DOI QR코드

DOI QR Code

Implications of telomerase reverse transcriptase in tumor metastasis

  • Zou, Yongkang (Institute of Cancer Research, Shenzhen Bay Laboratory) ;
  • Cong, Yu-sheng (Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Hangzhou Normal University) ;
  • Zhou, Junzhi (Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Hangzhou Normal University)
  • Received : 2020.05.22
  • Accepted : 2020.07.14
  • Published : 2020.09.30

Abstract

Metastasis is the main culprit of the great majority of cancerrelated deaths. However, the complicated process of the invasion-metastasis cascade remains the least understood aspect of cancer biology. Telomerase plays a pivotal role in bypassing cellular senescence and sustaining the cancer progression by maintaining telomere homeostasis and genomic integrity. Telomerase reverse transcriptase (TERT) exerts a series of fundamental functions that are independent of its enzymatic cellular activity, including proliferation, inflammation, epithelia-mesenchymal transition (EMT), angiogenesis, DNA repair, and gene expression. Accumulating evidence indicates that TERT may facilitate most steps of the invasion-metastasis cascade. In this review, we summarize important advances that have revealed some of the mechanisms by which TERT facilitates tumor metastasis, providing an update on the non-canonical functions of telomerase beyond telomere maintaining.

Keywords

References

  1. Finkel T, Serrano M and Blasco MA (2007) The common biology of cancer and ageing. Nature 448, 767-774 https://doi.org/10.1038/nature05985
  2. Palm W and de Lange T (2008) How shelterin protects mammalian telomeres. Annu Rev Genet 42, 301-334 https://doi.org/10.1146/annurev.genet.41.110306.130350
  3. Arndt GM and MacKenzie KL (2016) New prospects for targeting telomerase beyond the telomere. Nat Rev Cancer 16, 508-524 https://doi.org/10.1038/nrc.2016.55
  4. Yi X, Tesmer VM, Savre-Train I, Shay JW and Wright WE (1999) Both transcriptional and posttranscriptional mechanisms regulate human telomerase template RNA levels. Mol Cell Biol 19, 3989-3997 https://doi.org/10.1128/mcb.19.6.3989
  5. Cong Y and Shay JW (2008) Actions of human telomerase beyond telomeres. Cell Res 18, 725-732 https://doi.org/10.1038/cr.2008.74
  6. Cong YS, Wright WE and Shay JW (2002) Human telomerase and its regulation. Microbiol Mol Biol Rev 66, 407-425, table of contents https://doi.org/10.1128/MMBR.66.3.407-425.2002
  7. Lambert AW, Pattabiraman DR and Weinberg RA (2017) Emerging Biological Principles of Metastasis. Cell 168, 670-691 https://doi.org/10.1016/j.cell.2016.11.037
  8. Wan L, Pantel K and Kang Y (2013) Tumor metastasis: moving new biological insights into the clinic. Nat Med 19, 1450-1464 https://doi.org/10.1038/nm.3391
  9. Hanahan D and Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144, 646-674 https://doi.org/10.1016/j.cell.2011.02.013
  10. Park YJ, Kim EK, Moon S, Hong DP, Bae JY and Kim J (2014) Human telomerase reverse transcriptase is a promising target for cancer inhibition in squamous cell carcinomas. Anticancer Res 34, 6389-6395
  11. Ding D, Xi P, Zhou J, Wang M and Cong YS (2013) Human telomerase reverse transcriptase regulates MMP expression independently of telomerase activity via NFkappaB-dependent transcription. FASEB J 27, 4375-4383 https://doi.org/10.1096/fj.13-230904
  12. Ghosh A, Saginc G, Leow SC et al (2012) Telomerase directly regulates NF-kappaB-dependent transcription. Nat Cell Biol 14, 1270-1281 https://doi.org/10.1038/ncb2621
  13. Taniguchi K and Karin M (2018) NF-kappaB, inflammation, immunity and cancer: coming of age. Nat Rev Immunol 18, 309-324 https://doi.org/10.1038/nri.2017.142
  14. Sullivan NJ, Sasser AK, Axel AE et al (2009) Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene 28, 2940-2947 https://doi.org/10.1038/onc.2009.180
  15. Chuang MJ, Sun KH, Tang SJ et al (2008) Tumor-derived tumor necrosis factor-alpha promotes progression and epithelial-mesenchymal transition in renal cell carcinoma cells. Cancer Sci 99, 905-913 https://doi.org/10.1111/j.1349-7006.2008.00756.x
  16. Chua HL, Bhat-Nakshatri P, Clare SE, Morimiya A, Badve S and Nakshatri H (2007) NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2. Oncogene 26, 711-724 https://doi.org/10.1038/sj.onc.1209808
  17. Pastushenko I and Blanpain C (2019) EMT Transition States during Tumor Progression and Metastasis. Trends Cell Biol 29, 212-226 https://doi.org/10.1016/j.tcb.2018.12.001
  18. Thiery JP, Acloque H, Huang RY and Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139, 871-890 https://doi.org/10.1016/j.cell.2009.11.007
  19. Tam WL and Weinberg RA (2013) The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med 19, 1438-1449 https://doi.org/10.1038/nm.3336
  20. Liu Z, Li Q, Li K et al (2013) Telomerase reverse transcriptase promotes epithelial-mesenchymal transition and stem cell-like traits in cancer cells. Oncogene 32, 4203-4213 https://doi.org/10.1038/onc.2012.441
  21. Vlodavsky I, Ilan N, Naggi A and Casu B (2007) Heparanase: structure, biological functions, and inhibition by heparinderived mimetics of heparan sulfate. Curr Pharm Des 13, 2057-2073 https://doi.org/10.2174/138161207781039742
  22. Park YJ, Kim EK, Bae JY, Moon S and Kim J (2016) Human telomerase reverse transcriptase (hTERT) promotes cancer invasion by modulating cathepsin D via early growth response (EGR)-1. Cancer Lett 370, 222-231 https://doi.org/10.1016/j.canlet.2015.10.021
  23. Tang B, Xie R, Qin Y et al (2016) Human telomerase reverse transcriptase (hTERT) promotes gastric cancer invasion through cooperating with c-Myc to upregulate heparanase expression. Oncotarget 7, 11364-11379 https://doi.org/10.18632/oncotarget.6575
  24. Gocheva V, Zeng W, Ke D et al (2006) Distinct roles for cysteine cathepsin genes in multistage tumorigenesis. Genes Dev 20, 543-556 https://doi.org/10.1101/gad.1407406
  25. Turk V, Stoka V, Vasiljeva O et al (2012) Cysteine cathepsins: from structure, function and regulation to new frontiers. Biochim Biophys Acta 1824, 68-88 https://doi.org/10.1016/j.bbapap.2011.10.002
  26. Hu C, Ni Z, Li BS et al (2017) hTERT promotes the invasion of gastric cancer cells by enhancing FOXO3a ubiquitination and subsequent ITGB1 upregulation. Gut 66, 31-42 https://doi.org/10.1136/gutjnl-2015-309322
  27. He B, Xiao YF, Tang B et al (2016) hTERT mediates gastric cancer metastasis partially through the indirect targeting of ITGB1 by microRNA-29a. Sci Rep 6, 21955 https://doi.org/10.1038/srep21955
  28. Chen MB, Lamar JM, Li R, Hynes RO and Kamm RD (2016) Elucidation of the Roles of Tumor Integrin beta1 in the Extravasation Stage of the Metastasis Cascade. Cancer Res 76, 2513-2524 https://doi.org/10.1158/0008-5472.CAN-15-1325
  29. Xu Z, Zou L, Ma G et al (2017) Integrin beta1 is a critical effector in promoting metastasis and chemo-resistance of esophageal squamous cell carcinoma. Am J Cancer Res 7, 531-542
  30. Chen S, Yang L, Dong H and Guo H (2019) Human telomerase reverse transcriptase recruits the beta-catenin/TCF-4 complex to transactivate chemokine (C-C motif) ligand 2 expression in colorectal cancer. Biomed Pharmacother 112, 108700 https://doi.org/10.1016/j.biopha.2019.108700
  31. Kitamura T, Qian BZ and Pollard JW (2015) Immune cell promotion of metastasis. Nat Rev Immunol 15, 73-86 https://doi.org/10.1038/nri3789
  32. Peinado H, Zhang H, Matei IR et al (2017) Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer 17, 302-317 https://doi.org/10.1038/nrc.2017.6
  33. Dirat B, Bochet L, Dabek M et al (2011) Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res 71, 2455-2465 https://doi.org/10.1158/0008-5472.CAN-10-3323
  34. Karnoub AE, Dash AB, Vo AP et al (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449, 557-563 https://doi.org/10.1038/nature06188
  35. Wyckoff J, Wang W, Lin EY et al (2004) A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res 64, 7022-7029 https://doi.org/10.1158/0008-5472.CAN-04-1449
  36. Obenauf AC and Massague J (2015) Surviving at a Distance: Organ-Specific Metastasis. Trends Cancer 1, 76-91 https://doi.org/10.1016/j.trecan.2015.07.009
  37. Zhou L, Zheng D, Wang M and Cong YS (2009) Telomerase reverse transcriptase activates the expression of vascular endothelial growth factor independent of telomerase activity. Biochem Biophys Res Commun 386, 739-743 https://doi.org/10.1016/j.bbrc.2009.06.116
  38. Liu N, Ding D, Hao W et al (2016) hTERT promotes tumor angiogenesis by activating VEGF via interactions with the Sp1 transcription factor. Nucleic Acids Res 44, 8693-8703 https://doi.org/10.1093/nar/gkw549
  39. Bermudez Y, Yang H, Saunders BO, Cheng JQ, Nicosia SV and Kruk PA (2007) VEGF- and LPA-induced telomerase in human ovarian cancer cells is Sp1-dependent. Gynecol Oncol 106, 526-537 https://doi.org/10.1016/j.ygyno.2007.05.005
  40. Zaccagnini G, Gaetano C, Della Pietra L et al (2005) Telomerase mediates vascular endothelial growth factordependent responsiveness in a rat model of hind limb ischemia. J Biol Chem 280, 14790-14798 https://doi.org/10.1074/jbc.M414644200
  41. Giampieri S, Manning C, Hooper S, Jones L, Hill CS and Sahai E (2009) Localized and reversible TGFbeta signalling switches breast cancer cells from cohesive to single cell motility. Nat Cell Biol 11, 1287-1296 https://doi.org/10.1038/ncb1973
  42. Padua D, Zhang XH, Wang Q et al (2008) TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133, 66-77 https://doi.org/10.1016/j.cell.2008.01.046
  43. Ding Z, Wu CJ, Jaskelioff M et al (2012) Telomerase reactivation following telomere dysfunction yields murine prostate tumors with bone metastases. Cell 148, 896-907 https://doi.org/10.1016/j.cell.2012.01.039
  44. Massague J and Obenauf AC (2016) Metastatic colonization by circulating tumour cells. Nature 529, 298-306 https://doi.org/10.1038/nature17038
  45. Senft D and Ronai ZA (2016) Adaptive Stress Responses During Tumor Metastasis and Dormancy. Trends Cancer 2, 429-442 https://doi.org/10.1016/j.trecan.2016.06.004
  46. Chambers AF, Groom AC and MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2, 563-572 https://doi.org/10.1038/nrc865
  47. Senft D and Ronai ZE (2016) Adaptive Stress Responses During Tumor Metastasis and Dormancy. Trends Cancer 2, 429-442 https://doi.org/10.1016/j.trecan.2016.06.004
  48. Gorrini C, Harris IS and Mak TW (2013) Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 12, 931-947 https://doi.org/10.1038/nrd4002
  49. Piskounova E, Agathocleous M, Murphy MM et al (2015) Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 527, 186-191 https://doi.org/10.1038/nature15726
  50. Zheng Y, Miyamoto DT, Wittner BS et al (2017) Expression of beta-globin by cancer cells promotes cell survival during blood-borne dissemination. Nat Commun 8, 14344 https://doi.org/10.1038/ncomms14344
  51. Le Gal K, Ibrahim MX, Wiel C et al (2015) Antioxidants can increase melanoma metastasis in mice. Sci Transl Med 7, 308re308
  52. Ahmed S, Passos JF, Birket MJ et al (2008) Telomerase does not counteract telomere shortening but protects mitochondrial function under oxidative stress. J Cell Sci 121, 1046-1053 https://doi.org/10.1242/jcs.019372
  53. Haendeler J, Drose S, Buchner N et al (2009) Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage. Arterioscler Thromb Vasc Biol 29, 929-935 https://doi.org/10.1161/ATVBAHA.109.185546
  54. Singhapol C, Pal D, Czapiewski R, Porika M, Nelson G and Saretzki GC (2013) Mitochondrial telomerase protects cancer cells from nuclear DNA damage and apoptosis. PLoS One 8, e52989 https://doi.org/10.1371/journal.pone.0052989
  55. Hetz C (2012) The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 13, 89-102 https://doi.org/10.1038/nrm3270
  56. Zhou J, Mao B, Zhou Q et al (2014) Endoplasmic reticulum stress activates telomerase. Aging Cell 13, 197-200 https://doi.org/10.1111/acel.12161
  57. Yu M, Bardia A, Wittner BS et al (2013) Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339, 580-584 https://doi.org/10.1126/science.1228522
  58. Valastyan S and Weinberg RA (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147, 275-292 https://doi.org/10.1016/j.cell.2011.09.024
  59. Huang Y, Song N, Ding Y et al (2009) Pulmonary vascular destabilization in the premetastatic phase facilitates lung metastasis. Cancer Res 69, 7529-7537 https://doi.org/10.1158/0008-5472.CAN-08-4382
  60. Weis S, Cui J, Barnes L and Cheresh D (2004) Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis. J Cell Biol 167, 223-229 https://doi.org/10.1083/jcb.200408130
  61. Gupta GP, Perk J, Acharyya S et al (2007) ID genes mediate tumor reinitiation during breast cancer lung metastasis. Proc Natl Acad Sci U S A 104, 19506-19511 https://doi.org/10.1073/pnas.0709185104
  62. Qian BZ, Li J, Zhang H et al (2011) CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222-225 https://doi.org/10.1038/nature10138
  63. Pantel K and Brakenhoff RH (2004) Dissecting the metastatic cascade. Nat Rev Cancer 4, 448-456 https://doi.org/10.1038/nrc1370
  64. Aguirre-Ghiso JA, Estrada Y, Liu D and Ossowski L (2003) ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK). Cancer Res 63, 1684-1695
  65. Yu-Lee LY, Yu G, Lee YC et al (2018) Osteoblast-Secreted Factors Mediate Dormancy of Metastatic Prostate Cancer in the Bone via Activation of the TGFbetaRIII-p38MAPKpS249/T252RB Pathway. Cancer Res 78, 2911-2924 https://doi.org/10.1158/0008-5472.CAN-17-1051
  66. Aguirre Ghiso JA, Kovalski K and Ossowski L (1999) Tumor dormancy induced by downregulation of urokinase receptor in human carcinoma involves integrin and MAPK signaling. J Cell Biol 147, 89-104 https://doi.org/10.1083/jcb.147.1.89
  67. Shibue T and Weinberg RA (2009) Integrin beta1-focal adhesion kinase signaling directs the proliferation of metastatic cancer cells disseminated in the lungs. Proc Natl Acad Sci U S A 106, 10290-10295 https://doi.org/10.1073/pnas.0904227106
  68. Douma S, Van Laar T, Zevenhoven J, Meuwissen R, Van Garderen E and Peeper DS (2004) Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature 430, 1034-1039 https://doi.org/10.1038/nature02765
  69. Kobayashi A, Okuda H, Xing F et al (2011) Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J Exp Med 208, 2641-2655 https://doi.org/10.1084/jem.20110840
  70. Gao H, Chakraborty G, Lee-Lim AP et al (2012) The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites. Cell 150, 764-779 https://doi.org/10.1016/j.cell.2012.06.035
  71. Shiozawa Y, Havens AM, Pienta KJ and Taichman RS (2008) The bone marrow niche: habitat to hematopoietic and mesenchymal stem cells, and unwitting host to molecular parasites. Leukemia 22, 941-950 https://doi.org/10.1038/leu.2008.48
  72. Zhang XH, Wang Q, Gerald W et al (2009) Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell 16, 67-78 https://doi.org/10.1016/j.ccr.2009.05.017
  73. Okamoto N, Yasukawa M, Nguyen C et al (2011) Maintenance of tumor initiating cells of defined genetic composition by nucleostemin. Proc Natl Acad Sci U S A 108, 20388-20393 https://doi.org/10.1073/pnas.1015171108
  74. Cassar L, Li H, Pinto AR, Nicholls C, Bayne S and Liu JP (2008) Bone morphogenetic protein-7 inhibits telomerase activity, telomere maintenance, and cervical tumor growth. Cancer Res 68, 9157-9166 https://doi.org/10.1158/0008-5472.CAN-08-1323
  75. Li H, Xu D, Li J, Berndt MC and Liu JP (2006) Transforming growth factor beta suppresses human telomerase reverse transcriptase (hTERT) by Smad3 interactions with c-Myc and the hTERT gene. J Biol Chem 281, 25588-25600 https://doi.org/10.1074/jbc.M602381200
  76. Horn S, Figl A, Rachakonda PS et al (2013) TERT promoter mutations in familial and sporadic melanoma. Science 339, 959-961 https://doi.org/10.1126/science.1230062
  77. Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L and Garraway LA (2013) Highly recurrent TERT promoter mutations in human melanoma. Science 339, 957-959 https://doi.org/10.1126/science.1229259
  78. Vinagre J, Almeida A, Populo H et al (2013) Frequency of TERT promoter mutations in human cancers. Nat Commun 4, 2185 https://doi.org/10.1038/ncomms3185
  79. Bell RJ, Rube HT, Kreig A et al (2015) Cancer. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer. Science 348, 1036-1039 https://doi.org/10.1126/science.aab0015
  80. Griewank KG, Murali R, Puig-Butille JA et al (2014) TERT promoter mutation status as an independent prognostic factor in cutaneous melanoma. J Natl Cancer Inst 106, 1-13 https://doi.org/10.1093/jnci/dju200
  81. Landa I, Ganly I, Chan TA et al (2013) Frequent somatic TERT promoter mutations in thyroid cancer: higher prevalence in advanced forms of the disease. J Clin Endocrinol Metab 98, E1562-1566 https://doi.org/10.1210/jc.2013-2383
  82. Liu X, Qu S, Liu R et al (2014) TERT promoter mutations and their association with BRAF V600E mutation and aggressive clinicopathological characteristics of thyroid cancer. J Clin Endocrinol Metab 99, E1130-1136 https://doi.org/10.1210/jc.2013-4048
  83. Liu R and Xing M (2014) Diagnostic and prognostic TERT promoter mutations in thyroid fine-needle aspiration biopsy. Endocr Relat Cancer 21, 825-830 https://doi.org/10.1530/ERC-14-0359
  84. Melo M, da Rocha AG, Vinagre J et al (2014) TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas. J Clin Endocrinol Metab 99, E754-765 https://doi.org/10.1210/jc.2013-3734
  85. George JR, Henderson YC, Williams MD et al (2015) Association of TERT Promoter Mutation, But Not BRAF Mutation, With Increased Mortality in PTC. J Clin Endocrinol Metab 100, E1550-1559 https://doi.org/10.1210/jc.2015-2690
  86. Pestana A, Vinagre J, Sobrinho-Simoes M and Soares P (2017) TERT biology and function in cancer: beyond immortalisation. J Mol Endocrinol 58, R129-R146 https://doi.org/10.1530/JME-16-0195
  87. Wang K, Liu T, Ge N et al (2014) TERT promoter mutations are associated with distant metastases in upper tract urothelial carcinomas and serve as urinary biomarkers detected by a sensitive castPCR. Oncotarget 5, 12428-12439 https://doi.org/10.18632/oncotarget.2660
  88. Liu W, Yin Y, Wang J et al (2017) Kras mutations increase telomerase activity and targeting telomerase is a promising therapeutic strategy for Kras-mutant NSCLC. Oncotarget 8, 179-190 https://doi.org/10.18632/oncotarget.10162
  89. Liu R, Zhang T, Zhu G and Xing M (2018) Regulation of mutant TERT by BRAF V600E/MAP kinase pathway through FOS/GABP in human cancer. Nat Commun 9, 579 https://doi.org/10.1038/s41467-018-03033-1
  90. Low KC and Tergaonkar V (2013) Telomerase: central regulator of all of the hallmarks of cancer. Trends Biochem Sci 38, 426-434 https://doi.org/10.1016/j.tibs.2013.07.001
  91. Yuan X, Larsson C and Xu D (2019) Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players. Oncogene 38, 6172-6183 https://doi.org/10.1038/s41388-019-0872-9
  92. Zhou J, Ding D, Wang M and Cong YS (2014) Telomerase reverse transcriptase in the regulation of gene expression. BMB Rep 47, 8-14 https://doi.org/10.5483/BMBRep.2014.47.1.284
  93. Jafri MA, Ansari SA, Alqahtani MH and Shay JW (2016) Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies. Genome Med 8, 69 https://doi.org/10.1186/s13073-016-0324-x
  94. Marian CO, Cho SK, McEllin BM et al (2010) The telomerase antagonist, imetelstat, efficiently targets glioblastoma tumor-initiating cells leading to decreased proliferation and tumor growth. Clin Cancer Res 16, 154-163 https://doi.org/10.1158/1078-0432.CCR-09-2850
  95. Zanetti M (2017) A second chance for telomerase reverse transcriptase in anticancer immunotherapy. Nat Rev Clin Oncol 14, 115-128 https://doi.org/10.1038/nrclinonc.2016.67