and adjuvants, have enhanced immune responses. However, challenges remain in achieving consistent and durable anti-tumor immunity. Accordingly, we discuss the mechanisms of action, preclinical and clinical data, and the potential of these vaccines to elicit robust and durable anti-tumor immune responses. This review highlights the potential of telomerase-based vaccines as a promising strategy for cancer treatment and identifies areas for future research.

Telomerase reverse transcriptase (TERT) is a catalytic subunit of telomerase and required for cancer development. This study aims to reveal its clinical utility for diagnosis and prognosis of resectable NSCLC.

TERT was quantitatively evaluated by the enzyme-linked immunosorbent assay (ELISA) from 69 patients before and after the surgery. The prognostic value was evaluated by disease-free survival (DFS) and overall survival (OS).

Circulating TERT in NSCLC patients were significantly higher than that in the healthy group, possessing the AUC of 0.90. Importantly, TERT change between pre- and post- operation was significantly correlated with OS and DFS (p = 0.022, p = 0.046 respectively), acted as the independent prognostic factors for DFS and OS, indicating it can serve as the promising diagnostic and prognostic biomarker for resectable non-small cell lung cancer (NSCLC).

TERT change between pre- and post- resection can serve as the promising biomarker for prognosis of resectable NSCLC.

Biological age is a concept that reflects the physiological state of an individual rather than the chronological time since birth. It can help assess the risk of age-related diseases and mortality and the effects of interventions to slow down or reverse aging. However, there is no consensus on measuring biological age best, and different methods may yield different results. In this paper, which includes 140 relevant pieces of literature, out of 33,000, we review some new methods to measure biological age based on recent advances in biotechnology and data science. We discussed some novel biomarkers and algorithms that can capture the dynamic and multidimensional aspects of aging at different levels. We evaluate their performance and validity using various datasets and criteria and compare them with existing methods. We also discuss their potential applications and implications for aging research and clinical practice. We conclude that the new methods offer more accurate and reliable estimates of biological age and open new avenues for understanding and modulating the aging process.

Telomeres, which are situated at the terminal ends of chromosomes, undergo a reduction in length with each cellular division, ultimately reaching a critical threshold that triggers cellular senescence. Cancer cells circumvent this senescence by utilizing telomere maintenance mechanisms (TMMs) that grant them a form of immortality. These mechanisms can be categorized into two primary processes: the reactivation of telomerase reverse transcriptase and the alternative lengthening of telomeres (ALT) pathway, which is dependent on homologous recombination (HR). Various strategies have been developed to inhibit telomerase activation in 85-95% of cancers, including the use of antisense oligonucleotides such as small interfering RNAs and endogenous microRNAs, agents that simulate telomere uncapping, expression modulators, immunotherapeutic vaccines targeting telomerase, reverse transcriptase inhibitors, stabilization of G-quadruplex structures, and gene therapy approaches. Conversely, in the remaining 5-15% of human cancers that rely on ALT, mechanisms involve modifications in the chromatin environment surrounding telomeres, upregulation of TERRA long non-coding RNA, enhanced activation of the ataxia telangiectasia and Rad-3-related protein kinase signaling pathway, increased interactions with nuclear receptors, telomere repositioning driven by HR, and recombination events between non-sister chromatids, all of which present potential targets for therapeutic intervention. Additionally, combinatorial therapy has emerged as a strategy that employs selective agents to simultaneously target both telomerase and ALT, aiming for optimal clinical outcomes. Given the critical role of anti-TMM strategies in cancer treatment, this review provides an overview of the latest insights into the structure and function of telomeres, their involvement in tumorigenesis, and the advancements in TMM-based cancer therapies.

Epithelial-Mesenchymal Transition (EMT) is a fundamental biological process involved in embryonic development, wound healing, and cancer progression. In lung cancer, EMT is a key regulator of invasion and metastasis, significantly contributing to the fatal progression of the disease. Age-related factors such as cellular senescence, chronic inflammation, and epigenetic alterations exacerbate EMT, accelerating lung cancer development in the elderly. This review describes the complex mechanism among EMT and age-related pathways, highlighting key regulators such as TGF-β, WNT/β-catenin, NOTCH, and Hedgehog signalling. We also discuss the mechanisms by which oxidative stress, mediated through pathways involving NRF2 and ROS, telomere attrition, regulated by telomerase activity and shelterin complex, and immune system dysregulation, driven by alterations in cytokine profiles and immune cell senescence, upregulate or downregulate EMT induction. Additionally, we highlighted pathways of transcription such as SNAIL, TWIST, ZEB, SIRT1, TP53, NF-κB, and miRNAs regulating these processes. Understanding these mechanisms, we highlight potential therapeutic interventions targeting these critical molecules and pathways.

The current understanding highlights the intricate relationship between leukemic cells and their microenvironment, emphasizing the significant impact of environmental factors on chemotherapy resistance or sensitivity. Platelet-derived microparticles (PMPs) play a crucial role in facilitating intercellular communication, significantly contributing to the complex dynamics of cancer pathology and treatment outcomes. This study aims to investigate the cytotoxic and apoptotic effects of PMP, Ara-C, and their combinations on cancer cells, as well as their influence on the expression of critical genes like Bax, Bcl-2, P21, and h-TERT in the context of Acute Lymphoblastic Leukemia (ALL) cell line (Nalm-6).

PMPs were isolated through centrifugation at varying speeds, and their concentration was determined using the BCA assay. The size and immunophenotypic characteristics of PMPs were analyzed using dynamic light scattering (DLS) and flow cytometry. The cytotoxic and apoptotic effects of PMP, Ara-C, and their combinations on Nalm-6 cells were assessed using the MTT assay, the trypan blue exclusion assay, and flow cytometry. Gene expression levels were analyzed using real-time PCR.

According to our research findings, PMPs did not independently impact the viability and apoptosis of Nalm-6 cells; however, they synergistically augmented Ara-C's suppressive impact on viability and apoptosis. The MTT assay showed that both PMPs and Ara-C, whether administered alone or in combination, had a cytotoxic effect on the Nalm-6 cells. Furthermore, the combined treatment significantly affected the expression of Bax, Bcl-2, P21, and h-TERT genes.

Our study demonstrates that PMPs have the potential to improve the effectiveness of Ara-C chemotherapy in treating ALL. These findings contribute to a deeper understanding of the interplay between PMP and chemotherapy agents, offering potential insights for optimizing treatment strategies and improving patient outcomes in ALL.

Over-consumption of iron-rich red meat and hereditary or genetic iron overload are associated with an increased risk of colorectal carcinogenesis, yet the mechanistic basis of how metal-mediated signaling leads to oncogenesis remains enigmatic. Using fresh colorectal cancer samples we identify Pirin, an iron sensor, that overcomes a rate-limiting step in oncogenesis, by reactivating the dormant human telomerase reverse transcriptase (hTERT) subunit of the telomerase holoenzyme in an iron-(Fe3+)-dependent manner and thereby drives colorectal cancers. Chemical genetic screens combined with isothermal dose-response fingerprinting and mass spectrometry identified a small molecule SP2509 that specifically inhibits Pirin-mediated hTERT reactivation in colorectal cancers by competing with iron-(Fe3+) binding. Our findings, first to document how metal ions reactivate telomerase, provide a molecular mechanism for the well-known association between red meat and increased incidence of colorectal cancers. Small molecules like SP2509 represent a novel modality to target telomerase that acts as a driver of 90% of human cancers and is yet to be targeted in clinic. Significance: We show how iron-(Fe3+) in collusion with genetic factors reactivates telomerase, providing a molecular mechanism for the association between iron overload and increased incidence of colorectal cancers. Although no enzymatic inhibitors of telomerase have entered the clinic, we identify SP2509, a small molecule that targets telomerase reactivation and function in colorectal cancers.

We aimed to investigate the genomic and tumor microenvironmental (TME) profiles in non-muscle invasive bladder cancer (NMIBC) and explore potential predictive markers for Bacillus Calmette-Guérin (BCG) treatment response in high-risk NMIBC patients (according to European Association of Urology (EAU) risk stratification). 40 patients with high-risk NMIBC (cTis-T1N0M0) who underwent en bloc resection followed by BCG instillation were retrospectively enrolled. Surgical samples were subjected to Next Generation Sequencing (NGS) and multiplex immunofluorescence (mIF) assay. Genomic profiling revealed high prevalences of alterations in TERT (55%), KDM6A (32.5%), FGFR3(30%), PIK3CA (30%), TP53(27.5%) and ARID1A (20%). TME analysis showed different proportions of macrophages, NK cells, T cells subsets in tumoral and stromal compartment. Multivariate analysis identified TERT C228T and alteration in KDM6A as two independent factors associated with inferior RFS. The study comprehensively depicted the genomic and TME profiles in NMIBC and identified potential predictive biomarkers for BCG treatment.

Sex-specific differences in lifespan and ageing are observed in various species. In humans, women generally live longer but are frailer and suffer from different age-related diseases compared to men. The hallmarks of ageing, such as genomic instability, telomere attrition or loss of proteostasis, exhibit sex-specific patterns. Sex chromosomes and sex hormones, as well as the epigenetic regulation of the inactive X chromosome, have been shown to affect lifespan and age-related diseases. Here we review the current knowledge on the biological basis of sex-biased ageing. While our review is focused on humans, we also discuss examples of model organisms such as the mouse, fruit fly or the killifish. Understanding these molecular differences is crucial as the elderly population is expected to double worldwide by 2050, making sex-specific approaches in the diagnosis, treatment, therapeutic development and prevention of age-related diseases a pressing need.

Head and neck squamous cell carcinomas (HNSCCs), a heterogeneous group of cancers that arise from the mucosal epithelia cells in the head and neck areas, present great challenges in diagnosis, treatment and prognosis due to their complex aetiology and various clinical manifestations. Several factors, including smoking, alcohol consumption, oncogenic genes, growth factors, Epstein‑Barr virus and human papillomavirus infections can contribute to HNSCC development. The unpredictable tumour microenvironment adds to the complexity of managing HNSCC. Despite significant advances in therapies, the prediction of outcome after treatment for patients with HNSCC remains poor, and the 5‑year overall survival rate is low due to late diagnosis. Early detection greatly increases the chances of successful treatment. The present review aimed to bring together the latest findings related to the molecular mechanisms of HNSCC carcinogenesis and progression. Comprehensive genomic, transcriptomic, metabolomic, microbiome and proteomic analyses allow researchers to identify important biological markers such as genetic alterations, gene expression signatures and protein markers that drive HNSCC tumours. These biomarkers associated with the stages of initiation, progression and metastasis of cancer are useful in the management of patients with cancer in order to improve their life expectancy and quality of life.

Targeting DNA repair pathways is an important strategy in anticancer therapy. However, the unrevealed interactions between different DNA repair systems may interfere with the desired therapeutic effect. Among DNA repair systems, BER and NHEJ protect genome integrity through the entire cell cycle. BER is involved in the repair of DNA base lesions and DNA single-strand breaks (SSBs), while NHEJ is responsible for the repair of DNA double-strand breaks (DSBs). Previously, we showed that BER deficiency leads to downregulation of NHEJ gene expression. Here, we studied BER's response to NHEJ deficiency induced by knockdown of NHEJ scaffold protein XRCC4 and compared the knockdown effects in normal (TIG-1) and hTERT-modified cells (NBE1). We investigated the expression of the XRCC1, LIG3, and APE1 genes of BER and LIG4; the Ku70/Ku80 genes of NHEJ at the mRNA and protein levels; as well as p53, Sp1 and PARP1. We found that, in both cell lines, XRCC4 knockdown leads to a decrease in the mRNA levels of both BER and NHEJ genes, though the effect on protein level is not uniform. XRCC4 knockdown caused an increase in p53 and Sp1 proteins, but caused G1/S delay only in normal cells. Despite the increased p53 protein, p21 did not significantly increase in NBE1 cells with overexpressed hTERT, and this correlated with the absence of G1/S delay in these cells. The data highlight the regulatory function of the XRCC4 scaffold protein and imply its connection to a transcriptional regulatory network or mRNA metabolism.

Fasting potentially alters the aging process induced by obesity by regulating telomere integrity, which is related to longevity genes. However, the impact of periodic fasting (PF) on the expression of longevity genes, particularly Forkhead Box O Transcription Factors (FOXO3a) and the Human Telomerase Reverse Transcriptase (hTERT), is not fully understood. This study aimed to analyze the effects of PF, specifically on FOXO3a, hTERT expression, and other associated factors.

A quasi-experimental 10-day study was conducted in Surabaya, East Java, Indonesia. This study consisted of an intervention group (PFG), which carried out PF for ten days using a daily 12 h time-restricted eating protocol, and a control group (CG), which had daily meals as usual. FOXO3a and hTERT expression were analyzed by quantitative real-time qPCR. A paired t-test/Wilcoxon test, independent t-test/Mann-Whitney U-test, and Spearman's correlation test were used for statistical analysis.

Thirty-six young men participated in this study. During the post-test period, FOXO3a expression in the PFG increased 28.56 (±114.05) times compared to the pre-test, but the difference was not significant. hTERT expression was significantly higher in both the CG and PFG. The hTERT expression in the PFG was 10.26 (±8.46) times higher than in the CG, which was only 4.73 (±4.81) times higher. There was also a positive relationship between FOXO and hTERT in the CG.

PF significantly increased hTERT expression in the PFG; however, no significant increase was found in FOXO3a expression. PF regimens using the 12 h time-restricted eating approach may become a potential strategy for preventing obesity-induced premature aging by regulating longevity gene expression.

Cellular senescence, one of the hallmarks of cancer, is characterized by cell cycle arrest and the loss of most normal cellular functions while acquiring a hypersecretory, proinflammatory phenotype. The function of senescent cells in cancer cells varies depending on the cellular conditions. Before the occurrence of cancer, senescent cells act as a barrier to prevent its development. But once cancer has occurred, senescent cells play a procancer role. However, few of the current studies have adequately explained the diversity of cellular senescence across cancers. Herein, we concluded the latest intrinsic mechanisms of cellular senescence in detail and emphasized the senescence-associated secretory phenotype as a key contributor to heterogeneity of senescent cells in tumor. We also discussed five kinds of inducers of cellular senescence and the advancement of senolytics in cancer, which are drugs that tend to clear senescent cells. Finally, we summarized the various effects of senescent cells in different cancers and manifested that their functions may be diametrically opposed under different circumstances. In short, this paper contributes to the understanding of the diversity of cellular senescence in cancers and provides novel insight for tumor therapy.

MiRNAs, a class of non-coding RNA molecules, have emerged as critical modulators of telomere length and telomerase activity by finely tuning the expression of target genes (and not gene targets) within signaling pathways involved in telomere homeostasis. The primary objective of this systematic review was to compile and synthesize the existing body of knowledge on the role, association, and involvement of miRNAs in telomere length. Additionally, the review explored the regulation, function, and activation mechanism of the human telomerase reverse transcriptase (hTERT) gene and telomerase activity in tumor cells. A comprehensive analysis of 47 selected articles revealed 40 distinct miRNAs involved in these processes. These miRNAs were shown to exert their function, in both clinical cases and cell line models, either directly or indirectly, regulating hTERT and telomerase activity through distinct molecular mechanisms. The regulatory roles of these miRNAs significantly affected major cancer phenotypes, with outcomes largely dependent on the tissue type and the cellular actions within the tumor cells, whereby they functioned as oncogenes or tumor suppressors. These findings strongly support the pivotal role of miRNAs in modulating telomere length and telomerase activity, thereby contributing to the intricate and complex regulation of telomere homeostasis in tumor cells. Moreover, they emphasize the potential of targeting miRNAs and key regulatory genes as therapeutic strategies to disrupt cancer cell growth and promote senescence, offering promising avenues for novel cancer treatments.

Mixed-lineage kinase 3 (MLK3) is a serine/threonine kinase of the MAPK Kinase kinase (MAP3K) family that plays critical roles in various biological processes, including cancer. Upon activation, MLK3 differentially activates downstream MAPKs, such as JNK, p38, and ERK. In addition, it regulates various non-canonical signaling pathways, such as β-catenin, AMPK, Pin1, and PAK1, to regulate cell proliferation, apoptosis, invasion, and metastasis. Recent studies have also uncovered other potentially diverse roles of MLK3 in malignancy, which include metabolic reprogramming, cancer-associated inflammation, and evasion of cancer-related immune surveillance. The role of MLK3 in cancer is complex and cancer-specific, and an understanding of its function at the molecular level aligned specifically with the cancer hallmarks will have profound therapeutic implications for diagnosing and treating MLK3-dependent cancers. This review summarizes the current knowledge about the effect of MLK3 on the hallmarks of cancer, providing insights into its potential as a promising anticancer drug target.

Pancreatic adenocarcinoma represents one of the most challenging malignancies to treat, with dismal survival rates despite advances in therapeutic modalities. Immunotherapy, particularly vaccines, has emerged as a promising strategy to harness the body's immune system in combating this aggressive cancer. This abstract reviews the trials and tribulations encountered in the development of vaccines targeting pancreatic adenocarcinoma. Key challenges include the immunosuppressive tumor microenvironment, the heterogeneity of tumor antigens, and a limited understanding of immune evasion mechanisms employed by pancreatic cancer cells. Various vaccine platforms, including peptide-based, dendritic cell-based, and viral vector-based vaccines, have been explored in preclinical and clinical settings. However, translating promising results from preclinical models to clinical efficacy has proven elusive. In recent years, mRNA vaccines have emerged as a promising immunotherapeutic strategy in the fight against various cancers, including pancreatic adenocarcinoma. We will discuss the potential applications, opportunities, and challenges associated with mRNA vaccines in pancreatic cancer treatment.

Human telomerase reverse transcriptase (hTERT) may have noncanonical functions in transcriptional regulation and metabolic reprogramming in cancer cells, but it is a challenging target. We thus developed small-molecule ligands targeting hTERT promoter G-quadruplex DNA structures (hTERT G4) to downregulate hTERT expression. Ligand 5 showed high affinity toward hTERT G4 (Kd = 1.1 μM) and potent activity against triple-negative breast cancer cells (MDA-MB-231, IC50 = 1 μM). In cell-based assays, 5 not only exerts markedly inhibitory activity on classical telomere functions including decreased telomerase activity, shortened telomere length, and cellular senescence but also induces DNA damage, acute cellular senescence, and apoptosis. This study reveals that hTERT G4-targeting ligand may cause mitochondrial dysfunction, disrupt iron metabolism and activate ferroptosis in cancer cells. The in vivo antitumor efficacy of 5 was also evaluated in an MDA-MB-231 xenograft mouse model and approximately 78.7% tumor weight reduction was achieved. No observable toxicity against the major organs was observed.

Sarcoma is a rare tumor derived from the mesenchymal tissue and mainly found in children and adolescents. The outcome for patients with sarcoma is relatively poor compared with that for many other solid malignant tumors. Sarcomas have a highly heterogeneous pathogenesis, histopathology and biological behavior. Dysregulated signaling pathways and various gene mutations are frequently observed in sarcomas. The telomere maintenance mechanism (TMM) has recently been considered as a prognostic factor for patients with sarcomas, and alternative lengthening of telomeres (ALT) positivity has been correlated with poor outcomes in patients with several types of sarcomas. Therefore, telomeres and telomerases may be useful targets for treating sarcomas. This review aims to provide an overview of telomere and telomerase biology in sarcomas.

Several investigations are being done to increase the short lifetime of mesenchymal stem cells (MSCs). One of the crucial genes involved in the immortalization of MSCs, hTERT (human telomerase reverse transcriptase), is activated in most publications using viral-based techniques. In this work, we investigated the use of platelet-derived (PMPs) and B cell precursor leukemia-derived microparticles as a nonviral method to trigger and compare the expression of the hTERT gene in MSCs. MSCs were extracted from the umbilical cord for the current investigation and identified using a flow cytometry approach and an inverted microscope. The Nalm-6 cell line and platelet concentrate were used to isolate microparticles (MPs). MSCs and MPs were cocultured for 14 days at 25-, 50-, and 100 μg/ml concentrations. qRT-PCR was used to research the expression of the hTERT gene. SPSS 26.0's t test was used to compare the outcomes. After coculture with platelet MPs, MSCs had higher levels of hTERT gene expression than the control group. In contrast, this gene's expression was concurrently decreased in MSCs exposed to MPs generated from Nalm-6. We demonstrated that following 14-day treatment, PMP significantly boosted the hTERT gene expression in MSCs, while the Nalm-6 MPs lowered the gene expression. However, additional studies are necessary due to the stability of hTERT gene expression and the immortalization of MSCs following exposure.

Telomerase reverse transcriptase (TERT) promoter mutation is associated with an aggressive clinical course in thyroid carcinomas. Therefore, detection of TERT promoter mutation is essential for proper patient management. 5-Hydroxymethylcytosine (5hmC) is an epigenetic marker involved in the DNA demethylation pathway, and its loss has been observed in various tumors. Loss of 5hmC has also been reported in thyroid carcinomas and is presented as a possible predictive biomarker for TERT promoter mutation and worse prognosis. This study evaluated the expression of TERT and 5hmC by immunohistochemistry (IHC) in 105 patients (44 in the TERT mutant group and 61 in the TERT wild group) with various thyroid carcinomas. H-scores were calculated using an image analyzer. The median H-scores of TERT IHC were significantly higher in the TERT mutant group than in the TERT wild group (47.15 vs. 9.80). The sensitivity and specificity of TERT IHC for predicting TERT promoter mutations were 65.9 and 65.7 %, respectively. Regardless of TERT promoter mutation status, the 5hmC H-scores were markedly lower in all subtypes of thyroid carcinomas compared to those in their normal counterparts. Significant differences in 5hmC H-scores were observed between N0 and N1 in total thyroid carcinomas, but not within the papillary thyroid carcinoma subgroup. In conclusion, TERT and 5hmC IHC have limitations in predicting the presence of TERT promoter mutations. The expression of 5hmC was downregulated in various thyroid carcinomas compared to that in normal and benign lesions, but comprehensive further studies are required to elucidate the role of 5hmC in thyroid carcinomas.

Telomerase is activated or overexpressed in 85-90% of tumors, which maintains the length of telomere and has become an important anti-cancer target. Increasing clinical and preclinical data suggest that telomerase-targeted cancer immunotherapy could achieve effective killing of tumor cells in vivo. This article reviews the research progress of telomerase targeted cancer immunotherapy in clinical and pre-clinical trials, aiming to provide a reference for further clinical research and treatment of cancers.

We investigated the research progress of telomerase immunotherapy in the last 20 years from four electronic databases.

Telomerase-targeted immunotherapies have been developed with the arising of a new era in immuno-oncology, including peptide vaccines, DNA vaccines, dendritic cells (DCs), adoptive cell transfer (ACT) therapies, antibodies, etc. Some of them have been approved for undergoing clinical trials by the Food and Drug Administration (FDA) for the treatment of various cancers, such as pancreatic cancer, non-small cell lung cancer, melanoma, leukaemia. Of all the treatment modalities, vaccines are the primary treatment methods, some of which have been even entered into phase III clinical trials. The main clinical application direction of telomerase vaccine is the combination with other drugs and treatment modalities, including combination with other vaccines targeting human telomerase reverse transcriptase (hTERT), traditional chemotherapy drugs and immunosuppressors. We also summarized the recent findings of immunotherapy targeting hTERT, focusing on various vaccines and the current status of associated clinical trials. We further discussed the advantages, disadvantages and potential developmental directions of various telomerase-targeted immunotherapies.

Telomerase-targeted cancer immunotherapy has promising prospects in improving patient survival expectancy. This review may provide data support and design ideas for all researchers and pharmaceutical enterprises in this field.

Strong epigenetic pan-cancer biomarkers are required to meet several current, urgent clinical needs and to further improve the present chemotherapeutic standard. We have concentrated on the investigation of epigenetic alteration of the hTERT gene, which is frequently epigenetically dysregulated in a number of cancers in specific developmental stages. Distinct DNA methylation profiles were identified in our data on early urothelial cancer. An efficient EpihTERT assay could be developed utilizing suitable combinations with sequence-dependent thermodynamic parameters to distinguish between differentially methylated states. We infer from this data set, the epigenetic context, and the related literature that a CpG-rich, 2800 bp region, a prominent CpG island, surrounding the transcription start of the hTERT gene is the crucial epigenetic zone for the development of a potent biomarker. In order to accurately describe this region, we have named it "Acheron" (Ἀχέρων). In Greek mythology, this is the river of woe and misery and the path to the underworld. Exploitation of the DNA methylation profiles focused on this region, e.g., idiolocal normalized Methylation Specific PCR (IDLN-MSP), opens up a wide range of new possibilities for diagnosis, determination of prognosis, follow-up, and detection of residual disease. It may also have broad implications for the choice of chemotherapy.

The catalytic subunit telomerase reverse transcriptase (hTERT) is a prerequisite for malignant transformation of human cells. Colorectal cancer (CRC) is a common malignant tumor. The genetic association of hTERT gene rs2853669 and rs2736098 polymorphisms with CRC was surveyed in the Chinese population. Two hundreds patients with CRC and 200 healthy controls were taken for blood sample collection. Sanger sequencing was applied for genotyping. Multiple logistic regression analysis was performed, and odds ratio (OR) together with confidence interval (CI) were calculated to obtain the corresponding association power. Among CRC cases (49.50%), hTERT gene rs2736098 GA genotype carriers were more prevalent compared with the control group (41.00%, P = 0.035), which increased the risk of CRC by 1.576 times (95% CI, 1.031-2.409). Distribution of the rs2736098 genotypes was significantly associated with TNM stage, tumor differentiation, tumor size and lymph node metastasis (P < 0.05). The frequencies of hTERT gene rs2853669 polymorphism were not significantly different between CRC patients and healthy controls. Logistic regression analysis indicated that both body mass index (BMI) and hTERT gene rs2736098 polymorphism remained significantly correlated with CRC susceptibility. The frequencies of hTERT gene rs2853669 polymorphism did not differ significantly between CRC patients and control group (P > 0.05). The hTERT gene rs2736098 polymorphism was correlated with CRC risk in the Chinese Han population, and the GA genotype was a risk element for the onset of CRC.