• targeted therapies
• gene therapy

• Animals
• Humans
• Mice
• Genetic Therapy/methods
• NF-kappa B/metabolism
• Oncogenes
• Dependovirus/genetics
• Cell Line, Tumor
• CRISPR-Cas Systems
• Polo-Like Kinase 1
• Xenograft Model Antitumor Assays
• Telomerase/genetics
• Telomerase/antagonists & inhibitors
• Neoplasms/therapy
• Neoplasms/genetics
• Proto-Oncogene Proteins p21(ras)/genetics
• Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors
• Proto-Oncogene Proteins p21(ras)/metabolism
• Cell Proliferation

• 21KJB310015 Natural Science Research of Jiangsu Higher Education Institutions of China
• BK20210005 Natural Science Foundation of Jiangsu Province (Jiangsu Provincial Natural Science Foundation)
• 82372342 National Natural Science Foundation of China (National Science Foundation of China)
• Research Foundation for Advanced Talents(jit-b-202105)
• Natural Science Foundation of National Health Commission (WKZX2023JG0235)

• Everolimus
• Immunosuppression
• Liver transplantation
• Recommendations
• Transplant oncology

• Liver Transplantation
• Humans
• Liver Neoplasms/surgery
• Immunosuppression Therapy/methods
• Italy
• Immunosuppressive Agents/therapeutic use
• Carcinoma, Hepatocellular/surgery
• Neoplasm Recurrence, Local

• adoptive cell therapy
• checkpoint inhibitors
• colorectal cancer
• immunotherapy
• telomeres
• therapy

• EBV-immortalized and fully transformed B cells
• MYC
• NF-kB p65
• TERT extra-telomeric functions
• TERT/telomerase
• new therapeutic approach
• xenograft
• zebrafish

• 5x1000 2017 - Cancer Genomics Research Platform Istituto Oncologico Veneto
• Department of Surgery, Oncology and Gastroenterology DOR 2021 and BIRD 2021 to SG University of Padua

Human telomerase reverse transcriptase (hTERT)- mRNA was shown to be elevated in exosomes derived from the sera of a variety of hematological and solid cancer patients. We aimed to evaluate its role as a diagnostic marker in patients with newly diagnosed colon cancer and in hereditary syndromes with predisposition to colon cancer.

hTERT -mRNA levels were determined in serum-derived exosomes from 88 patients with colon cancer, 71 Lynch-syndrome carriers with unknown active malignancies and 50 healthy controls. Data, including demographics, background diseases, clinical data regarding tumor characteristics and genetic data, were retrieved data from medical files.

Patients with colon cancer had both higher exosomal hTERT mRNA levels and a higher proportion of patients with positive exosomal hTERT mRNA than controls (29.5% vs. 4%, respectively, P values < 0.001). Within the cancer group, patients with a metastatic disease had higher levels of telomerase mRNA than non-metastatic disease patients, and these levels correlated with CEA levels. Likewise, Lynch syndrome carriers had a higher proportion of positive exosomal hTERT mRNA than controls (21.1% vs. 4%, respectively, P value 0.008) but only a trend towards higher exosomal hTERT mRNA levels. Higher telomerase mRNA levels were not correlated with the mutated gene.

Exosomal serum hTERT –mRNA levels are associated with metastatic colon cancer and were also demonstrated in a subset of Lynch syndrome carriers. Its significance as a biomarker for developing malignancy should be elucidated.

Colorectal cancer (CRC) is still a leading cause of cancer death worldwide. Less than half of cases are diagnosed when the cancer is locally advanced. CRC is a heterogenous disease associated with a number of genetic or somatic mutations. Diagnostic markers are used for risk stratification and early detection, which might prolong overall survival. Nowadays, the widespread use of semi-invasive endoscopic methods and feacal blood tests characterised by suboptimal accuracy of diagnostic results has led to the detection of cases at later stages. New molecular noninvasive tests based on the detection of CRC alterations seem to be more sensitive and specific then the current methods. Therefore, research aiming at identifying molecular markers, such as DNA, RNA and proteins, would improve survival rates and contribute to the development of personalized medicine. The identification of “ideal” diagnostic biomarkers, having high sensitivity and specificity, being safe, cheap and easy to measure, remains a challenge. The purpose of this review is to discuss recent advances in novel diagnostic biomarkers for tumor tissue, blood and stool samples in CRC patients.

• colorectal cancer
• diagnostic biomarkers
• early detection

• T cells
• cancer
• circulating TERT mRNA
• immunosuppression
• oncological surveillance
• transplant

• Extracellular vesicles
• biomarkers
• exosomes
• prostate cancer

• Animals
• Biomarkers, Tumor/metabolism
• Extracellular Vesicles/pathology
• Extracellular Vesicles/physiology
• Humans
• Male
• Prostatic Neoplasms/diagnosis
• Prostatic Neoplasms/etiology
• Prostatic Neoplasms/pathology
• Prostatic Neoplasms/therapy

• R41 CA268344 NCI NIH HHS
• T32 CA009138 NCI NIH HHS
• Targets of Cancer Training Program
• Department of Defense Prostate Cancer Research Program

• CRC
• cancer genetics
• cancer therapy development
• colorectal cancer
• tumor microenviornment

• EVs
• RBPs
• RNA
• RNA consensus
• RNA‐binding proteins
• extracellular vesicles
• inhibitors
• protein domains

• Animals
• Extracellular Vesicles/genetics
• Extracellular Vesicles/metabolism
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• RNA-Binding Proteins/genetics
• RNA-Binding Proteins/metabolism

• Ministero della Salute
• Fondazione Cassa Di Risparmio Di Trento E Rovereto

High levels of thymidylate synthase (TS) and dihydrofolate reductase (DHFR) expression in tumour tissues are an indicator of ineffective responses to pemetrexed-based chemotherapy in various tumours, including non-small cell lung cancer (NSCLC). However, tumour tissues are highly heterogeneous, so a single biopsy may not reflect genetic alterations during disease progression. This study investigated the potential use of plasma TS and DHFR mRNA levels as biomarkers for predicting sensitivity to pemetrexed-based chemotherapy.

Plasma samples were obtained from 245 patients with advanced NSCLC and 30 healthy donors. Total RNA was extracted from the plasma samples, and TS and DHFR mRNA levels were determined via real-time PCR. TS and DHFR mRNA levels between cancer patients and healthy controls were compared. The association between plasma TS and DHFR mRNA levels and tumour response to pemetrexed/cisplatin chemotherapy was analysed.

The plasma TS and DHFR mRNA levels decreased in patients with advanced NSCLC compared with healthy controls. Moreover, plasma TS and DHFR mRNA levels negatively correlated with tumour response to pemetrexed/cisplatin chemotherapy in patients with advanced NSCLC. Overall survival time was prolonged in patients with low TS mRNA expression compared with those with high TS mRNA expression, although the difference was not statistically significant.

Low expression levels of plasma TS and DHFR mRNA confer increased tumour sensitivity to pemetrexed/cisplatin chemotherapy in patients with advanced NSCLC. The results suggested that plasma TS and DHFR mRNA levels are promising biomarkers for choosing patients who are likely to respond and benefit the most from pemetrexed-based chemotherapy.

• Thymidylate synthase (TS)
• dihydrofolate reductase (DHFR)
• mRNA
• non-small cell lung cancer (NSCLC)

The human circulation contains cell-free DNA and non-coding microRNA (miRNA). Less is known about the presence of messenger RNA (mRNA). This report profiles the human circulating mRNA transcriptome in people with liver cirrhosis (LC) and hepatocellular carcinoma (HCC) to determine whether mRNA analytes can be used as biomarkers of liver disease. Using RNAseq and RT-qPCR, we investigate circulating mRNA in plasma from HCC and LC patients and demonstrate detection of transcripts representing more than 19,000 different protein coding genes. Remarkably, the circulating mRNA expression levels were similar from person to person over the 21 individuals whose samples were analyzed by RNAseq. Liver derived circulating transcripts such as albumin (ALB), apolipoprotein (APO) A1, A2 & H, serpin A1 & E1, ferritin light chain (FTL) and fibrinogen like 1 (FGL1) were significantly upregulated in HCC patient samples. Higher levels of some of these liver-specific transcripts in the plasma of HCC patients were confirmed by RT-qPCR in another cohort of 20 individuals. Several less abundant circulating transcripts associated with cancer were detected in most HCC samples, but not in healthy subjects. Liver specificity of circulating transcripts was confirmed by investigating their expression in HCC tumor and liver cancer cell lines. Liver specific mRNA sequences in the plasma were predominantly present outside circulating extracellular vesicles.

Conclusions: The circulating “mRNA” transcriptome is remarkably consistent in diversity and expression from person to person. Detection of transcripts corresponding to disease selective polypeptides suggests the possibility that circulating mRNA can work as a biomarker analyte for cancer detection.

• biomarkers
• circulating transcripts
• extracellular vesicles
• hepatocellular carcinoma
• liver cirrhosis

• Head and neck squamous cell carcinoma
• Mutation
• Promoter
• Telomerase reverse transcriptase
• Telomere

• Adult
• Aged
• Aged, 80 and over
• Cohort Studies
• Female
• Head and Neck Neoplasms/genetics
• Head and Neck Neoplasms/metabolism
• Head and Neck Neoplasms/pathology
• Humans
• Male
• Middle Aged
• Mutation
• Promoter Regions, Genetic
• Prospective Studies
• Squamous Cell Carcinoma of Head and Neck/genetics
• Squamous Cell Carcinoma of Head and Neck/metabolism
• Squamous Cell Carcinoma of Head and Neck/pathology
• Survival Analysis
• Telomerase/genetics
• Telomerase/metabolism
• Telomere/genetics
• Telomere/metabolism
• Telomere/pathology

• Biomarker
• Head and neck squamous cell carcinoma
• Telomerase

A growing body of evidence indicates that the expression of TERT, the catalytic subunit of telomerase, is a biological marker of progression in several cancers. We investigated the predictive and prognostic role of TERT levels and telomere length in tissues and peripheral blood in patients with head and neck squamous cell carcinoma (HNSCC). High TERT levels in cancer tissues were independently associated with worse response to therapy (odds ratio [OR]:6.26), regional failure (hazard ratio [HR]:5.75), progression (HR:2.12), and death (HR:3.53). Longer telomeres in the mucosa surrounding the tumor (SM) were independently associated with a lower risk of mucosal failure (HR:0.39). While telomere length in peripheral blood mononuclear cells (PBMC) significantly decreased with age, no correlation was found between age and telomere length in SM. No associations were found between TERT levels in plasma and telomere length in PBMC and the prognostic variables. High levels of TERT transcripts in cancer cells represent a reliable prognostic marker for identifying HNSCC patients with risk of progression. The altered relationship of telomere length to age in SM compared with PBMC suggests that in a subset of cases the phenotypically normal SM constitutes an acquired telomere-shortened epithelial field prone to genetic instability.

• Ki-67
• colorectal cancer
• mRNA expression
• matrix metalloproteinase

• Chemokine (C-C motif) ligand 2
• Human telomerase reverse transcriptase
• Metastasis
• Tumor promotion
• Wnt signaling pathway

• Cell Culture Techniques
• Cell Movement
• Cell Proliferation
• Cell Survival
• Chemokine CCL2/metabolism
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• HCT116 Cells
• Humans
• Neoplasm Invasiveness
• Signal Transduction
• Telomerase/metabolism
• Transcription Factor 7-Like 2 Protein/metabolism
• beta Catenin/metabolism

• Biomarkers
• Liquid biopsies
• Non-coding RNA
• YRNA
• circRNA
• lncRNA
• miRNA
• piRNA
• snRNA
• snoRNA

• Cancer
• Cell-free DNA
• Liquid biopsy
• Molecular diagnostics
• Molecular pathology
• Sequencing

• Cell-Free Nucleic Acids/blood
• DNA, Neoplasm/genetics
• High-Throughput Nucleotide Sequencing
• Humans
• Neoplasms/blood
• Neoplasms/genetics
• Polymerase Chain Reaction/methods

• P30 CA008748 NCI NIH HHS
• P50 CA092629 NCI NIH HHS

Colorectal cancer is the leading cause of cancer-related deaths in Saudi Arabia. Cancer has a multifactorial nature and can be described as a disease of altered gene expression. The profiling of gene expression has been used to identify cancer subtypes and to predict patients’ responsiveness. Telomere-associated proteins that regulate telomere biology are essential molecules in cancer development. Thus, the present study examined their contributions to colorectal cancer progression in Saudi patients.

The expression of hTERT, TRF1, TRF2, POT1, ATR, ATM, Chk1 and Chk2 were measured via real-time PCR in matched cancerous and adjacent tissues of CRC patients. The protein level of hTERT, TRF1, TRF2, ATR, ATM, Chk1 and Chk2 were measured using immunohistochemistry. A region of hTERT core promoter was sequenced via Sanger sequencing. Methylation of CTCF binding site was examined via methylation-specific PCR. Finally, the length of telomere was estimated using q-PCR.

Our results showed that POT1, ATR, Chk1 and Chk2 show increased expression in CRC relative to the adjacent mucosa. The expression levels of each gene were associated with clinicopathological characteristics of patients with CRC. There was a positive correlation between the age of the patients and hTERT expression. Regarding tumor site, telomere length, ATR, ATM and Chk1 were shown to be altered. No somatic mutation was detected in hTERT core promoter, and no differences in methylation patterns at CTCF binding site in the promoter between normal and cancer tissues.

Analysis of targeted genes expression in colorectal cancer based on the clinical variables revealed that tumor location and age could have a role in gene expression and telomere length variations and this could be taken under consideration during CRC diagnosis and therapy. Other epigenetic mechanisms could influence hTERT expression in cancers. Our findings warrant further validation through experiments involving a larger number of patients.

• Adult
• Aged
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• DNA Damage
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Intestinal Mucosa/metabolism
• Intestinal Mucosa/pathology
• Male
• Middle Aged
• Neoplasm Proteins/biosynthesis
• Neoplasm Proteins/genetics
• Telomere Homeostasis
• Telomere-Binding Proteins/biosynthesis
• Telomere-Binding Proteins/genetics

• rectal cancer
• plasma tert
• predictive marker
• prognostic marker

• Aged
• Biomarkers, Tumor/blood
• Biomarkers, Tumor/genetics
• Chemoradiotherapy, Adjuvant
• Female
• Humans
• Male
• Middle Aged
• Neoadjuvant Therapy
• Neoplasm Staging
• Predictive Value of Tests
• Prognosis
• Progression-Free Survival
• RNA, Neoplasm/blood
• RNA, Neoplasm/genetics
• Rectal Neoplasms/blood
• Rectal Neoplasms/enzymology
• Rectal Neoplasms/pathology
• Rectal Neoplasms/therapy
• Retrospective Studies
• Telomerase/blood
• Telomerase/genetics

• DNA sequencing
• PCR
• cancer
• cell-free nucleic acids
• circulating tumour DNA
• genomics
• liquid biopsy
• molecular pathology

Metastasis is the major cause of mortality in cancer disease and still constitutes one of the most controversial mechanism, not yet fully understood. What is almost beyond doubt is that circulatory system is crucial for cancer propagation. Regarding this system, much attention has been recently paid to liquid biopsy. This technique is aimed to detect circulating tumor cells (CTCs) and circulating nucleic acids so it can be used as a tool for diagnostic, prognostic and follow-up of patients. Whereas CTCs tend to be scarce in serum and plasma from cancer patient, abundant circulating nucleic acids can be detected in the same location. This fact, together with the genetic origin of cancer, stands out the relevance of circulating nucleic acids and shed light into the role of nucleic acids as drivers of metastasis, a recently discovered phenomenon called Genometastasis. This innovative theory supports the transfer of oncogenes from cancer cells to normal and susceptible cells located in distant target organs through circulatory system. What is more, many biological processes haven been described to deliver and secrete circulating nucleic acids into the circulation which can allow such horizontal transfer of oncogenes. In this review, we focus not only on these mechanisms but also we demonstrate its putative role in cancer propagation and give insights about possible therapeutic strategies based on this theory. Our objective is to demonstrate how findings about cell-to-cell communications and previous results can agree with this unprecedented theory.

• Genometastasis
• Cancer metastasis
• Circulating Nucleic acids: Circulating tumor cells
• Liquid biopsy
• Exosomes
• Virtosomes

Colorectal cancer is characterized by aberrant Cyclooxigenase-2 (COX-2) and β-Catenin pathways. Recently, the protease inhibitor SerpinB3 has been described overexpressed in more advanced stages of this tumor. Aim of the study was to explore the possible relationship between these molecules in this setting. We evaluated colorectal cancer specimens from 105 patients and a positive correlation between SerpinB3, COX-2 and β-Catenin expression was observed, with higher levels in tumor than in adjacent tissue. The highest levels were associated with pathologic parameters of poor prognosis, including vascular invasion, lymph node metastasis and perineural invasion. The molecular and protein profiles of COX-2 and β-Catenin were analyzed in cell lines with different expression of SerpinB3. In those with high expression of SerpinB3, COX-2 and β-Catenin were higher than in controls. Cells with high levels of SerpinB3 showed higher proliferation and invasion compared to controls. In conclusion, in colorectal cancer SerpinB3, COX-2 and β-Catenin are positively correlated and associated with more advanced tumor stage. The in vitro experimental results support a driving role of SerpinB3 in the upregulation of COX-2/ β-Catenin positive loop, associated with a more aggressive cellular phenotype.

• COX-2
• SerpinB3
• colorectal cancer
• tumor stage
• β-Catenin

The study was aimed to quantitatively detect mRNA levels of the catalytic subunit of telomerase (hTERT) in both peripheral blood and circulating tumor cells (CTCs) of patients with nasopharyngeal carcinoma (NPC) and explore its significance in early diagnosis and treatment of NPC.

hTERT mRNA levels in peripheral blood and CTCs of 33 NPC patients before and after treatment with intensity-modulated radiation therapy (IMRT) or/and chemotherapy and 24 healthy controls were measured using real-time quantitative PCR (qPCR) and their correlations to clinic pathological factors of NPC were analyzed.

Peripheral hTERT mRNA content was 10.75 ± 4.29 in NPC patients and 0.95 ± 0.37 in control subjects (P < 0.05), and had a significant correlation with patients’ clinical stage, T stage, and N stage (P < 0.05). Treatment of NPC patients at stages I and II with simple IMRT significantly reduced hTERT mRNA level from 5.60 ± 2.33 to 3.43 ± 1.42 (P < 0.05) and treatment of patients at advanced stage (III and IV) with induction chemotherapy followed by IMRT significantly reduced hTERT mRNA levels from 12.68 ± 3.08 to 10.68 ± 2.48 to 3.13 ± 1.69 (P < 0.05), respectively. In addition, the study also showed that hTERT mRNA content in CTCs of NPC patients was 10.65 ± 4.28, evidently higher than that of 1.09 ± 0.40 in control subjects (P < 0.05) and hTERT mRNA level in CTCs of NPC patients was obviously correlated to patients’ clinical stage, T stage and N stage (P < 0.05). After treatment, hTERT mRNA level in CTCs of NPC patients lowered from 10.65 ± 4.28 to 5.59 ± 2.32 (P < 0.05). The correlation analysis found that hTERT mRNA level in peripheral blood and CTCs of NPC patients were highly correlated with a correlation coefficient of 0.981.

hTERT mRNA levels in peripheral blood and CTCs of NPC patients were significantly enhanced compared to that in healthy controls and highly correlated. Changes in hTERT mRNA level was closely correlated to patients’ clinical stage and T stage. Radiochemotherapy could effectively reduce hTERT mRNA level in peripheral blood and CTCs. Thus, it is possible using the joint detection of hTERT mRNA level in peripheral blood and CTCs as a new biomarker for early diagnosis, treatment efficacy and prognosis of NPC.

• CTCs
• Nasopharyngeal carcinoma
• Peripheral blood
• Real-time quantitative PCR
• hTERT

Telomerase (human telomerase reverse transcriptase (hTERT)) is considered a hallmark of cancer. The aim of our study was to evaluate the feasibility of the detection of hTERT transcripts in serum as a ‘pan-cancer’ diagnostic method.

Human telomerase reverse transcriptase mRNA levels were determined in serum and serum-derived exosomes from 133 patients with different malignancies and 45 healthy controls. In four patients hTERT mRNA levels were measured in different clinical stages.

Human telomerase reverse transcriptase transcript was absent in all controls and was variably detected in 67.5% of patients with all cancer types. A correlation between hTERT transcript levels and the clinical course was found in several cases.

Human telomerase reverse transcriptase mRNA levels may reflect the tumour burden and the clinical status of the patient. In patients with detectable levels, this assay may potentially serve as a diagnostic and follow-up ‘pan-cancer’ marker. Owing to the large variety of patients and small sample size in each diagnosis, the statistical power is limited and will be explored further in larger groups.

The activity levels of telomerase and its mRNA have been found to be more diagnostically sensitive than cytological results in many cancerous tissues and correlate well with the clinical disease stage. Currently, there are several methods of detecting telomerase in tissues and in blood. The most commonly used method is a conventional quantitative real-time polymerase chain reaction (PCR) which is time and labor exhausting.

We have developed a simple and innovative blood test method that allows us to diagnose cancer and relapsed cancer in a cost- and time -effective manner. We had evaluated our novel method in two populations: 1) in vivo in three mice with pancreatic ductal adenocarcinoma (PDAC) versus one control mouse and 2) clinically in 30 cancer patients versus 10 individuals without cancer. We compared our novel method with the old conventional method. At least one sample was obtained from each patient included in the study.

The novel method substantially increased the sensitivity (from 37% to 77%, p<0.001) and negative predictive value (from 32% to 56%, p = 0.005) of the telomerase test for all cancer patients (those who were substantially treated and those who were not). There was no significant difference in telomerase activity between cancer patients and healthy volunteers using the conventional method (p = 0.13), whereas there was a significant difference using the novel method (p = 0.001).

Conventional method shows no significant difference in telomerase activity between cancer patients and healthy volunteers (p = 0.13), whereas there was a significant difference using the novel method (p = 0.001).

• Animals
• Carcinoma, Pancreatic Ductal/diagnosis
• Carcinoma, Pancreatic Ductal/enzymology
• Case-Control Studies
• Humans
• Mice
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/enzymology
• Real-Time Polymerase Chain Reaction
• Sensitivity and Specificity
• Telomerase/blood

• human telomerase reverse transcriptase (hTERT)
• laryngeal cancer
• liquid biopsy
• mRNA

Predictive biomarkers based individualized chemotherapy can improve efficacy. However, for those advanced patients, it may be impossible to obtain the tissues from operation. Tissues from biopsy may not be always enough for gene detection. Thus, biomarker from blood could be a non-invasive and useful tool to provide real-time information in the procedure of treatment. To further understand the role of plasma mRNA in chemo-efficiency prediction, several mRNA expression levels were assessed in plasma and paired tumor tissues from 133 locally advanced gastric cancer patients (stage III), and mRNA levels were correlated with chemosensitivity to docetaxel, pemetrexed, platinum, and irinotecan. mRNA expression level in 64 advanced gastric cancer patients (stage IV) was also examined (55 in test group, and 9 in control), and chemotherapy in the test group were given according to the plasma gene detection. As a result, in the 133 patients with locally advanced gastric cancer (Stage III), correlations were observed between the mRNA expression of plasma/tumor BRCA1 levels and docetaxel sensitivity (P<0.001), plasma/tumor TS and pemetrexed sensitivity (P<0.001), plasma/tumor BRCA1 and platinum sensitivity (plasma, P=0.016; tumor, P<0.001), and plasma/tumor TOPO1 and irinotecan sensitivity (plasma, P=0.015; tumor, P=0.011). Among another 64 patients with advanced cancer (Stage IV), the median OS of test group was 15.5m (95% CI=10.1 to 20.9m), the PFS was 9.1m (95% CI=8.0 to 10.2m), which were significant longer than the control (P=0.047 for OS, P=0.038 for PFS). The mortality risk was higher in the control than patients treated according to the plasma gene detection (HR in the control=2.34, 95% CI=0.93 to 5.88, P=0.071). Plasma mRNA as liquid biopsy could be ideal recourse for examination to predict chemo-sensitivity in gastric cancer.

• Plasma mRNA
• chemosensitivity
• gastric cancer
• individualized chemotherapy.
• liquid biopsy

Strongly associated with tobacco use, heavy alcohol consumption, and with high-risk human papillomavirus (HPV) infection, head and neck squamous cell carcinoma (HNSCC) is a frequently lethal, heterogeneous disease whose pathogenesis is a multistep and multifactorial process involving genetic and epigenetic events. The majority of HNSCC patients present with locoregional advanced stage disease and are treated with combined modality strategies that can markedly impair quality of life and elicit unpredictable results. A large fraction of those who undergo locoregional treatment and achieve a complete response later develop locoregional recurrences or second field tumors. Biomarkers that are thus able to stratify risk and enable clinicians to tailor treatment plans and to personalize post-therapeutic surveillance strategies are highly desirable. To date, only HPV status is considered a reliable independent predictor of treatment response and survival in patients with HNSCC arising from the oropharyngeal site. Recent studies suggest that telomere attrition, which may be an early event in human carcinogenesis, and telomerase activation, which is detected in up to 90 % of malignancies, could be potential markers of cancer risk and disease outcome. This review examines the current state of knowledge on and discusses the implications linked to telomere dysfunction and telomerase activation in the development and clinical outcome of HNSCC.

• Field cancerization
• Head and neck cancer
• Human papillomavirus
• Molecular biology
• Recurrence
• Survival
• TERT
• Telomerase reverse transcriptase
• Telomere

• Animals
• Biomarkers, Tumor
• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/metabolism
• Carcinoma, Squamous Cell/mortality
• Carcinoma, Squamous Cell/pathology
• Cell Transformation, Neoplastic/genetics
• Cell Transformation, Neoplastic/metabolism
• Gene Expression Regulation, Neoplastic
• Genetic Predisposition to Disease
• Genetic Variation
• Genomic Instability
• Head and Neck Neoplasms/genetics
• Head and Neck Neoplasms/metabolism
• Head and Neck Neoplasms/mortality
• Head and Neck Neoplasms/pathology
• Humans
• Leukocytes, Mononuclear/metabolism
• Leukocytes, Mononuclear/pathology
• Mice
• Prognosis
• Squamous Cell Carcinoma of Head and Neck
• Telomerase/metabolism
• Telomere/genetics
• Telomere Homeostasis

In human cancer, high telomerase expression is correlated with tumor aggressiveness and metastatic potential. Telomerase activation occurs through telomerase reverse transcriptase (hTERT) induction, which contributes to malignant transformation by stabilizing telomeres. Previous studies have shown that hTERT can promote tumor invasion and metastasis of gastric cancer, liver cancer and esophageal cancer. Epithelial-to-mesenchymal transition (EMT), a requirement for tumor invasion and metastasis, plays a key role in cancer progression. Although hTERT promotes EMT through Wnt signaling in several cancers, it is unknown if other signaling pathways are involved. In the present study, we found that hTERT and ZEB1 form a complex, which directly binds to the E-cadherin promoter, and then inhibits E-cadherin expression and promots EMT in colorectal cancer cells. hTERT overexpression in HCT116 and SW480 cells could induce E-cadherin down-regulation. However, E-cadherin expression was recovered when ZEB1 function was impaired even during hTERT overexpression. Taken together, our findings suggest that hTERT can promote cancer metastasis by stimulating EMT through the ZEB1 pathway and therefore inhibiting them may prevent cancer progression.

• CRC
• EMT
• ZEB1
• hTERT

• Colon cancer
• Epithelial-mesenchymal transition
• Metastasis
• Neuromedin U
• Snail

• Biologic therapy
• Colorectal
• Metastatic colorectal cancer
• Molecular markers
• Targeted therapy

• ASOs
• CDK4
• Cyclin D1
• Human muscle cell models
• Immortalization
• Myotonic dystrophy type 1
• TERT

• LARC
• MRI
• NCRT
• PET-CT
• Predictive markers

• Biomarkers, Tumor/metabolism
• Chemoradiotherapy, Adjuvant/methods
• Humans
• Magnetic Resonance Imaging/methods
• Molecular Imaging/methods
• Neoadjuvant Therapy/methods
• Positron-Emission Tomography/methods
• Prognosis
• Rectal Neoplasms/pathology
• Rectal Neoplasms/therapy
• Tomography, X-Ray Computed/methods
• Treatment Outcome

Epstein–Barr virus (EBV)-associated malignancies, as well as lymphoblastoid cell lines (LCLs), obtained in vitro by EBV infection of B cells, express latent viral proteins and maintain their ability to grow indefinitely through inappropriate activation of telomere-specific reverse transcriptase (TERT), the catalytic component of telomerase. Our previous studies demonstrated that high levels of TERT expression in LCLs prevent the activation of EBV lytic cycle, which is instead triggered by TERT silencing. As lytic infection promotes the death of EBV-positive tumor cells, understanding the mechanism(s) by which TERT affects the latent/lytic status of EBV may be important for setting new therapeutic strategies. BATF, a transcription factor activated by NOTCH2, the major NOTCH family member in B cells, negatively affects the expression of BZLF1, the master regulator of viral lytic cycle. We therefore analyzed the interplay between TERT, NOTCH and BATF in LCLs and found that high levels of endogenous TERT are associated with high NOTCH2 and BATF expression levels. In addition, ectopic expression of TERT in LCLs with low levels of endogenous telomerase was associated with upregulation of NOTCH2 and BATF at both mRNA and protein levels. By contrast, infection of LCLs with retroviral vectors expressing functional NOTCH2 did not alter TERT transcript levels. Luciferase reporter assays, demonstrated that TERT significantly activated NOTCH2 promoter in a dose-dependent manner. We also found that NF-κB pathway is involved in TERT-induced NOTCH2 activation. Lastly, pharmacologic inhibition of NOTCH signaling triggers the EBV lytic cycle, leading to the death of EBV-infected cells. Overall, these results indicate that TERT contributes to preserve EBV latency in B cells mainly through the NOTCH2/BAFT pathway, and suggest that NOTCH2 inhibition may represent an appealing therapeutic strategy against EBV-associated malignancies.

• Field cancerization
• Head and neck cancer
• Human papilloma virus
• Local relapse
• Molecular biology
• Survival
• TERT
• Telomerase reverse transcriptase
• Telomeres

• Circulating tumor cells
• Gene expression
• Liver resection
• Metastatic colorectal cancer
• Real-time PCR