The role of telomeres in predicting individual radiosensitivity of patients with cancer in the era of personalized radiotherapy

Mirjolet, Céline; Boidot, Romain; Saliques, Sébastien; Ghiringhelli, François; Maingon, P.; Créhange, G.

doi:10.1016/j.ctrv.2015.02.005

Cited by 24 publications

(19 citation statements)

References 73 publications

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“…TERT serves as an enzyme with reverse transcription activity that is essential for adding telomeric repeats to the chromosome end (5). Previous studies have verified that there is a negative correlation between TERT and the radiosensitivity of cancer cells (11,14). We found that expression of TERT also decreased while HMBOX1 was downregulated.…”

Section: Discussionsupporting

confidence: 57%

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Knockdown of homeobox containing 1 increases the radiosensitivity of cervical cancer cells through telomere shortening

et al. 2017

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Abstract. Homeobox containing 1 (HMBOX1) modulates telomere length in various types of tumor cells by binding to double-stranded telomeric DNA. There is a negative correlation between telomere length and radiosensitivity in tumor cells. In the present study, we aimed to investigate the relationship among HMBOX1, telomere and radiosensitivity in cervical cancer cells. Lentivirus-based shRNAs were used to establish stable transfected cell lines in which protein and mRNA levels of HMBOX1 were notably decreased. Knockdown of HMBOX1 increased the radiosensitivity of HeLa and C33A cells. TERT protein was also decreased while HMBOX1 was downregulated. Knockdown of HMBOX1 shortened telomere length in the HeLa cells, while TERT overexpression rescued telomere shortening in the HeLa-HMBOX1 cells. Knockdown of HMBOX1 increased the apoptosis rate, decreased radiationinduced DNA damage foci, and inhibited the expression of ATM, ATR, p-ATM, p-ATR and BRCA1 in the homologous recombination repair pathway. Our data suggest a possible role of HMBOX1 in regulating radiosensitivity in cervical cancer cells. Moreover, HMBOX1 may be a potential factor in the radiotherapy of cervical cancer. IntroductionCervical cancer is the most common malignant tumor of the female reproductive system. It is the second most commonly diagnosed cancer and the third leading cause of cancerrelated death among females in developing countries (1). Radiotherapy is the major treatment for cervical cancer. For patients with early-stage disease, radiotherapy and surgery alone have equal effects. In recent years, chemoradiotherapy has gradually become a new treatment pattern for patients with locally advanced disease. It has been demonstrated that radiotherapy plays a crucial role in the treatment of cervical cancer. However, patients who suffer pelvic recurrence account for ~70% of the cases of radiotherapy failure (2). Thus, the identification of new factors that influence radiosensitivity has important significance in cervical cancer treatment.Homeobox containing 1 (HMBOX1), a new member of the homeobox genes, was identified and isolated from the human pancreatic cDNA library. HMBOX1 was described as a transcription repressor (3). In the ALT (alternative lengthening of telomeres) cell line WI38-VA13 and telomerase-positive HeLa cells, HMBOX1 was identified as a double-stranded telomeric DNA binding protein (4) and acted as a positive regulator of telomere length (5). In U2OS (ALT cells), HMBOX1 was found to modulate telomere maintenance without influencing telomere length (6). However, the further function of HMBOX1 is not fully clear.Telomeres, nucleoprotein complexes at the end of eukaryotic chromosomes, are composed of 5'-TTAGGG-3' repeats and are maintained by telomerase. Telomeres contain protein complexes and shelterin, and play a crucial role in protecting chromosome ends from DNA damage. Moreover, telomere length may serve as a target in predicting the individual radiosensitivity of patients with cancers (7-11).However, to date, the relationship bet...

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Section: Discussionsupporting

confidence: 57%

“…Telomeres contain protein complexes and shelterin, and play a crucial role in protecting chromosome ends from DNA damage. Moreover, telomere length may serve as a target in predicting the individual radiosensitivity of patients with cancers (7)(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Knockdown of homeobox containing 1 increases the radiosensitivity of cervical cancer cells through telomere shortening

et al. 2017

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“…Another compelling observation is the inhibition of telomerase and telomere shortening in response to platinum-based and radiotherapy, suggesting that TL and TERT may modulate treatment efficacy (24)(25)(26)(27). In addition to genetic variation and treatment, TL may also be affected by lifestyle and environmental factors, such as cigarette smoking, alcohol consumption, and air pollution, as well as socioeconomic factors and psychologic stress (28)(29)(30)(31)(32)(33)(34).…”

Section: Introductionmentioning

confidence: 99%

Systematic Review of Genetic Variation in Chromosome 5p15.33 and Telomere Length as Predictive and Prognostic Biomarkers for Lung Cancer

Kachuri

Latifovic

Liu

et al. 2016

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Lung cancer remains the leading cause of cancer mortality worldwide. Known histomolecular characteristics and genomic profiles provide limited insight into factors influencing patient outcomes. Telomere length (TL) is important for genomic integrity and has been a growing area of interest as agents targeting telomerase are being evaluated. Chromosome 5p15.33, an established cancer susceptibility locus, contains a telomerase-regulatory gene, TERT, and CLPTM1L, a gene associated with cisplatin-induced apoptosis. This review offers a summary of the clinical utility of 5p15.33 polymorphisms and TL. A total of 621 abstracts were screened, and 14 studies (7 for 5p15.33, 7 for TL) were reviewed. Endpoints included overall survival (OS), progression-free survival (PFS), therapy response, and toxicity. Of the 23 genetic variants identified, significant associations with OS and/or PFS were reported for rs401681 (CLPTM1L), rs4975616 (TERT-CLPTM1L), and rs2736109 (TERT). Both shorter and longer TL, in tumor and blood, was linked to OS and PFS. Overall, consistent evidence across multiple studies of 5p15.33 polymorphisms and TL was lacking. Despite the potential to become useful prognostic biomarkers in lung cancer, the limited number of reports and their methodologic limitations highlight the need for larger, carefully designed studies with clinically defined subpopulations and higher resolution genetic analyses. Cancer Epidemiol Biomarkers Prev; 25(12); 1537-49. ©2016 AACR.

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“…The effects of IR exposure, particularly radiations of different qualities, on telomere maintenance and/or function are poorly understood [reviewed in Ref. ( 51 )], even though telomeres themselves have been regarded as “hallmarks of radiosensitivity” ( 52 ), and recently proposed as informative biomarkers of radiosenstivity for the purposes of personalized medicine ( 53 ). Indeed, short telomeres have been shown to enhance IR sensitivity in several settings ( 54 – 57 ), being associated with impaired and/or delayed DSB repair kinetics ( 54 , 58 ), as well as with persistent chromosomal breaks and cytogenetic profiles characterized by complex aberrations and massive fragmentation ( 54 ).…”

Section: Introductionmentioning

confidence: 99%

Telomeres and Telomerase in the Radiation Response: Implications for Instability, Reprograming, and Carcinogenesis

et al. 2015

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Telomeres are nucleoprotein complexes comprised of tandem arrays of repetitive DNA sequence that serve to protect chromosomal termini from inappropriate degradation, as well as to prevent these natural DNA ends from being recognized as broken DNA (double-strand breaks) and triggering of inappropriate DNA damage responses. Preservation of telomere length requires telomerase, the specialized reverse transcriptase capable of maintaining telomere length via template-mediated addition of telomeric repeats onto the ends of newly synthesized chromosomes. Loss of either end-capping function or telomere length maintenance has been associated with genomic instability or senescence in a variety of settings; therefore, telomeres and telomerase have well-established connections to cancer and aging. It has long been recognized that oxidative stress promotes shortening of telomeres, and that telomerase activity is a radiation-inducible function. However, the effects of ionizing radiation (IR) exposure on telomeres per se are much less well understood and appreciated. To gain a deeper understanding of the roles, telomeres and telomerase play in the response of human cells to IRs of different qualities, we tracked changes in telomeric end-capping function, telomere length, and telomerase activity in panels of mammary epithelial and hematopoietic cell lines exposed to low linear energy transfer (LET) gamma(γ)-rays or high LET, high charge, high energy (HZE) particles, delivered either acutely or at low dose rates. In addition to demonstrating that dysfunctional telomeres contribute to IR-induced mutation frequencies and genome instability, we reveal non-canonical roles for telomerase, in that telomerase activity was required for IR-induced enrichment of mammary epithelial putative stem/progenitor cell populations, a finding also suggestive of cellular reprograming. Taken together, the results reported here establish the critical importance of telomeres and telomerase in the radiation response and, as such, have compelling implications not only for accelerated tumor repopulation following radiation therapy but also for carcinogenic potential following low dose exposures as well, including those of relevance to spaceflight-associated galactic cosmic radiations.

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The role of telomeres in predicting individual radiosensitivity of patients with cancer in the era of personalized radiotherapy

Cited by 24 publications

References 73 publications

Knockdown of homeobox containing 1 increases the radiosensitivity of cervical cancer cells through telomere shortening

Knockdown of homeobox containing 1 increases the radiosensitivity of cervical cancer cells through telomere shortening

Systematic Review of Genetic Variation in Chromosome 5p15.33 and Telomere Length as Predictive and Prognostic Biomarkers for Lung Cancer

Telomeres and Telomerase in the Radiation Response: Implications for Instability, Reprograming, and Carcinogenesis

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