Edited by: Paola Gehrig, University of North Carolina at Chapel Hill, United States
Reviewed by: Marilyn Huang, Sylvester Comprehensive Cancer Center, United States; Saori Furuta, University of Toledo, United States
This article was submitted to Women's Cancer, a section of the journal Frontiers in Oncology
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Telomeres at the termini of human chromosomes are shortened with each round of cell division due to the “end replication problem” as well as oxidative stress. During carcinogenesis, cells acquire or retain mechanisms to maintain telomeres to avoid initiation of cellular senescence or apoptosis and halting cell division by critically short telomeres. The unique reverse transcriptase enzyme complex, telomerase, catalyzes the maintenance of telomeres but most human somatic cells do not have sufficient telomerase activity to prevent telomere shortening. Tissues with high and prolonged replicative potential demonstrate adequate cellular telomerase activity to prevent telomere erosion, and high telomerase activity appears to be a critical feature of most (80–90%) epithelial cancers, including endometrial cancer. Endometrial cancers regress in response to progesterone which is frequently used to treat advanced endometrial cancer. Endometrial telomerase is inhibited by progestogens and deciphering telomere and telomerase biology in endometrial cancer is therefore important, as targeting telomerase (a downstream target of progestogens) in endometrial cancer may provide novel and more effective therapeutic avenues. This review aims to examine the available evidence for the role and importance of telomere and telomerase biology in endometrial cancer.
Telomeres are specialized structures that are found at the ends of linear chromosomes, containing a tandemly repeated specific DNA sequence and associated protective proteins. The protective function of telomeres in preventing the loss of genomic DNA in proliferating cells is well-established (
Human endometrium is a unique somatic organ that contains a relatively high yet dynamic pattern of telomerase activity that changes according to the menstrual cycle, correlating with endometrial cellular proliferation (
Endometrial cancer is the fourth common cancer in women in the UK and is the commonest gynecological cancer (CRUK). Increasing obesity and longevity have both caused the incidence of EC to increase at an alarming rate. For example, in the United Kingdom, the incidence of EC increased by more than 40% since 1993. European estimates predict a 100% increase in the incidence by 2025 not only in older post-menopausal women but also in younger women (
Although EC is an important disease with a significant clinical and economic consequence, the molecular biology of endometrial carcinogenesis is not well-described or understood when compared with other female-specific malignancies, such as breast or ovarian cancer. Human endometrium is a unique organ with a massive regenerative potential (
We performed systematic PubMed (Medline) and Ovid searches using a combination of relevant controlled vocabulary terms and free-text terms related to telomeres and telomerase. The key words used included: telomerase, telomeres, telomere length, telomerase reverse transcriptase (TERT), telomeric RNA component (TERC), shelterin proteins, telomerase associated proteins, with endometrium, endometriosis, endometrial hyperplasia, endometrial cancer (EC), endometrial carcinomas, uterine cancer, cancers. All studies investigating telomerase or telomere biology in endometrium in women or animals or respective cell lines, either primary cells or tissue explants in culture, and published from database inception until December 2018, were included in this review.
Human telomeres consist of a repetitive TTAGGG hexanucleotide sequence bound by six-proteins forming the shelterin complex [(
Schematic illustration of the telomere and main telomerase complex components. The human telomere and telomerase enzyme complex (only one half of the dimeric holoenzyme complex is shown for clarity), adapted from Hapangama et al. (
Most of the non-coding telomeric DNA is double-stranded whilst the terminal nucleotides (nt) form the single stranded 3′ G-rich overhang, which serves as the primer for telomerase action (
Another mechanism to protect telomeres from being recognized as DNA damage is the formation a t
The shelterin complex (
The main function of telomeres is to protect chromosomal ends from degradation and end-to end-fusion (
The shelterin complex supports the chromosome protective function of telomeres and stabilization of telomere lengths, and the complex interaction of shelterin proteins at the chromosomal ends have a key role in telomere maintenance via a negative feedback loop which also has an inhibitory effect on the telomerase enzyme (
In cells which have replicative capability, telomere shortening can lead to chromosomal instability by promoting end-to-end fusions leading to multiple chromosomal aberrations, such as breakages, fusions, and translocations rendering the genome aneuploid and therefore promoting carcinogenesis. To maintain telomere length, the homeostasis mechanism that involves telomerase, uses both TRF1 and TRF2 as negative regulators that stabilize and limit telomere length elongation (
Telomere length is the main determinant of a cell's replicative life span. Dysfunctional telomeres which result from either progressive telomere shortening, internal DNA damage (
Telomeres were initially thought to be transcriptionally silent, but recently they have been found to be transcribed into telomeric repeat containing, long non-coding RNAs, termed TERRAs (
The most widely known classical telomere maintenance mechanism is dependent on telomerase reverse transcriptase activity. However, another telomerase-independent telomere maintaining pathway has been described in cells that do not have measurable telomerase activity, termed alternative lengthening of telomeres (ALT) pathway (
Telomere maintenance mechanisms. Cells can maintain their telomeres via either telomerase-dependent pathway or a telomerase-independent ALT pathway. Activated Wnt signaling pathway can maintain telomere length by activating both these maintenance mechanism and by maintaining the level of TRF2 and POT1 sheltrin components that are essential for telomere protection (
Telomerase, the only RNA dependent DNA polymerase in mammals, was first discovered in protozoans in 1985 (
Telomerase associated proteins [adapted from Hapangama et al. (
Hsp 90, P23 | Hsp90 is an essential modulator for the proper folding and stabilization of several client proteins and it is a major contributor to carcinogenesis. Hsp90 and P23 act together to regulate telomerase DNA binding. Since heat shock protein 90 (Hsp90) client proteins have major cancer biological hallmarks, targeting Hsp90 provides the prospect for simultaneous disturbance of multiple oncogenic pathways. In triple-negative breast cancer, inhibition of Hsp90 has shown to be a promising therapeutic avenue ( |
Protein 14-3-3 | These proteins are involved in regulating multiple cellular functions via their interaction with phosphorylated partners. An elevated level of 14-3-3 proteins facilitates tumor progression in a variety of malignancies. The observations of Seimiya et al. identified the 14-3-3 signaling proteins as human TERT (hTERT)-binding partners and suggested that 14-3-3 improves nuclear localization of TERT. A dominant-negative 14-3-3 redistributed hTERT into the cytoplasm, which was normally localized in the nucleus ( |
DHX36 (DEAH-Box Helicase 36) | It mediates AU-rich element mRNA degradation and as a resolvase for G-quadruplex DNA |
Pontin and reptin | Pontin and Reptin are conserved proteins belong to AAA + ATPases family, they have a role in various cellular processes that are critical for oncogenesis, such as transcriptional regulation, chromatin remodeling, DNA damage signaling and repair, assembly of macromolecular complexes, regulation of cell cycle/mitotic progression, and cellular motility, all of which contribute to their central roles in activating cell proliferation and survival ( |
Dyskerin | Dyskerin is one of H/ACA ribonucleoproteins (RNPs) which also include (NOP10, NHP2, and GAR1) ( |
NOP10 | NOP10 as an H/ACA RNP contributes to telomerase enzyme assembly and stabilization, post-transcriptional processing of nascent ribosomal RNA and pre-mRNA splicing. Therefore, it is essential for ribosome biogenesis, pre-mRNA splicing, and telomere maintenance ( |
NHP2 | NHP2 has the same function as other H/ACA RNPs, increased NHP2 protein in gastric and colorectal cancer relative to healthy controls ( |
GAR1 | GAR1 is one of the four H/ACA RNPs. It also involved in telomerase assembly and stabilization, post-transcriptional processing of nascent ribosomal RNA and pre-mRNA splicing. All these RNPs are concentrated in nucleoli and Cajal bodies of mammalian cells, reflecting the location of H/ACA RNPs. GAR1 binds only to Dyskerin and it is crucial for the nucleolar localization and function of the RNP complex. In CLL patients, a significant decrease of GAR1 mRNA level in patients with CLL compared to controls ( |
TEP1 (telomerase protein component 1) | TEP1 is overexpressed in tumor cells compared to normal cells and it contributes to carcinogenesis and progression of renal cell carcinoma, bladder and prostate cancer ( |
TCAB1 (telomerase and Cajal body protein 1, encoded by WRAP53) | TCAB1 is a subunit of active telomerase and is essential for the telomerase holoenzyme to be accumulated in Cajal bodies and to elongate telomeres ( |
A1/UP1 | Findings of Nagata et al. suggested that UP1, a proteolytic product of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), can unfold the quadruplex structure of telomeric DNA into a single-stranded structure. Therefore, UP1 may enhance the telomerase activity via unfolding of the quadruplex structure of telomeric DNA and resultant provision of the accessible overhang. The authors assumed that both unfolding and recruitment by hnRNP A1/UP1 contribute to improve telomerase activity and maintain proper telomere length. Thus, hnRNP A1/UP1 may be promising targets to control telomerase activity which is associated with several cancers ( |
The human telomerase RNA (TERC or hTR) consists of 451 nt and is an essential constituent of the telomerase catalytic core complex. Although the length is variable among eukaryotes, the structure of TERC remains conserved. For example, the length ranges from ~150 nt in ciliates, 400–600 nt in vertebrates to ~1,300 nt in yeast (
Vertebrate TERC's secondary structure has four conserved elements: a pseudoknot domain (CR2/CR3), a CR4/CR5 (conserved region 4 and conserved region 5) domain, box H/ACA (CR6/CR8) domain and a CR7 domain (
As mentioned before, an active telomerase enzyme can be generated by combining the two RNA domains from the TERC subunit with the TERT protein on oligodeoxynucleotide substrates
TERT is the catalytic component of the telomerase enzyme and as described above, together with TERC, it is essential for telomerase activity and thus for the maintenance of telomere length, chromosomal stability, and cellular immortality. The human TERT gene (hTERT) is located at chromosome 5p15, and encompasses more than 37 kb and contains 16 exons (
Dyskerin is a highly conserved, nucleolar, 514-amino-acid long protein, also known as NAP57 in rat (
Complete dyskerin depletion is lethal in mice, Drosophila (they do not have telomerase activity therefore a non-telomerase related function) and yeast (
Telomerase is a specialized reverse transcriptase, which maintains and elongates telomeres at the 3′-single strand in the absence of a DNA template while using the inherent RNA (TERC) for the template function and is thus a RNA dependent DNA polymerase. In the subsequent S-phase of the cell cycle, the conventional DNA replication machinery can then replicate the complementary C-rich strand. Thus, telomerase ascertains chromosomal stability and cellular proliferation in proliferative somatic cells, tissue progenitor cells and in cancer cells (
Ataxia-Telangiectasia Mutated (ATM) and ATM and Rad3 related (ATR) DNA damage response kinases have essential roles in telomerase-mediated telomere maintenance (
Stalled replication forks increased telomerase localization to telomeres in an ATR-dependent manner (
Wnt family proteins are essential for regulating cell proliferation, cell polarity, and cell fate determination during embryonic development and tissue homeostasis (
The Wnt pathway may regulate telomere maintenance via its effect on several essential shelterin components, including TRF2 and POT1. Recently, in human somatic and cancer cells as well as in mouse intestinal tissue, activation of canonical Wnt/β-catenin pathway activated TRF2 and also increased telomere protection were demonstrated (
Further to the enhancement of shelterin protection, the Wnt/β-catenin signaling pathway also activates TERT (
Non-canonical functions of TERT have been discovered later than telomerase activity, and they also play a role in tumorigenesis, for example via TERT's role in regulating the Wnt signaling as a cofactor for the β-catenin pathway (
There is evidence from multiple studies that telomerase is under the regulation of steroid hormones in hormone responsive tissues. This corroborates with the known direct regulation of cell fate and proliferation in such tissues by steroid hormones, for example the ovarian hormone, estradiol, induces a mitotic response in endometrial epithelial cells (
Telomerase regulation by TERRAs has initially been examined in yeast although recent work also suggests a similar regulation in human cells. In yeast cells, TERRAs were found to sequester and direct telomerase to the specific telomeres which were the shortest (
TERRA was found to be induced in cells with short telomeres and acted as a scaffold for spatial organization of the telomerase components forming a TERRA-telomerase complex which helped in recruitment of telomerase to the telomere of its origin hence TERRA was proposed to be a recruiter of telomerase enzyme rather than an inhibitor (
Cells can maintain their telomeres
The first evidence for the presence of an ALT mechanism was described in several immortalized human cell lines that did not have telomerase activity but maintained telomere lengths for hundreds of population doublings, and this mechanism occurs in ~15% of cancers including osteosarcomas, soft tissue sarcoma subtypes, and some glial brain tumors (
In human cells, where ALT activity is elevated to a degree sufficient for telomere length maintenance, telomeres are characterized by their highly heterogeneous length, but the average length (>17 kb) is about double that of most cells where telomeres are elongated by telomerase (
Mutations in the ATRX/DAXX chromatin remodeling complex have been observed in cancers and cell lines that use the ALT mechanism, suggesting that ATRX may suppress the ALT pathway (
Limitless proliferation is a cardinal feature of cancer cells, whist increased proliferation is common to all premalignant changes including hyperplasia. The excessive proliferation observed in these malignant/premalignant conditions is maintained by avoiding senescence and crisis/apoptosis. Senescence/apoptosis exist as barriers for mitosis, thus they are tumor suppressor mechanisms in normal cells, which are regulated intricately by telomeres and checkpoint activation (
The involvement of telomeres and telomerase activity in epithelial cancers. The initial acquisition of tumor promoting mutations is promoted by short dysfunctional telomeres which are subsequently stabilized by high telomerase activity levels that is characteristic for most cancer cells, with the overall result being pre-requisite for unregulated proliferation capacity.
During ongoing proliferation in normal somatic cells without telomerase or other telomere-maintenance mechanisms, telomeres shorten until reaching a certain minimal length. Beyond this, when tumor suppressor checkpoints, such as p53 are functioning, senescence or apoptosis can be induced. In contrast, when p53 or other important DNA damage checkpoints are not functioning, cells can enter a crisis state where ongoing proliferation promotes further telomere shortening and telomere dysfunction (
However, importantly, acquiring telomerase activity can stabilize even short telomeres in genetically unstable cells and provide sufficient capping for them to attain an unlimited proliferation potential. Thereby, telomerase re-activation conserves genomic mutations and instabilities and contributes further to tumourigenesis (
Significant telomere length shortening results in end-to-end fusion, thus increasing the potential for genome instability and carcinogenesis. There are few other generic associations which lead to telomere attrition, such as oxidative stress, lifestyle choices, environmental factors, smoking and obesity (
Meta-analyses of available studies also revealed that shorter peripheral blood mono-nucleocyte (PBMC) telomeres are associated with a significant increase in the risk of developing cancer (OR = 1.35, 95% CI = 1.14–1.60) than longer telomeres (
Telomere dysfunction may also be a resultant of altered telomere-associated proteins that are also essential for regular end-capping function (
Such as
Tumors with high
Common inherited variants of telomere related genes, such as
A high frequency of
The early observation that telomerase activity is absent in most human somatic tissues during differentiation but strongly upregulated in tumors, agrees with the hypothesis that telomerase playing an important role in the carcinogenesis process (
The endometrium is the inner mucosal lining of the uterus that contains several cell types including tissue specific epithelial and stromal cells, as well as leucocytes and blood vessels (
From Valentijn et al. (
The role of telomeres and telomerase in benign endometrial disorders was recently reviewed in detail in Hapangama et al (
Published literature on telomerase biology in benign endometrial disorders, telomerase, and telomere length.
hTERT/TL | Endometrial telomerase shows specific expression patterns in different types of reproductive failure | ( |
Control group ( |
IHC (telomerase protein level) real-time PCR (TL) | In recurrent reproductive failure samples, the immunostaining for telomerase was significantly high in various endometrial cellular compartments and this indicates that there are specific alterations occur in the regulation of endometrial cell fate are associated with recurrent reproductive failure various types |
hTERT/TL/TA | Endometriosis is associated with aberrant endometrial expression of telomerase and increased telomere length | ( |
Group 1: healthy fertile ( |
IHC (Telomerase and ERβ) qPCR (Mean TL), TRAP (TA) | Either weak or absent telomerase immunoreactivity was observed in the endometria of fertile healthy women throughout the luteal phase. Increased telomerase protein level (IHC) during the implantation window and the premenstrual endometria of women with endometriosis. The mean TL were significantly longer in endometria of women with endometriosis during the implantation window This study suggested that aberrant expression of telomerase in endometrium alters the cell fate and enhances the cellular proliferation and that leads to the occurrence of endometriosis |
hTERT | The expression levels of stem cell markers importin13, c-kit, CD146, and telomerase are decreased in endometrial polyps | ( |
Control (proliferative phase |
IHC (Telomerase protein) | In endometrial polyp tissue, the level of telomerase was decreased in comparison with normal endometrial tissue |
hTERT | Enhanced differentiation and clonogenicity of human endometrial polyp stem cells | ( |
Endometrial polyp ( |
Quantitative RT-PCR (TERT) | No telomerase reverse transcriptase (TERT) expression was noted in endometrial polyp tissue |
hTERT | Aberrant Telomerase Expression in the Endometrium of Infertile Women with Deep Endometriosis | ( |
Control group: Fertile women without endometriosis ( |
qRT-PCR (hTERT and GAPDH mRNA) based on TaqMan methodology | Telomerase (hTERT mRNA) level is associated with the development and progression of endometriosis |
hTERT | The Status of Telomerase Enzyme Activity in Benign and Malignant Gynaecologic Pathologies | ( |
Benign endometrial tissue ( |
Real-time reverse transcriptase polymerase chain reaction RT-PCR (hTERT mRNA) | hTERT was positive only in the irregular proliferative phase endometrium (14.2%) and hTERT was also positive in one of 13 endometriosis ectopic specimens (7.7%) |
TA, hTERT, TL | Human endometrial epithelial telomerase is important for epithelial proliferation and glandular formation with potential implications in endometriosis | ( |
Group 1 ( |
TRAP (TA), qPCR and Q-FISH (TL), immunoblotting (histone H3) (cell proliferation), 3D-culture (assess the ability of EECs to form spheroids, IHC (TERT and Ki67) | High TA and short TLs were observed in proliferating EECs |
hTERT | Endometrial expression of telomerase, progesterone, and estrogen receptors during the implantation window in patients with recurrent implantation failure | ( |
Endometrial biopsies fertile ( |
qRT-PCR (TERT, ER alpha and PR), western blotting and IHC (TERT and ER alpha) | Expression of endometrial telomerase was substantially increased as ER alpha decreased in women with RIF during the implantation window. |
TA | Does telomerase activity have an effect on infertility in patients with endometriosis? | ( |
Healthy control ( |
PCR (TA) | In peripheric blood analysis, telomerase activity is useless as a biomarker. Telomerase activity is absent in cystic wall and that suggesting a high differentiation of endometriosis tissue and that might be considered as a cause of low malignancy risk. Whereas, telomerase activity is high in the eutopic endometrium of the infertile group which may be the possible reason of endometriosis-related infertility. |
hTERT, TA | Increased telomerase activity and human telomerase reverse transcriptase mRNA expression in the endometrium of patients with endometriosis | ( |
Healthy control ( |
qRT-PCR (hTERT), TRAP (TA) | In the endometrium of endometriosis patients, the hTERT mRNA is overexpressed and telomerase activity is increased suggesting that the replication potential of endometrial cells might be crucial in the pathogenesis of endometriosis |
The progesterone dominant window of implantation in healthy women has shown virtually no hTERT immunoreactivity (
Endometrial epithelial hyper-proliferation with increased glandular to stromal cell ratio is defined as endometrial hyperplasia. Pathogenesis of endometrial hyperplasia is virtually always associated with relative predominance of the mitotic estrogen signal, due to direct excess of Estrogen or due to insufficient levels of progesterone (
The involvement of telomere shortening in chromosomal instability has been associated with the initiation of carcinogenesis (
By using a three-dimensional (3D) imaging technique, a specific 3D arrangement of telomeres was revealed in tumor cell nuclei (
The existence of telomere aggregates in precancerous lesions, such as in human cervical intraepithelial neoplasia supports the notion that changes in the organization of the 3D nucleus may facilitate tumorigenesis (
High hTERT levels and elevated telomerase activity were reported in all types of endometrial hyperplasia, including simple, complex and complex with atypia subtypes (
Traditionally, EC had been divided into two major groups: estrogen-dependent, type-I (endometrioid type) and estrogen-independent, type-II (non-endometrioid), with the former accounting for 80% of ECs. Five-years survival rates are exceptionally poor for advanced type-I and type-II (high grade) EC at 23% which is a far worse rate than for most other common cancers, such as breast cancer (CRUK). However, the recent trend had been to apply for an alternative classification system that more accurately defines ECs into prognostically distinct molecular subtypes that reflect the underlying molecular alterations with well-described underlying genomic aberrations (
A study in 1992 found that endometrial adenocarcinomas have reduced telomeric repeat sequences suggesting shorter telomeres compared with normal tissue (
The role of telomere and telomerase activity in endometrial cancer. Hormonal imbalance (excess of Estrogen or insufficient levels of progesterone) will increase telomerase and elevate telomerase activity was described in all types of endometrial hyperplasia and in endometrial cancer. Dysfunctional telomeres results in genomic instability, the first step in endometrial carcinogenesis. Telomerase dependent pathway is the most widely reported classical telomere length maintenance mechanism but ALT pathway; telomerase independent telomere maintenance was described in some cancer types that lack telomerase activity.
Published literature on telomerase biology in endometrial cancer: telomerase activity and telomere length.
TL | Telomere reduction in endometrial adenocarcinoma. | ( |
Normal endometrium and EC samples ( |
The relative number of telomeric repeat sequences in each sample was measured by hybridization of these deoxyribonucleic acids (DNA) to a probe specific for the human telomeric repeat. quantifion of the Hybridization signals were performed by autoradiography and a β-particle detection system | Telomeric repeat sequences were reduced in EC vs. normal endometium (in 10 out of 11 cases) and also reduced in endometrial carcinoma cell lines. the data of this study suggested that Telomeric reduction is a genetic characteristic of many endometrial cancers. Telomere reduction may play an essential role in the genesis and progression of endometrial carcinoma, or it may be a secondary effect of the tumorigenesis process |
TA | Telomerase activity in gynecological tumors | ( |
EC cell lines ( |
TRAP assay with dilution assay | 5 of 5 EC cell lines displayed strong signals for TA |
TA | Telomerase Activity in Human Endometrium | ( |
Normal ( |
TRAP assay |
TA regulated during the menstrual cycle |
TA | Proliferation-associated regulation of telomerase activity in human endometrium and its potential implication in early cancer diagnosis | ( |
Normal ( |
TRAP assay (TA) | TA detected in 28 of 30 ECs |
TA | Telomerase expression in normal endometrium, endometrial hyperplasia, and endometrial adenocarcinoma. | ( |
Normal endometrium (pre and post-menopausal) ( |
TRAP assay (TA) | Telomerase activity was detected in 40 of 48 cases of endometrial adenocarcinoma. In this study telomerase activity did not correlated with tumor grade, myometrial invasion, or cancer stage. However, there was a statistical significant association between telomerase activity in benign atrophic endometrium vs. any endometrial abnormality in women 52 years of age or older |
TA | Telomerase Activity in Benign Endometrium and Endometrial Carcinoma. | ( |
EC ( |
TRAP-eze using PCR Quantitative DNA analysis using Feulgen method | Strong TA detected in 8 of 8 benign, premenopausal endometrial specimens (proliferative |
TA | Telomerase activity in human gynecological malignancies. | ( |
EC ( |
TRAP assay using PCR | TA was detected in 6 of 6 EC |
TA | Telomerase activity in gynecologic tumors. | ( |
EC ( |
TRAP assay using PCR | TA activity was detected in all ECs |
TA | Expression of telomerase activity in human endometrium is localized to epithelial glandular cells and regulated in a menstrual phase-dependent manner correlated with cell proliferation | ( |
Normal ( |
TRAP assay (stretch PCR) |
TA regulated in menstrual-phase-dependent manner |
TA | Telomerase activity correlates with histo-pathological factors in uterine endometrial carcinoma. | ( |
EC ( |
TRAP assay | TA detected in 31 of 35 ECs |
TA | Human telomerase reverse transcriptase as a critical determinant of telomerase activity in normal and malignant endometrial tissues | ( |
Normal ( |
TRAP assay | TA detected in 12 of 12 proliferative endometria |
hTERT, TA | Quantitative analysis of telomerase hTERT mRNA and telomerase activity in endometrioid adenocarcinoma and in normal endometrium | ( |
Normal ( |
RT-PCR of hTERT mRNA TRAP assay | In normal endometrium hTERT mRNA and TA levels were highest in the proliferative phase and relatively low in secretory and atrophic endometrium |
TA/TL | The relationship between telomere length and telomerase activity in gynecologic cancers | ( |
EC ( |
TRAP(EZE) ELISA kit (TA) Southern blot (TL) | TA detected in 18 of 22 ECs |
TA | Is the telomerase assay useful for screening of endometrial lesions? | ( |
Normal ( |
TRAP assay (TRAP-eze telomerase detection kit) | TA detected in 10 of 15 proliferative phase endometrial samples |
TL | Differential Roles of Telomere Attrition in Type I and II Endometrial Carcinogenesis | ( |
EC ( |
Evaluated telomere lengths |
Telo-CISH demonstrates telomere shortening is a general feature of type I and II endometrial carcinogenesis |
TL | Telomere length and genetic analyses in population-based studies of endometrial cancer risk. | ( |
EC ( |
Relative leukocyte TL measured using qPCR based telomere assay from blood sample | No relationship between leukocyte TL and EC |
hTERT | The status of telomerase enzyme activity in benign and malignant gynaecologic pathologies. | ( |
EC ( |
hTERT mRNA quantification using RT-PCR (presence of hTERT, not assessing TA) | 6 of 6 ECs found to be hTERT positive |
TL | Association of leukocyte telomere length in peripheral blood leukocytes with endometrial cancer risk in Caucasian Americans | ( |
EC ( |
Relative leukocyte TL measured using qPCR based telomere assay from blood sample | Normalized LTL was significantly longer in EC cases than in controls |
A recent paper that considered germline genetic variants in a genome wide association study (GWAS) as instrumental variables to appraise the causal relevance of telomere length for the risk of cancer, demonstrated that their predicted increase in telomere lengths was strongly associated with some specific cancers, such as gliomas, low grade serous ovarian cancers, lung adenocarcinomas, neuroblastomas, bladder cancers, melanomas, testicular cancers, and also endometrial cancers (
The protein and/or mRNA levels of the most conserved out of all shelterin proteins, POT1 (
There are no published studies examining the expression or function of other shelterin proteins or TERRAs in EC to date.
Kyo et al. examining 13 endometrial cancers and 5 cell lines derived from endometrial cancers using a Telomerase Repeated Amplification Protocol (TRAP) assay reported that 92% of cancer samples displayed detectable telomerase activity (
Immunohistochemical staining with an anti-human telomerase antibody in healthy and endometrial tissue samples. Endometrial tissue sections demonstrating hTERT immunostaining in full thickness post-menopausal (PM) section and pipelle biopsy from a patient with endometrial cancer (EC) using a polyclonal rabbit anti-human telomerase antibody (ab27573, Abcam, Cambridge UK), detected with ImmPRESS anti-rabbit polymer and visualization with ImmPACT DAB (Vector Laboratories, Peterborough, UK). Positive nuclear hTERT brownish staining was observed in endometrial normal and cancer glands (red arrow). Magnification ×400, scale bar 10 μm.
Detection of hTERT mRNA in peripheral blood (PBMCs) has been reported to be significantly higher in women with EC compared to patients with benign uterine diseases and healthy controls. Using a relatively moderate sample size (
Recently, in two progesterone responsive and progesterone-insensitive human endometrial cancer cell lines (
Activating
In endometrial cancer cell lines, telomerase activity and expression of hTERT were both increased by estrogen in an estrogen receptor alpha (ERα) dependent and estrogen responsive element (ERE) dependent effect in the
Lehner et al. (
PTEN regulates telomerase activity, most likely through its known effects on the PI3-kinase/Akt pathway (
Telomerase was thought to be a suitable target for anti-cancer agents due to the high activity levels seen in most cancers. Available anti-telomerase strategies can be grouped into three main categories: (
Progestogens remain to be one of the main hormone-based chemotherapeutic agents that are used in early, advanced and recurrent EC with only modest benefit (
Telomere and telomerase have an intricate relationship with cancer-related multiple cellular functional pathway aberrations. Collectively, the available evidence suggests that endometrial cancer tissues have relatively short telomeres that are maintained by high telomerase activity. Further studies should shed light into different endometrial cancer subtype-associated changes in telomere length, which might facilitate exploring alternative therapeutic strategies to prevent occurrence and progression or recurrence of this devastating disease. Future studies examining the involvement of various telomere and telomerase associated proteins as prognostic markers that potentially could be used in stratifying patients for adjuvant therapies in endometrial cancer are also warranted. In addition, a comprehensive understanding of the telomere and telomerase biology in endometrial cancer will facilitate assessment of targeting telomerase as a personalized therapeutic strategy in endometrial cancer.
DH conceived the manuscript. RA, MA, LB, and DH prepared the first draft. GS, RA, MA, and DH revised the manuscript critically for important intellectual content and RA, MA, and DH prepared the figures and references. All authors revised and read the manuscript and approved the submitted final version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors are grateful for department of Women's and Children's Health of University of Liverpool in supporting this work (RA, MA, and DH).