Telomerase reverse transcriptase potentially promotes the progression of oral squamous cell carcinoma through induction of epithelial-mesenchymal transition

Zhao,Tengda; Hu,Fengchun; Qiao,Bin; Chen,Zhifeng; Tao,Qian

doi:10.3892/ijo.2015.2927

Telomerase reverse transcriptase potentially promotes the progression of oral squamous cell carcinoma through induction of epithelial-mesenchymal transition

Authors:
- Tengda Zhao
- Fengchun Hu
- Bin Qiao
- Zhifeng Chen
- Qian Tao
View Affiliations

Affiliations: Guangdong Provincial Key Laboratory of Stomatology, Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, P.R. China, Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China, Department of Oral and Maxillofacial Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, P.R. China
Published online on: March 13, 2015 https://doi.org/10.3892/ijo.2015.2927
Pages: 2205-2215

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

In recent years, researchers have found the critical role of telomerase in cellular transformation, proliferation, stemness and cell survival. High levels of telomerase reverse transcriptase (TERT) expression and telomerase activation have been reported in most cancer cells. Moreover, overexpression of human TERT (hTERT) is reported to be correlated with advanced invasive stage of the tumor progression and poor prognosis. Epithelial-mesenchymal transition (EMT), characterized by the loss of the cell-cell contact of epithelial cells and the acquisition of migratory and motile properties, is known to be a central mechanism responsible for invasiveness and metastasis of various cancers. Thus, we investigated whether hTERT plays a potential role in the development of EMT. As we expected, our clinical results showed that hTERT is overexpressed in oral epithelial dysplasia (OED) and OSCC tissues and correlates with clinical aggressiveness of oral squamous cell carcinoma (OSCC) patients. We then overexpressed hTERT in primary human oral epithelial cells (HOECS) and found that hTERT has the potential to prolong the lifespan, a process confering the characteristics of EMT by activating the Wnt/β-catenin pathway. Our findings provided an explanation for the aggressive nature of human tumors overexpressing hTERT and the possibly mechanism that links hTERT to EMT property, which represents a possible therapeutic target in highly metastatic cancers.

View Figures

View References

1	Bray F, Sankila R, Ferlay J and Parkin DM: Estimates of cancer incidence and mortality in Europe in 1995. Eur J Cancer. 38:99–166. 2002. View Article : Google Scholar
2	Parkin DM, Bray F, Ferlay J and Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 55:74–108. 2005. View Article : Google Scholar : PubMed/NCBI
3	Liu JP, Chen SM, Cong YS, Nicholls C, Zhou SF, Tao ZZ and Li H: Regulation of telomerase activity by apparently opposing elements. Ageing Res Rev. 9:245–256. 2010. View Article : Google Scholar : PubMed/NCBI
4	Shay JW and Wright WE: Hallmarks of telomeres in ageing research. J Pathol. 211:114–123. 2007. View Article : Google Scholar : PubMed/NCBI
5	Kapanadze B, Morris E, Smith E and Trojanowska M: Establishment and characterization of scleroderma fibroblast clonal cell lines by introduction of the hTERT gene. J Cell Mol Med. 14:1156–1165. 2010.
6	Wieser M, Stadler G, Jennings P, Streubel B, Pfaller W, Ambros P, Riedl C, Katinger H, Grillari J and Grillari-Voglauer R: hTERT alone immortalizes epithelial cells of renal proximal tubules without changing their functional characteristics. Am J Physiol Renal Physiol. 295:F1365–F1375. 2008. View Article : Google Scholar : PubMed/NCBI
7	Stewart SA, Hahn WC, O’Connor BF, et al: Telomerase contributes to tumorigenesis by a telomere length-independent mechanism. Proc Natl Acad Sci USA. 99:12606–12611. 2002. View Article : Google Scholar : PubMed/NCBI
8	Smith LL, Coller HA and Roberts JM: Telomerase modulates expression of growth-controlling genes and enhances cell proliferation. Nat Cell Biol. 5:474–479. 2003. View Article : Google Scholar : PubMed/NCBI
9	Yang C, Przyborski S, Cooke MJ, Zhang X, Stewart R, Anyfantis G, Atkinson SP, Saretzki G, Armstrong L and Lako M: A key role for telomerase reverse transcriptase unit in modulating human embryonic stem cell proliferation, cell cycle dynamics, and in vitro differentiation. Stem Cells. 26:850–863. 2008. View Article : Google Scholar : PubMed/NCBI
10	Lee J, Sung YH, Cheong C, Choi YS, Jeon HK, Sun W, Hahn WC, Ishikawa F and Lee HW: TERT promotes cellular and organismal survival independently of telomerase activity. Oncogene. 27:3754–3760. 2008. View Article : Google Scholar : PubMed/NCBI
11	Bertorelle R, Briarava M, Rampazzo E, et al: Telomerase is an independent prognostic marker of overall survival in patients with colorectal cancer. Br J Cancer. 108:278–284. 2013. View Article : Google Scholar : PubMed/NCBI
12	Eid MM, Helmy NA, Omar IM, Mohamed AA, El Sewefy D, Fadel IM and Helal RA: Clinical significance of telomerase genes (hTERC and hTERT) amplification in patients with acute myeloid leukemia. Gulf J Oncol. 1:51–60. 2013.
13	Lötsch D, Ghanim B, Laaber M, Wurm G, Weis S, Lenz S, Webersinke G, Pichler J, Berger W and Spiegl-Kreinecker S: Prognostic significance of telomerase-associated parameters in glioblastoma: Effect of patient age. Neurooncol. 15:423–432. 2013.
14	Nakashima A, Murakami Y, Uemura K, Hayashidani Y, Sudo T, Hashimoto Y, Ohge H, Oda M, Sueda T and Hiyama E: Usefulness of human telomerase reverse transcriptase in pancreatic juice as a biomarker of pancreatic malignancy. Pancreas. 38:527–533. 2009. View Article : Google Scholar : PubMed/NCBI
15	Tsuji T, Ibaragi S and Hu GF: Epithelial-mesenchymal transition and cell cooperativity in metastasis. Cancer Res. 69:7135–7139. 2009. View Article : Google Scholar : PubMed/NCBI
16	Liu Z, Li Q, Li K, et al: Telomerase reverse transcriptase promotes epithelial-mesenchymal transition and stem cell-like traits in cancer cells. Oncogene. 32:4203–4213. 2013. View Article : Google Scholar
17	Gröger S, Michel J and Meyle J: Establishment and characterization of immortalized human gingival keratinocyte cell lines. J Periodontal Res. 43:604–614. 2008. View Article : Google Scholar : PubMed/NCBI
18	Rheinwald JG, Hahn WC, Ramsey MR, Wu JY, Guo Z, Tsao H, De Luca M, Catricala C and O’Toole KM: A two-stage, p16 (INK4A)- and p53-dependent keratinocyte senescence mechanism that limits replicative potential independent of telomere status. Mol Cell Biol. 22:5157–5172. 2002. View Article : Google Scholar : PubMed/NCBI
19	Dissanayake SK, Wade M, Johnson CE, et al: The Wnt5A/protein kinase C pathway mediates motility in melanoma cells via the inhibition of metastasis suppressors and initiation of an epithelial to mesenchymal transition. J Biol Chem. 282:17259–17271. 2007. View Article : Google Scholar : PubMed/NCBI
20	Park JI, Venteicher AS, Hong JY, et al: Telomerase modulates Wnt signalling by association with target gene chromatin. Nature. 460:66–72. 2009. View Article : Google Scholar : PubMed/NCBI
21	Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T and Thun MJ: Cancer statistics, 2008. CA Cancer J Clin. 58:71–96. 2008. View Article : Google Scholar : PubMed/NCBI
22	Thiery JP, Acloque H, Huang RY and Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell. 139:871–890. 2009. View Article : Google Scholar : PubMed/NCBI
23	Prieur A and Peeper DS: Cellular senescence in vivo: A barrier to tumorigenesis. Curr Opin Cell Biol. 20:150–155. 2008. View Article : Google Scholar : PubMed/NCBI
24	Pelosi G, Schianchi E, Dell’orto P, Veronesi G, Spaggiari L, Pasini F, Sozzi G, Brambilla E, Griso C and Viale G: Detecting cell-free circulating hTERT mRNA in the plasma may identify a subset of nonsmall cell lung cancer patients. Virchows Arch. 448:7–15. 2006. View Article : Google Scholar
25	Gigek CO, Leal MF, Silva PNO, Lisboa LC, Lima EM, Calcagno DQ, Assumpção PP, Burbano RR and Smith MA: hTERT methylation and expression in gastric cancer. Biomarkers. 14:630–636. 2009. View Article : Google Scholar : PubMed/NCBI
26	Saini N, Srinivasan R, Chawla Y, Sharma S, Chakraborti A and Rajwanshi A: Telomerase activity, telomere length and human telomerase reverse transcriptase expression in hepatocellular carcinoma is independent of hepatitis virus status. Liver Int. 29:1162–1170. 2009. View Article : Google Scholar : PubMed/NCBI
27	Divella R, Tommasi S, Lacalamita R, et al: Circulating hTERT DNA in early breast cancer. Anticancer Res. 29:2845–2849. 2009.PubMed/NCBI
28	Capkova L, Kalinova M, Krskova L, Kodetova D, Petrik F, Trefny M, Musil J and Kodet R: Loss of heterozygosity and human telomerase reverse transcriptase (hTERT) expression in bronchial mucosa of heavy smokers. Cancer. 109:2299–2307. 2007. View Article : Google Scholar : PubMed/NCBI
29	Pucciarelli S, Rampazzo E, Briarava M, et al: Telomere-specific reverse transcriptase (hTERT) and cell-free RNA in plasma as predictors of pathologic tumor response in rectal cancer patients receiving neoadjuvant chemoradiotherapy. Ann Surg Oncol. 19:3089–3096. 2012. View Article : Google Scholar : PubMed/NCBI
30	Sasaki T, Kuniyasu H, Luo Y, Kitayoshi M, Tanabe E, Kato D, Shinya S, Fujii K, Ohmori H and Yamashita Y: AKT activation and telomerase reverse transcriptase expression are concurrently associated with prognosis of gastric cancer. Pathobiology. 81:36–41. 2014. View Article : Google Scholar
31	Chang L, Graham PH, Hao J, Ni J, Bucci J, Cozzi PJ, Kearsley JH and Li Y: Acquisition of epithelial-mesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/Akt/mTOR pathway in prostate cancer radioresistance. Cell Death Dis. 4:e8752013. View Article : Google Scholar : PubMed/NCBI
32	Li NY, Weber CE, Wai PY, Cuevas BD, Zhang J, Kuo PC and Mi Z: An MAPK-dependent pathway induces epithelial-mesenchymal transition via Twist activation in human breast cancer cell lines. Surgery. 154:404–410. 2013. View Article : Google Scholar : PubMed/NCBI
33	Kypta RM and Waxman J: Wnt/beta-catenin signalling in prostate cancer. Nat Rev Urol. 9:418–428. 2012. View Article : Google Scholar : PubMed/NCBI
34	Kahlert UD, Maciaczyk D, Doostkam S, et al: Activation of canonical WNT/β-catenin signaling enhances in vitro motility of glioblastoma cells by activation of ZEB1 and other activators of epithelial-to-mesenchymal transition. Cancer Lett. 325:42–53. 2012. View Article : Google Scholar : PubMed/NCBI
35	Bertrand FE, McCubrey JA, Angus CW, Nutter JM and Sigounas G: NOTCH and PTEN in prostate cancer. Adv Biol Regul. 56:51–65. 2014. View Article : Google Scholar : PubMed/NCBI
36	Cichon MA and Radisky DC: ROS-induced epithelial-mesenchymal transition in mammary epithelial cells is mediated by NF-κB-dependent activation of Snail. Oncotarget. 5:2827–2838. 2014.PubMed/NCBI
37	Hoffmeyer K, Raggioli A, Rudloff S, Anton R, Hierholzer A, Del Valle I, Hein K, Vogt R and Kemler R: Wnt/β-catenin signaling regulates telomerase in stem cells and cancer cells. Science. 336:1549–1554. 2012. View Article : Google Scholar : PubMed/NCBI