Upregulated forkhead‑box A3 elevates the expression of forkhead‑box A1 and forkhead‑box A2 to promote metastasis in esophageal cancer

Chen,Bing; Yu,Jiegen; Lu,Linming; Dong,Fangyuan; Zhou,Fangfang; Tao,Xiangxiang; Sun,Entao

doi:10.3892/ol.2019.10078

Upregulated forkhead‑box A3 elevates the expression of forkhead‑box A1 and forkhead‑box A2 to promote metastasis in esophageal cancer

Authors:
- Bing Chen
- Jiegen Yu
- Linming Lu
- Fangyuan Dong
- Fangfang Zhou
- Xiangxiang Tao
- Entao Sun
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Affiliations: Department of Pathology, School of Basic Medical Sciences, Wannan Medical College, Wuhu, Anhui 241002, P.R. China, Department of Management Science, School of Humanities and Management, Wannan Medical College, Wuhu, Anhui 241002, P.R. China, Department of Health Inspection and Quarantine, School of Laboratory Medicine, Wannan Medical College, Wuhu, Anhui 241002, P.R. China
Published online on: February 26, 2019 https://doi.org/10.3892/ol.2019.10078
Pages: 4351-4360
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Esophageal cancer (EC) is one of the most lethal cancers currently known. Members of the forkhead‑box A (FOXA) family, including FOXA1 and FOXA2, have been reported to regulate EC progression. However, the role of FOXA3, which is another FOXA member, has not yet been investigated. In the present study, public dataset analyses and immunohistochemistry of 96 samples from patients with EC were performed to determine the potential roles of FOXA3 in EC. The results revealed that FOXA3 was significantly upregulated in EC tumor tissues and Barrett's esophagus tissues. In addition, FOXA3 upregulation was positively associated with tumor invasion, distant metastasis, tumor‑node‑metastasis stage and shorter overall survival in patients with EC, and multivariate analysis identified FOXA3 as an independent prognostic marker. In vitro experiments demonstrated that the migratory and invasive abilities of EC109 and EC9706 cell lines were inhibited following FOXA3 knockdown. Notably, FOXA3 expression levels were positively correlated with FOXA1 and FOXA2 expression levels according to The Cancer Genome Atlas dataset analysis. Furthermore, FOXA3 knockdown decreased the expression levels of FOXA1 and FOXA2 in EC109 and EC9706 cell lines. Conversely, FOXA1 or FOXA2 overexpression compensated for the effects of FOXA3 knockdown on the migratory and invasive capacities of EC cells. In conclusion, the present study demonstrated that FOXA3 upregulation in EC cells promoted metastasis through regulation of other FOXA members.

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1	Chen W, He Y, Zheng R, Zhang S, Zeng H, Zou X and He J: Esophageal cancer incidence and mortality in China, 2009. J Thorac Dis. 5:19–26. 2013.PubMed/NCBI
2	Cook MB, Chow WH and Devesa SS: Oesophageal cancer incidence in the United States by race, sex, and histologic type, 1977–2005. Br J Cancer. 101:855–859. 2009. View Article : Google Scholar : PubMed/NCBI
3	Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 127:2893–2917. 2010. View Article : Google Scholar : PubMed/NCBI
4	Xu XC: Risk factors and gene expression in esophageal cancer. Methods Mol Biol. 471:335–360. 2009. View Article : Google Scholar : PubMed/NCBI
5	Paulson TG and Reid BJ: Focus on Barrett's esophagus and esophageal adenocarcinoma. Cancer Cell. 6:11–16. 2004. View Article : Google Scholar : PubMed/NCBI
6	Besnard V, Wert SE, Hull WM and Whitsett JA: Immunohistochemical localization of Foxa1 and Foxa2 in mouse embryos and adult tissues. Gene Expr Patterns. 5:193–208. 2004. View Article : Google Scholar : PubMed/NCBI
7	Kaestner KH, Hiemisch H, Luckow B and Schütz G: The HNF-3 gene family of transcription factors in mice: Gene structure, cDNA sequence, and mRNA distribution. Genomics. 20:377–385. 1994. View Article : Google Scholar : PubMed/NCBI
8	Kaestner KH: The making of the liver: Developmental competence in foregut endoderm and induction of the hepatogenic program. Cell Cycle. 4:1146–1148. 2005. View Article : Google Scholar : PubMed/NCBI
9	Zaret K: Developmental competence of the gut endoderm: Genetic potentiation by GATA and HNF3/fork head proteins. Dev Biol. 209:1–10. 1999. View Article : Google Scholar : PubMed/NCBI
10	Augello MA, Hickey TE and Knudsen KE: FOXA1: Master of steroid receptor function in cancer. EMBO J. 30:3885–3894. 2011. View Article : Google Scholar : PubMed/NCBI
11	Gao N, Le Lay J, Qin W, Doliba N, Schug J, Fox AJ, Smirnova O, Matschinsky FM and Kaestner KH: Foxa1 and Foxa2 maintain the metabolic and secretory features of the mature beta-cell. Mol Endocrinol. 24:1594–1604. 2010. View Article : Google Scholar : PubMed/NCBI
12	Ferri AL, Lin W, Mavromatakis YE, Wang JC, Sasaki H, Whitsett JA and Ang SL: Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner. Development. 134:2761–2769. 2007. View Article : Google Scholar : PubMed/NCBI
13	Mavromatakis YE, Lin W, Metzakopian E, Ferri AL, Yan CH, Sasaki H, Whisett J and Ang SL: Foxa1 and Foxa2 positively and negatively regulate Shh signalling to specify ventral midbrain progenitor identity. Mech Dev. 128:90–103. 2011. View Article : Google Scholar : PubMed/NCBI
14	Carroll JS, Liu XS, Brodsky AS, Li W, Meyer CA, Szary AJ, Eeckhoute J, Shao W, Hestermann EV, Geistlinger TR, et al: Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell. 122:33–43. 2005. View Article : Google Scholar : PubMed/NCBI
15	Gao N, White P and Kaestner KH: Establishment of intestinal identity and epithelial-mesenchymal signaling by Cdx2. Dev Cell. 16:588–599. 2009. View Article : Google Scholar : PubMed/NCBI
16	Slack JM: Metaplasia and transdifferentiation: From pure biology to the clinic. Nat Rev Mol Cell Biol. 8:369–378. 2007. View Article : Google Scholar : PubMed/NCBI
17	Robbins CM, Tembe WA, Baker A, Sinari S, Moses TY, Beckstrom-Sternberg S, Beckstrom-Sternberg J, Barrett M, Long J, Chinnaiyan A, et al: Copy number and targeted mutational analysis reveals novel somatic events in metastatic prostate tumors. Genome Res. 21:47–55. 2011. View Article : Google Scholar : PubMed/NCBI
18	Jain RK, Mehta RJ, Nakshatri H, Idrees MT and Badve SS: High-level expression of forkhead-box protein A1 in metastatic prostate cancer. Histopathology. 58:766–772. 2011. View Article : Google Scholar : PubMed/NCBI
19	Salem M, O'Brien JA, Bernaudo S, Shawer H, Ye G, Brkić J, Amleh A, Vanderhyden BC, Refky B, Yang BB, et al: miRNA-590-3p promotes ovarian cancer growth and metastasis via a novel FOXA2-versican pathway. Cancer Res. 78:4175–4190. 2018. View Article : Google Scholar : PubMed/NCBI
20	Wang B, Liu G, Ding L, Zhao J and Lu Y: FOXA2 promotes the proliferation, migration and invasion, and epithelial mesenchymal transition in colon cancer. Exp Ther Med. 16:133–140. 2018.PubMed/NCBI
21	Watts JA, Zhang C, Klein-Szanto AJ, Kormish JD, Fu J, Zhang MQ and Zaret KS: Study of FoxA pioneer factor at silent genes reveals Rfx-repressed enhancer at Cdx2 and a potential indicator of esophageal adenocarcinoma development. PLoS Genet. 7:e10022772011. View Article : Google Scholar : PubMed/NCBI
22	Lin L, Miller CT, Contreras JI, Prescott MS, Dagenais SL, Wu R, Yee J, Orringer MB, Misek DE, Hanash SM, et al: The hepatocyte nuclear factor 3 alpha gene, HNF3alpha (FOXA1), on chromosome band 14q13 is amplified and overexpressed in esophageal and lung adenocarcinomas. Cancer Res. 62:5273–5279. 2002.PubMed/NCBI
23	Sano M, Aoyagi K, Takahashi H, Kawamura T, Mabuchi T, Igaki H, Tachimori Y, Kato H, Ochiai A, Honda H, et al: Forkhead box A1 transcriptional pathway in KRT7-expressing esophageal squamous cell carcinomas with extensive lymph node metastasis. Int J Oncol. 36:321–330. 2010.PubMed/NCBI
24	Wang DH, Tiwari A, Kim ME, Clemons NJ, Regmi NL, Hodges WA, Berman DM, Montgomery EA, Watkins DN, Zhang X, et al: Hedgehog signaling regulates FOXA2 in esophageal embryogenesis and Barrett's metaplasia. J Clin Invest. 124:3767–3780. 2014. View Article : Google Scholar : PubMed/NCBI
25	Edge SB, Byrd DR, Compton CC, et al: AJCC Cancer Staging Manual. (7th). (New York). Springer. 2010.
26	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
27	Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, et al: Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 6:pl12013. View Article : Google Scholar : PubMed/NCBI
28	Hao Y, Triadafilopoulos G, Sahbaie P, Young HS, Omary MB and Lowe AW: Gene expression profiling reveals stromal genes expressed in common between Barrett's esophagus and adenocarcinoma. Gastroenterology. 131:925–933. 2006. View Article : Google Scholar : PubMed/NCBI
29	Kim SM, Park YY, Park ES, Cho JY, Izzo JG, Zhang D, Kim SB, Lee JH, Bhutani MS, Swisher SG, et al: Prognostic biomarkers for esophageal adenocarcinoma identified by analysis of tumor transcriptome. PLoS One. 5:e150742010. View Article : Google Scholar : PubMed/NCBI
30	Wang S, Zhan M, Yin J, Abraham JM, Mori Y, Sato F, Xu Y, Olaru A, Berki AT, Li H, et al: Transcriptional profiling suggests that Barrett's metaplasia is an early intermediate stage in esophageal adenocarcinogenesis. Oncogene. 25:3346–3356. 2006. View Article : Google Scholar : PubMed/NCBI
31	Liu YP, Ma L, Wang SJ, Chen YN, Wu GX, Han M and Wang XL: Prognostic value of lymph node metastases and lymph node ratio in esophageal squamous cell carcinoma. Eur J Surg Oncol. 36:155–159. 2010. View Article : Google Scholar : PubMed/NCBI
32	Yazbeck R, Jaenisch SE and Watson DI: From blood to breath: New horizons for esophageal cancer biomarkers. World J Gastroenterol. 22:10077–10083. 2016. View Article : Google Scholar : PubMed/NCBI
33	Duncan SA, Navas MA, Dufort D, Rossant J and Stoffel M: Regulation of a transcription factor network required for differentiation and metabolism. Science. 281:692–695. 1998. View Article : Google Scholar : PubMed/NCBI
34	Kalkuhl A, Kaestner K, Buchmann A and Schwarz M: Expression of hepatocyte-enriched nuclear transcription factors in mouse liver tumours. Carcinogenesis. 17:609–612. 1996. View Article : Google Scholar : PubMed/NCBI
35	Chen G, Korfhagen TR, Karp CL, Impey S, Xu Y, Randell SH, Kitzmiller J, Maeda Y, Haitchi HM, Sridharan A, et al: Foxa3 induces goblet cell metaplasia and inhibits innate antiviral immunity. Am J Respir Crit Care Med. 189:301–313. 2014. View Article : Google Scholar : PubMed/NCBI
36	Park SW, Verhaeghe C, Nguyenvu LT, Barbeau R, Eisley CJ, Nakagami Y, Huang X, Woodruff PG, Fahy JV and Erle DJ: Distinct roles of FOXA2 and FOXA3 in allergic airway disease and asthma. Am J Respir Crit Care Med. 180:603–610. 2009. View Article : Google Scholar : PubMed/NCBI
37	Ma X, Xu L, Gavrilova O and Mueller E: Role of forkhead box protein A3 in age-associated metabolic decline. Proc Natl Acad Sci USA. 111:14289–14294. 2014. View Article : Google Scholar : PubMed/NCBI
38	Shen W, Scearce LM, Brestelli JE, Sund NJ and Kaestner KH: Foxa3 (hepatocyte nuclear factor 3gamma) is required for the regulation of hepatic GLUT2 expression and the maintenance of glucose homeostasis during a prolonged fast. J Biol Chem. 276:42812–42817. 2001. View Article : Google Scholar : PubMed/NCBI
39	Ang SL, Wierda A, Wong D, Stevens KA, Cascio S, Rossant J and Zaret KS: The formation and maintenance of the definitive endoderm lineage in the mouse: involvement of HNF3/forkhead proteins. Development. 119:1301–1315. 1993.PubMed/NCBI
40	Monaghan AP, Kaestner KH, Grau E and Schütz G: Postimplantation expression patterns indicate a role for the mouse forkhead/HNF-3 alpha, beta and gamma genes in determination of the definitive endoderm, chordamesoderm and neuroectoderm. Development. 119:567–578. 1993.PubMed/NCBI