Objective: ZNF750, an epidermal differentiation regulator, has been suggested to act as a tumor suppressor of esophageal squamous cell carcinoma (ESCC). Although a correlation between the epidermal differentiation gene and resistance to chemoradiotherapy (CRT) has been posited, no data regarding the ZNF750 status in ESCC have been reported. The aim of the present study was to evaluate the relationship between ZNF750 expression and response to CRT in ESCC. Methods: Eighty-seven patients who had been pathologically diagnosed with ESCC were evaluated in the present study. All patients underwent neoadjuvant CRT, followed by curative esophagectomy. The expression of ZNF750 in pretreatment biopsy samples was immunohistochemically investigated and compared to the histopathological effectiveness of CRT in surgical specimens. Results: High expression of ZNF750 was closely correlated with good sensitivity to CRT (p = 0.016). A univariate analysis showed that high/intermediate expression of ZNF750 was a significant predictive factor for good sensitivity to CRT (p = 0.006). High/intermediate expression of ZNF750 (30% or more) remained an independent predictive factor for sensitivity to CRT in a multivariate analysis (p = 0.033). Conclusions: ZNF750 expression predicts sensitivity to CRT and can be a biomarker that reliably predicts the response of ESCC to CRT.

Keywords:
Chemoradiotherapy, Biomarker, Sensitivity, Resistance, ZNF750, Esophageal cancer, Squamous cell carcinoma
1.
Altorki N, Kent M, Ferrara C, Port J: Three-field lymph node dissection for squamous cell and adenocarcioma of the esophagus. Ann Surg 2002;236:177-183.
2.
Medical Research Council Oesophageal Cancer Working Group: Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomized controlled trial. Lancet 2002;359:1727-1733.
3.
Garraway LA, Verweij J, Ballman KV: Precision oncology: an overview. J Clin Oncol 2013;31:1803-1805.
4.
Akutsu Y, Hanari N, Yusup G, Komatsu-Akimoto A, Ikeda N, Mori M, et al: COX2 expression predicts resistance to chemoradiotherapy in esophageal squamous cell carcinoma. Ann Surg Oncol 2011;18:2946-2951.
5.
Gao Y, Zhu J, Zhang X, Wu Q, Jiang S, Liu Y, et al: BRCA1 mRNA expression as a predictive and prognostic marker in advanced esophageal squamous cell carcinoma treated with cisplatin- or docetaxel-based chemotherapy/chemoradiotherapy. PLoS One 2013;8:e52589.
6.
Makuuchi Y, Honda K, Osaka Y, Kato K, Kojima T, Daiko H, et al: Soluble interleukin-6 receptor is a serum biomarker for the response of esophageal carcinoma to neoadjuvant chemoradiotherapy. Cancer Sci 2013;104:1045-1051.
7.
Okamoto H, Fujishima F, Nakamura Y, Zuguchi M, Miyata G, Kamei T, et al: Murine double minute 2 and its association with chemoradioresistance of esophageal squamous cell carcinoma. Anticancer Res 2013;33:1463-1471.
8.
Zhang JX, Tong ZT, Yang L, Wang F, Chai HP, Zhang F, et al: PITX2: a promising predictive biomarker of patients' prognosis and chemoradioresistance in esophageal squamous cell carcinoma. Int J Cancer 2013;132:2567-2577.
9.
Takahashi T, Yamahsita S, Matsuda Y, Kishino T, Nakajima T, Kushima R, et al: ZNF695 methylation predicts a response of esophageal squamous cell carcinoma to definitive chemoradiotherapy. J Cancer Res Clin Oncol 2015;141:453-463.
10.
Zhou XL, Wang WW, Zhu WG, Yu CH, Tao GZ, Wu QQ, et al: High expression of long non-coding RNA AFAP1-AS1 predicts chemoradioresistance and poor prognosis in patients with esophageal squamous cell carcinoma treated with definitive chemoradiotherapy. Mol Carcinog 2016;55:2095-2105.
11.
Zhang L, Zhou Y, Cheng C, Cui H, Cheng L, Kong P, et al: Genomic analyses reveal mutational signatures and frequently altered genes in esophageal squamous cell carcinoma. Am J Hum Genet 2015;96:597-611.
12.
Lin DC, Hao JJ, Nagata Y, Xu L, Shang L, Meng X, et al: Genomic and molecular characterization of esophageal squamous cell carcinoma. Nat Genet 2014;46:467-473.
13.
Sawada G, Niida A, Uchi R, Hirata H, Shimamura T, Suzuki Y, et al: Genomic landscape of esophageal squamous cell carcinoma in a Japanese population. Gastroenterology 2016;150:1171-1182.
14.
Sen GL, Boxer LD, Webster DE, Bussat RT, Qu K, Zarnegar BJ, et al: ZNF750 is a p63 target gene that induces KLF4 to drive terminal epidermal differentiation. Dev Cell 2012;22:669-677.
15.
Birnbaum RY, Zvulunov A, Hallel-Halevy D, Cagnano E, Finer G, Ofir R, et al: Seborrhea-like dermatitis with psoriasiform elements caused by a mutation in ZNF750, encoding a putative C2H2 zinc finger protein. Nat Genet 2006;38:749-751.
16.
Luthra R, Wu TT, Luthra MG, Izzo J, Lopez-Alvarez E, Zhang L, et al: Gene expression profiling of localized esophageal carcinomas: association with pathologic response to preoperative chemoradiation. J Clin Oncol 2006;24:259-267.
17.
Luthra MG, Ajani JA, Izzo J, Ensor J, Wu TT, Rashid A, et al: Decreased expression of gene cluster at chromosome 1q21 defines molecular subgroups of chemoradiotherapy response in esophageal cancers. Clin Cancer Res 2007;13:912-919.
18.
Volz A, Korge BP, Compton JG, Ziegler A, Steinert PM, Mischke D: Physical mapping of a functional cluster of epidermal differentiation genes on chromosome 1q21. Genomics 1993;18:92-99.
19.
Sobin LH, Gospodarowicz MK, Wittekind C: TNM Classification of Malignant Tumors, ed 7. Oxford, Wiley-Blackwell, 2010.
20.
Japan Esophageal Society: Japanese Classification of Esophageal Cancer, ed 11. Part I. Esophagus 2017;14:1-36.
21.
Japan Esophageal Society: Japanese Classification of Esophageal Cancer, ed 11. Parts II and III. Esophagus 2017;14:37-65.
22.
Akutsu Y, Matsubara H, Shuto K, Uesato M, Mori M, Hoshino I, et al: Clinical and pathologic evaluation of the effectiveness of neoadjuvant chemoradiation therapy in advanced esophageal cancer patients. World J Surg 2009;33:1002-1009.
23.
Wijnhoven BP, van Lanschot JJ, Tilanus HW, Steyerberg EW, van der Gaast A: Neoadjuvant chemoradiotherapy for esophageal cancer: a review of meta-analyses. World J Surg 2009;33:2606-2614.
24.
Takeuchi H, Ozawa S, Ando N, Kitagawa Y, Ueda M, Kitajima M: Cell-cycle regulators and the Ki-67 labeling index can predict the response to chemoradiotherapy and the survival of patients with locally advanced squamous cell carcinoma of the esophagus. Ann Surg Oncol 2003;10:792-800.
25.
Boxer LD, Barajas B, Tao S, Zhang J, Khavari PA: ZNF750 interacts with KLF4 and RCOR1, KDM1A, and CTBP1/2 chromatin regulators to repress epidermal progenitor genes and induce differentiation genes. Genes Dev 2014;28:2013-2026.
26.
Hazawa M, Lin DC, Handral H, Xu L, Chen Y, Jiang YY, et al: ZNF750 is a lineage-specific tumour suppressor in squamous cell carcinoma. Oncogene 2017;36:2243-2254.
27.
Miller KA, Eklund EA, Peddinghaus ML, Cao Z, Fernandes N, Turk PW, et al: Kruppel-like factor 4 regulates laminin α3A expression in mammary epithelial cells. J Biol Chem 2001;276:42863-42868.
28.
Zhou G, Hamik A, Nayak L, Tian H, Shi H, Lu Y, et al: Endothelial Kruppel-like factor 4 protects against atherothrombosis in mice. J Clin Invest 2012;122:4727-4731.
29.
Shin SH, Kwon YW, Heo SC, Jeong GO, Kim BR, Seo EJ, et al: Krüppel-like factor 4 mediates lysophosphatidic acid-stimulated migration and proliferation of PC3M prostate cancer cells. Exp Mol Med 2014;46:e104.
30.
Ma MQ, Zhang HD, Tang P, Jiang HJ, Chen CG: Association of Kruppel-like factor 4 expression with the prognosis of esophageal squamous cell carcinoma patients. Int J Clin Exp Pathol 2014;7:6679-6685.
31.
Zhang P, Hong H, Sun X, Jiang H, Ma S, Zhao S, et al: MicroRNA-10b regulates epithelial-mesenchymal transition by modulating KLF4/Notch1/E-cadherin in cisplatin-resistant nasopharyngeal carcinoma cells. Am J Cancer Res 2016;6:141-156.
32.
Hara J, Miyata H, Yamasaki M, Sugimura K, Takahashi T, Kurokawa Y, et al: Mesenchymal phenotype after chemotherapy is associated with chemoresistance and poor clinical outcome in esophageal cancer. Oncol Rep 2014;31:589-596.
33.
Zhang H, Luo H, Jiang Z, Yue J, Hou Q, Xie R, et al: Fractionated irradiation-induced EMT-like phenotype conferred radioresistance in esophageal squamous cell carcinoma. J Radiat Res 2016;57:370-380.
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2017
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