Abstract
Zinc finger E-box binding homeobox factor 1 (ZEB1), as a crucial mediator of “epithelial-mesenchymal transition,” contributes to malignant progression of various epithelial tumors. However, its involvement in human esophageal squamous cell carcinoma (ESCC) remains unclear. In order to investigate the expression pattern of ZEB1 in ESCC tissues and evaluate its associations with tumor progression and patients’ prognosis, 100 pairs of formalin-fixed and paraffin-embedded cancerous and adjacent noncancerous tissues from patients with ESCC were used to detect the expression pattern of ZEB1 by immunohistochemistry. Then, the association between ZEB1 expression, clinicopathological parameters, and prognosis of ESCC was examined. We also performed migration and invasion assays of small interfering RNA (siRNA)-targeted ZEB1-transfected cells in vitro. As a result, expression level of ZEB1 was significantly higher in ESCC tissues compared to that in adjacent noncancerous tissues (P < 0.001). High expression of ZEB1 was observed in 55.00 % (55/100) of ESCCs. In addition, high ZEB1 expression was found to be closely correlated with advanced tumor stage (P = 0.001), positive lymph node metastasis (P = 0.001), great tumor depth (P = 0.03), and high histologic grade (P = 0.008). Moreover, multivariate analysis showed that the status of ZEB1 expression was an independent predictor for overall survival in ESCC. Furthermore, knockdown of ZEB1 by transfection of siRNA-ZEB1 abrogated the migration and invasion of ESCC cells in vitro. Taken together, our data offer the convincing evidence that ZEB1 may play a crucial role in promoting aggressive ESCC progression. ZEB1 may serve as an effective prognostic marker and a potential target for therapeutic intervention of ESCC.
Similar content being viewed by others
References
D’Journo XB, Thomas PA. Current management of esophageal cancer. J Thorac Dis. 2014;6 Suppl 2:S253–64.
Nakajima M, Kato H. Treatment options for esophageal squamous cell carcinoma. Expert Opin Pharmacother. 2013;14:1345–54.
Toh Y, Egashira A, Yamamoto M. Epigenetic alterations and their clinical implications in esophageal squamous cell carcinoma. Gen Thorac Cardiovasc Surg. 2013;61:262–9.
Lehrbach DM, Nita ME, Cecconello I. Molecular aspects of esophageal squamous cell carcinoma carcinogenesis. Arq Gastroenterol. 2003;40:256–61.
Gheldof A, Hulpiau P, van Roy F, De Craene B, Berx G. Evolutionary functional analysis and molecular regulation of the ZEB transcription factors. Cell Mol Life Sci. 2012;69:2527–41.
Browne G, Sayan AE, Tulchinsky E. ZEB proteins link cell motility with cell cycle control and cell survival in cancer. Cell Cycle. 2010;9:886–91.
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;66:773–87.
Son H, Moon A. Epithelial-mesenchymal transition and cell invasion. Toxicol Res. 2010;26:245–52.
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;5:564–8.
Okugawa Y, Toiyama Y, Tanaka K, Matsusita K, Fujikawa H, Saigusa S, et al. Clinical significance of Zinc finger E-box binding homeobox 1 (ZEB1) in human gastric cancer. J Surg Oncol. 2012;106:280–5.
Chen Z, Li S, Huang K, Zhang Q, Wang J, Li X, et al. The nuclear protein expression levels of SNAI1 and ZEB1 are involved in the progression and lymph node metastasis of cervical cancer via the epithelial-mesenchymal transition pathway. Hum Pathol. 2013;44:2097–105.
Yokobori T, Suzuki S, Tanaka N, Inose T, Sohda M, Sano A, et al. MiR-150 is associated with poor prognosis in esophageal squamous cell carcinoma via targeting the EMT inducer ZEB1. Cancer Sci. 2013;104:48–54.
Harazono Y, Muramatsu T, Endo H, Uzawa N, Kawano T, Harada K, et al. miR-655 Is an EMT-suppressive microRNA targeting ZEB1 and TGFBR2. PLoS One. 2013;8:e62757.
Remmele W, Stegner HE. Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe. 1987;8:138–40.
Qi YJ, Chao WX, Chiu JF. An overview of esophageal squamous cell carcinoma proteomics. J Proteomics. 2012;75:3129–37.
Kuwano H, Nakajima M, Miyazaki T, Kato H. Distinctive clinicopathological characteristics in esophageal squamous cell carcinoma. Ann Thorac Cardiovasc Surg. 2003;9:6–13.
Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15:178–96.
Samatov TR, Tonevitsky AG, Schumacher U. Epithelial-mesenchymal transition: focus on metastatic cascade, alternative splicing, non-coding RNAs and modulating compounds. Mol Cancer. 2013;12:107.
Cervantes-Arias A, Pang LY, Argyle DJ. Epithelial-mesenchymal transition as a fundamental mechanism underlying the cancer phenotype. Vet Comp Oncol. 2013;11:169–84.
Miyazono K. Transforming growth factor-beta signaling in epithelial-mesenchymal transition and progression of cancer. Proc Jpn Acad Ser B Phys Biol Sci. 2009;85:314–23.
Aigner K, Dampier B, Descovich L, Mikula M, Sultan A, Schreiber M, et al. The transcription factor ZEB1 (deltaEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene. 2007;26:6979–88.
Lindley LE, Briegel KJ. Molecular characterization of TGFbeta-induced epithelial-mesenchymal transition in normal finite lifespan human mammary epithelial cells. Biochem Biophys Res Commun. 2010;399:659–64.
Chen D, Wang J, Zhang Y, Chen J, Yang C, Cao W, et al. Effect of down-regulated transcriptional repressor ZEB1 on the epithelial-mesenchymal transition of ovarian cancer cells. Int J Gynecol Cancer. 2013;23:1357–66.
Singh M, Spoelstra NS, Jean A, Howe E, Torkko KC, Clark HR, et al. ZEB1 expression in type I vs type II endometrial cancers: a marker of aggressive disease. Mod Pathol. 2008;21:912–23.
Conflicts of interest
None
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yang, X., Wang, Q., Dai, W. et al. Overexpression of zinc finger E-box binding homeobox factor 1 promotes tumor invasiveness and confers unfavorable prognosis in esophageal squamous cell carcinoma. Tumor Biol. 35, 11977–11984 (2014). https://doi.org/10.1007/s13277-014-2494-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13277-014-2494-8