Biomedical Science Letters (대한의생명과학회지)

The Korean Society for Biomedical Laboratory Sciences (대한의생명과학회)
권호 표지
DOI QR코드

DOI QR Code

Zinc Finger E-box binding Homeobox 1 as Prognostic Biomarker and its Correlation with Infiltrating Immune Cells and Telomerase in Lung Cancer

  • Kim, Hye-Ran (Department of Biomedical Laboratory Science, Dong-Eui Institute of Technology) ;
  • Seo, Choong-Won (Department of Biomedical Laboratory Science, Dong-Eui Institute of Technology) ;
  • Kim, Jongwan (Department of Biomedical Laboratory Science, Dong-Eui Institute of Technology)
  • Received : 2022.03.02
  • Accepted : 2022.03.24
  • Published : 2022.03.31
Download PDF
⟨ Previous Next ⟩

Abstract

The aim of this study was to identify the expression of zinc finger E-box binding homeobox 1 (ZEB1), its prognostic significance, and correlation between ZEB1 and infiltrating immune cells in lung cancer. Correlation between ZEB1 and telomerase was also analyzed in different types of cancers. RNA sequencing analysis and survival rates of patients were confirmed by Gene Expression Profiling Interactive Analysis (GEPIA). The Kaplan-Meier plotter and PrognoScan databases were used to analyze the prognostic value of ZEB1 in various cancers. The Tumor IMmune Estimation Resource (TIMER) was used to determine the correlation between ZEB1 and infiltrating immune cells. Lower ZEB1 expression was lower in lung cancer and was related to poor prognosis in lung adenocarcinoma (LUAD). ZEB1 expression exhibited a significantly positive correlation with infiltration levels of immune cells in LUAD and lung squamous cell carcinoma. Furthermore, we found that the ZEB1 expression correlated with subunits of telomerase. Our findings suggest ZEB1 as a potential biomarker to be used for prognostic significance and tumor immunology in lung cancer. The correlation between the expression of ZEB1 and telomere-related gene will help in understand the cancer-promoting mechanisms.

Keywords

References

  1. Aghdassi A, Sendler M, Guenther A, Mayerle J, Behn CO, Heidecke CD, Friess H, Buchler M, Evert M, Lerch MM, Weiss FU. Recruitment of histone deacetylases HDAC1 and HDAC2 by the transcriptional repressor ZEB1 downregulates E-cadherin expression in pancreatic cancer. Gut. 2012. 61: 439-448. https://doi.org/10.1136/gutjnl-2011-300060
  2. Aigner K, Dampier B, Descovich L, Mikula M, Sultan A, Schreiber M, Mikulits W, Brabletz T, Strand D, Obrist P, Sommergruber W, Schweifer N, Wernitznig A, Beug H, Foisner R, Eger A. The transcription factor ZEB1 (deltaEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene. 2007. 26: 6979-6988. https://doi.org/10.1038/sj.onc.1210508
  3. Block CJ, Dyson G, Campeanu IJ, Watza D, Ratnam M, Wu G. A stroma-corrected ZEB1 transcriptional signature is inversely associated with antitumor immune activity in breast cancer. Sci Rep. 2019. 9: 17807. https://doi.org/10.1038/s41598-019-54282-z
  4. Bronsert P, Kohler I, Timme S, Kiefer S, Werner M, Schilling O, Vashist Y, Makowiec F, Brabletz T, Hopt UT, Bausch D, Kulemann B, Keck T, Wellner UF. Prognostic significance of Zinc finger E-box binding homeobox 1 (ZEB1) expression in cancer cells and cancer-associated fibroblasts in pancreatic head cancer. Surgery. 2014. 156: 97-108. https://doi.org/10.1016/j.surg.2014.02.018
  5. Cagle PT, Allen TC, Olsen RJ. Lung cancer biomarkers: present status and future developments. Arch Pathol Lab Med. 2013. 137: 1191-1198. https://doi.org/10.5858/arpa.2013-0319-CR
  6. Cayuela ML, Flores JM, Blasco MA. The telomerase RNA component Terc is required for the tumour-promoting effects of Tert overexpression. EMBO Rep. 2005. 6: 268-274. https://doi.org/10.1038/sj.embor.7400359
  7. Chae YK, Chang S, Ko T, Anker J, Agte S, Iams W, Choi WM, Lee K, Cruz M. Epithelial-mesenchymal transition (EMT) signature is inversely associated with T-cell infiltration in non-small cell lung cancer (NSCLC). Sci Rep. 2018. 8: 2918. https://doi.org/10.1038/s41598-018-21061-1
  8. Chen B, Chen B, Zhu Z, Ye W, Zeng J, Liu G, Wang S, Gao J, Xu G, Huang Z. Prognostic value of ZEB-1 in solid tumors: a meta-analysis. BMC Cancer. 2019. 19: 635. https://doi.org/10.1186/s12885-019-5830-y
  9. Chen B, Lai J, Dai D, Chen R, Li X, Liao N. JAK1 as a prognostic marker and its correlation with immune infiltrates in breast cancer. Aging (Albany NY). 2019. 11: 11124-11135. https://doi.org/10.18632/aging.102514
  10. Cristofari G, Lingner J. Telomere length homeostasis requires that telomerase levels are limiting. EMBO J. 2006. 25: 565-574. https://doi.org/10.1038/sj.emboj.7600952
  11. Dome JS, Bockhold CA, Li SM, Baker SD, Green DM, Perlman EJ, Hill DA, Breslow NE. High telomerase RNA expression level is an adverse prognostic factor for favorable-histology Wilms' tumor. J Clin Oncol. 2005. 23: 9138-9145. https://doi.org/10.1200/JCO.2005.00.562
  12. Fujimoto J, Wistuba II. Current concepts on the molecular pathology of non-small cell lung carcinoma. Semin Diagn Pathol. 2014. 31: 306-313. https://doi.org/10.1053/j.semdp.2014.06.008
  13. Goscinski MA, Xu R, Zhou F, Wang J, Yang H, Huang R, Li Y, Larsen SG, Giercksky KE, Nesland JM, Suo Z. Nuclear, cytoplasmic, and stromal expression of ZEB1 in squamous and small cell carcinoma of the esophagus. APMIS. 2015. 123: 1040-1047. https://doi.org/10.1111/apm.12473
  14. Gu Y, Li X, Bi Y, Zheng Y, Wang J, Li X, Huang Z, Chen L, Huang Y, Huang Y. CCL14 is a prognostic biomarker and correlates with immune infiltrates in hepatocellular carcinoma. Aging (Albany NY). 2020. 12: 784-807. https://doi.org/10.18632/aging.102656
  15. Gyorffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q, Szallasi Z. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat. 2010. 123: 725-731. https://doi.org/10.1007/s10549-009-0674-9
  16. Hashiguchi M, Ueno S, Sakoda, M, Iino S, Hiwatashi K, Minami K, Ando K, Mataki Y, Maemura K, Shinchi H, Ishigami S, Natsugoe S. Clinical implication of ZEB-1 and E-cadherin expression in hepatocellular carcinoma (HCC). BMC Cancer. 2013. 13: 572. https://doi.org/10.1186/1471-2407-13-572
  17. Hiyama E, Hiyama K. Clinical utility of telomerase in cancer. Oncogene. 2002. 21: 643-649. https://doi.org/10.1038/sj.onc.1205070
  18. Hou J, Aerts, J, den Hamer B, van Ijcken W, den Bakker M, Riegman P, van der Leest C, van der Spek P, Foekens A, Hoogsteden HC, Grosveld F, Philipsen S. Gene expression-based classification of non-small cell lung carcinomas and survival prediction. PLoS One. 2010. 5: e10312. https://doi.org/10.1371/journal.pone.0010312
  19. Japanese Gastric Cancer Association, Japanese gastric cancer treatment guidelines 2014 (ver. 4). Gastric Cancer. 2017. 20: 1-19. https://doi.org/10.1007/s10120-016-0622-4
  20. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009. 119: 1420-1428. https://doi.org/10.1172/JCI39104
  21. Kerr KM, Bubendorf L, Edelman MJ, Marchetti A, Mok T, Novello S, O'Byrne K, Stahel R, Peters S, Felip E, Panel M. Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer. Ann Oncol. 2014. 25: 1681-1690. https://doi.org/10.1093/annonc/mdu145
  22. Kitamura T, Qian BZ, Pollard JW. Immune cell promotion of metastasis. Nat Rev Immunol. 2015. 15: 73-86. https://doi.org/10.1038/nri3789
  23. Kurahara H, Takao S, Maemura K, Mataki Y, Kuwahata T, Maeda K, Ding, Q, Sakoda M, Iino S, Ishigami S, Ueno S, Shinchi H, Natsugoe S. Epithelial-mesenchymal transition and mesenchymal-epithelial transition via regulation of ZEB-1 and ZEB-2 expression in pancreatic cancer. J Surg Oncol. 2012. 105: 655-661. https://doi.org/10.1002/jso.23020
  24. Li B, Severson E, Pignon JC, Zhao H, Li T, Novak J, Jiang P, Shen H, Aster JC, Rodig S, Signoretti S, Liu JS, Liu XS. Comprehensive analyses of tumor immunity: implications for cancer immunotherapy. Genome Biol. 2016. 17: 174. https://doi.org/10.1186/s13059-016-1028-7
  25. Li T, Fan J, Wang B, Traugh N, Chen Q, Liu JS, Li B, Liu XS. TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. Cancer Res. 2017. 77: e108-e110. https://doi.org/10.1158/1538-7445.AM2017-108
  26. Li X, Jin J, Yang S, Xu W, Meng X, Deng H, Zhan J, Gao S, Zhang H. GATA3 acetylation at K119 by CBP inhibits cell migration and invasion in lung adenocarcinoma. Biochem Biophys Res Commun. 2018. 497: 633-638. https://doi.org/10.1016/j.bbrc.2018.02.120
  27. Liu Z, Li Q, Li K, Chen L, Li W, Hou M, Liu T, Yang J, Lindvall C, Bjorkholm M, Jia J, Xu D. Telomerase reverse transcriptase promotes epithelial-mesenchymal transition and stem cell-like traits in cancer cells. Oncogene. 2013. 32: 4203-4213. https://doi.org/10.1038/onc.2012.441
  28. Mabey Gilsenan J, Cooley J, Bowyer P. CADRE: the Central Aspergillus Data REpository 2012. Nucleic Acids Res. 2012. 40: D660-666. https://doi.org/10.1093/nar/gkr971
  29. MacMahon B. A code of ethical conduct for epidemiologists? J Clin Epidemiol. 1991. 44: 147S-149S. https://doi.org/10.1016/0895-4356(91)90191-B
  30. Maitra A, Yashima K, Rathi A, Timmons CF, Rogers BB, Shay JW, Gazdar AF. The RNA component of telomerase as a marker of biologic potential and clinical outcome in childhood neuroblastic tumors. Cancer. 1999. 85: 741-749. https://doi.org/10.1002/(SICI)1097-0142(19990201)85:3<741::AID-CNCR25>3.0.CO;2-6
  31. Miranda A, Hamilton PT, Zhang AW, Pattnaik S, Becht E, Mezheyeuski A, Bruun J, Micke P, de Reynies A, Nelson BH. Cancer stemness, intratumoral heterogeneity, and immune response across cancers. Proc Natl Acad Sci. U S A. 2019. 116: 9020-9029. https://doi.org/10.1073/pnas.1818210116
  32. Miyazono K. Transforming growth factor-beta signaling in epithelial-mesenchymal transition and progression of cancer. Proc Jpn Acad Ser B Phy Biol Sci. 2009. 85: 314-323. https://doi.org/10.2183/pjab.85.314
  33. Mizuno H, Kitada K, Nakai K, Sarai A. PrognoScan: a new database for meta-analysis of the prognostic value of genes. BMC Med Genomics. 2009. 2: 18. https://doi.org/10.1186/1755-8794-2-18
  34. Mooney SM, Parsana P, Hernandez JR, Liu X, Verdone JE, Torga G, Harberg CA, Pienta KJ. The presence of androgen receptor elements regulates ZEB1 expression in the absence of androgen receptor. J Cell Biochem. 2015. 116: 115-123. https://doi.org/10.1002/jcb.24948
  35. Moroishi T, Hansen CG, Guan KL. The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer. 2015. 15: 73-79. https://doi.org/10.1038/nrc3876
  36. Murai T, Yamada S, Fuchs BC, Fujii T, Nakayama G, Sugimoto H, Koike M, Fujiwara M, Tanabe KK, Kodera Y. Epithelial-to-mesenchymal transition predicts prognosis in clinical gastric cancer. J Surg Oncol. 2014. 109: 684-689. https://doi.org/10.1002/jso.23564
  37. Navarro A, Moises J, Santasusagna S, Marrades RM, Vinolas N, Castellano JJ, Canals J, Munoz C, Ramirez J, Molins L, Monzo M. Clinical significance of long non-coding RNA HOTTIP in early-stage non-small-cell lung cancer. BMC Pulm Med. 2019. 19: 55. https://doi.org/10.1186/s12890-019-0816-8
  38. Ohtani H. Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human colorectal cancer. Cancer Immun. 2007. 7: 4.
  39. Okugawa Y, Toiyama Y, Tanaka K, Matsusita K, Fujikawa H, Saigusa S, Ohi M, Inoue Y, Mohri Y, Uchida K, Kusunoki M. Clinical significance of Zinc finger E-box Binding homeobox 1 (ZEB1) in human gastric cancer. J Surg Oncol. 2012. 106: 280-285. https://doi.org/10.1002/jso.22142
  40. Qin Y, Tang B, Hu CJ, Xiao YF, Xie R, Yong X, Wu YY, Dong H, Yang SM. An hTERT/ZEB1 complex directly regulates E-cadherin to promote epithelial-to-mesenchymal transition (EMT) in colorectal cancer. Oncotarget. 2016. 7: 351-361. https://doi.org/10.18632/oncotarget.5968
  41. Rhodes DR, Kalyana-Sundaram S, Mahavisno V, Varambally R, Yu J, Briggs BB, Barrette TR, Anstet MJ, Kincead-Beal C, Kulkarni P, Varambally S, Ghosh D, Chinnaiyan AM. Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia. 2007. 9: 166-180. https://doi.org/10.1593/neo.07112
  42. Sahay D, Leblanc R, Grunewald TG, Ambatipudi S, Ribeiro J, Clezardin P, Peyruchaud O. The LPA1/ZEB1/miR-21-activation pathway regulates metastasis in basal breast cancer. Oncotarget. 2015. 6: 20604-20620. https://doi.org/10.18632/oncotarget.3774
  43. Sanchez-Tillo E, de Barrios O, Siles L, Cuatrecasas M, Castells A, Postigo A. beta-catenin/TCF4 complex induces the epithelial-to-mesenchymal transition (EMT)-activator ZEB1 to regulate tumor invasiveness. Proc Natl Acad Sci U S A. 2011. 108: 19204-19209. https://doi.org/10.1073/pnas.1108977108
  44. Sanchez-Tillo E, de Barrios O, Valls E, Darling DS, Castells A, Postigo A. ZEB1 and TCF4 reciprocally modulate their transcriptional activities to regulate Wnt target gene expression. Oncogene. 2015. 34: 5760-5770. https://doi.org/10.1038/onc.2015.352
  45. Sanchez-Tillo E, Lazaro A, Torrent R, Cuatrecasas M, Vaquero EC, Castells A, Engel P, Postigo A. ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1. Oncogene. 2010. 29: 3490-3500. https://doi.org/10.1038/onc.2010.102
  46. Sanchez-Tillo E, Siles L, de Barrios O, Cuatrecasas M, Vaquero EC, Castells A, Postigo A. Expanding roles of ZEB factors in tumorigenesis and tumor progression. Am J Cancer Res. 2011. 1: 897-912.
  47. Sato M, Shames DS, Gazdar AF, Minna JD. A translational view of the molecular pathogenesis of lung cancer. J Thorac Oncol. 2007. 2: 327-343. https://doi.org/10.1097/01.jto.0000263718.69320.4c
  48. Schmalhofer O, Brabletz S, Brabletz T. E-cadherin, beta-catenin, and ZEB1 in malignant progression of cancer. Cancer Metastasis Rev. 2009. 28: 151-166. https://doi.org/10.1007/s10555-008-9179-y
  49. Scott CL, Omilusik KD. ZEBs: Novel Players in Immune Cell Development and Function. Trends Immunol. 2019. 40: 431-446. https://doi.org/10.1016/j.it.2019.03.001
  50. Sekido Y, Fong KM, Minna JD. Molecular genetics of lung cancer. Annu Rev Med. 2003. 54: 73-87. https://doi.org/10.1146/annurev.med.54.101601.152202
  51. Shen ZY, Xu LY, Li EM, Cai WJ, Chen MH, Shen J, Zeng Y. Telomere and telomerase in the initial stage of immortalization of esophageal epithelial cell. World J Gastroenterol. 2002. 8: 357-362. https://doi.org/10.3748/wjg.v8.i2.357
  52. Siegel R, Naishadham D, Jemal A. Cancer statistics. 2012. CA. Cancer J Clin. 2012. 62: 10-29. https://doi.org/10.3322/caac.20138
  53. Siles L, Sanchez-Tillo E, Lim JW, Darling DS, Kroll KL, Postigo A. ZEB1 imposes a temporary stage-dependent inhibition of muscle gene expression and differentiation via CtBP-mediated transcriptional repression. Mol Cell Biol. 2013. 33: 1368-1382. https://doi.org/10.1128/MCB.01259-12
  54. Singh AB, Sharma A, Smith JJ, Krishnan M, Chen X, Eschrich S, Washington MK, Yeatman TJ, Beauchamp RD, Dhawan P. Claudin-1 up-regulates the repressor ZEB-1 to inhibit Ecadherin expression in colon cancer cells. Gastroenterology. 2011. 41: 2140-2153.
  55. Suzuki K, Kawataki T, Endo K, Miyazawa K, Kinouchi H, Saitoh M. Expression of ZEBs in gliomas is associated with invasive properties and histopathological grade. Oncol Lett. 2018. 16: 1758-1764.
  56. Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017. 45: W98-W102. https://doi.org/10.1093/nar/gkx247
  57. Terashita K, Chuma M, Hatanaka Y, Hatanaka K, Mitsuhashi T, Yokoo H, Ohmura T, Ishizu H, Muraoka S, Nagasaka A, Tsuji T, Yamamoto Y, Kurauchi N, Shimoyama N, Toyoda H, Kumada T, Kaneoka Y, Maeda A, Ogawa K, Natsuizaka M, Kamachi H, Kakisaka T, Kamiyama T, Taketomi A, Matsuno Y, Sakamoto N. ZEB1 expression is associated with prognosis of intrahepatic cholangiocarcinoma. J Clin Pathol. 2016. 69: 593-599. https://doi.org/10.1136/jclinpath-2015-203115
  58. Tsuji T, Ibaragi S, Hu GF. Epithelial-mesenchymal transition and cell cooperativity in metastasis. Cancer Res. 2009. 69: 7135-7139. https://doi.org/10.1158/0008-5472.CAN-09-1618
  59. Vandewalle C, Van Roy F, Berx G. The role of the ZEB family of transcription factors in development and disease. Cell Mol Life Sci. 2009. 66: 773-787. https://doi.org/10.1007/s00018-008-8465-8
  60. Wellner U, Schubert J, Burk UC, Schmalhofer O, Zhu F, Sonntag A, Waldvogel B, Vannier C, Darling D, zur Hausen A, Brunton VG, Morton J, Sansom O, Schuler J, Stemmler MP, Herzberger C, Hopt U, Keck T, Brabletz S, Brabletz T. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol. 2009. 11: 1487-1495. https://doi.org/10.1038/ncb1998
  61. Wu DW, Lin PL, Cheng YW, Huang CC, Wang L, Lee H. DDX3 enhances oncogenic KRASinduced tumor invasion in colorectal cancer via the betacatenin/ZEB1 axis. Oncotarget. 2016. 7: 22687-22699. https://doi.org/10.18632/oncotarget.8143
  62. Yang X, Wang Q, Dai W, Zhang J, Chen X. Overexpression of zinc finger E-box binding homeobox factor 1 promotes tumor invasiveness and confers unfavorable prognosis in esophageal squamous cell carcinoma. Tumour Biol. 2014. 35: 11977-11984. https://doi.org/10.1007/s13277-014-2494-8
  63. Yao X, Sun S, Zhou X, Zhang Q, Guo W, Zhang L. Clinicopathological significance of ZEB-1 and E-cadherin proteins in patients with oral cavity squamous cell carcinoma. Onco Targets Ther. 2017. 10: 781-790. https://doi.org/10.2147/OTT.S111920
  64. Yashima K, Litzky LA, Kaiser L, Rogers T, Lam S, Wistuba II, Milchgrub S, Srivastava S, Piatyszek MA, Shay JW, Gazdar AF. Telomerase expression in respiratory epithelium during the multistage pathogenesis of lung carcinomas. Cancer Res. 1997. 57: 2373-2377.
  65. Yu P, Shen X, Yang W, Zhang Y, Liu C, Huang T. ZEB1 stimulates breast cancer growth by up-regulating hTERT expression. Biochem Biophys Res Commun. 2018. 495: 2505-2511. https://doi.org/10.1016/j.bbrc.2017.12.139
  66. Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest. 2009. 119: 1429-1437. https://doi.org/10.1172/JCI36183
  67. Zhang GJ, Zhou T, Tian HP, Liu ZL, Xia SS. High expression of ZEB1 correlates with liver metastasis and poor prognosis in colorectal cancer. Oncol Lett. 2013. 5: 564-568. https://doi.org/10.3892/ol.2012.1026
  68. Zhang P, Sun Y, Ma, L. ZEB1: at the crossroads of epithelialmesenchymal transition, metastasis and therapy resistance. Cell Cycle. 2015. 14: 481-487. https://doi.org/10.1080/15384101.2015.1006048
  69. Zhou YM, Cao L, Li B, Zhang RX, Sui CJ, Yin ZF, Yang JM. Clinicopathological significance of ZEB1 protein in patients with hepatocellular carcinoma. Ann Surg Oncol. 2012. 19: 1700-1706. https://doi.org/10.1245/s10434-011-1772-6