HIF-1α promotes ZEB1 expression and EMT in a human bladder cancer lung metastasis animal model Corrigendum in /10.3892/ol.2021.12860

Zhu,Jianning; Huang,Zhixin; Zhang,Mengzhao; Wang,Weiyi; Liang,Hua; Zeng,Jin; Wu,Kaijie; Wang,Xinyang; Hsieh,Jer‑Tsong; Guo,Peng; Fan,Jinhai

doi:10.3892/ol.2018.7764

HIF-1α promotes ZEB1 expression and EMT in a human bladder cancer lung metastasis animal model

Corrigendum in: /10.3892/ol.2021.12860

Authors:
- Jianning Zhu
- Zhixin Huang
- Mengzhao Zhang
- Weiyi Wang
- Hua Liang
- Jin Zeng
- Kaijie Wu
- Xinyang Wang
- Jer‑Tsong Hsieh
- Peng Guo
- Jinhai Fan
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Affiliations: Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Pathology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Published online on: January 10, 2018 https://doi.org/10.3892/ol.2018.7764
Pages: 3482-3489
Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Lung is one of the most common sites for bladder cancer to metastasize. Although the involvement of the epithelial-to-mesenchymal transition (EMT) in bladder cancer progression has been established, the mechanism of EMT induction remains unclear. In order to investigate this, T24‑parental (P) and T24‑lung (L) bladder cancer cells were obtained from primary tumors and lung metastatic sites of an animal model with orthotopic spontaneous metastatic bladder cancer, according to a protocol previously described. Compared with T24‑P cells, mesenchymal‑like T24‑L cells exhibited an increased ability in tumor invasion and metastasis, as well as an increased expression of hypoxia‑inducible factor (HIF)‑1α, zinc finger E‑box‑binding homeobox 1 (ZEB1), vimentin and N‑cadherin and lower level of cytokeratin 18 were observed. Mechanistically, it was identified that HIF‑1α increases ZEB1 expression and subsequently regulates the expression of EMT‑related genes in both HIF‑1α knocking down by siRNA and gain‑in HIF‑1α by hypoxia culture cell models. In addition, the expression of HIF‑1α and ZEB1 in bladder cancer tissues were increased compared with normal bladder epithelial tissues, as well as significantly increased in the high‑grade, invasive and metastatic bladder cancer tissues compared with low‑grade, superficial and non‑metastatic bladder cancer tissues by using immune‑histochemical staining assay. Notably, the protein level of HIF‑1α was positively associated with that of ZEB1 in bladder cancer tissues. Results from the present study indicate that HIF‑1α promotes ZEB1 expression and EMT in the T24‑L human bladder cancer lung metastasis animal model, suggesting that HIF‑1α serves an important function in the metastasis of bladder cancer, and HIF‑1α and ZEB1 may be potential targets for inhibiting bladder metastasis in the future.

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1	Jemal A, Siegel R, Xu J and Ward E: Cancer statistics, 2010. CA Cancer J Clin. 60:277–300. 2010. View Article : Google Scholar : PubMed/NCBI
2	Raghavan D, Shipley WU, Garnick MB, Russell PJ and Richie JP: Biology and management of bladder cancer. N Engl J Med. 322:1129–1138. 1990. View Article : Google Scholar : PubMed/NCBI
3	Stenzl A, Cowan NC, De Santis M, Jakse G, Kuczyk MA, Merseburger AS, Ribal MJ, Sherif A and Witjes JA: The updated EAU guidelines on muscle-invasive and metastatic bladder cancer. Eur Urol. 55:815–825. 2009. View Article : Google Scholar : PubMed/NCBI
4	Kurian A, Lee J and Born A: Urothelial bladder cancer with cavitary lung metastases. Can Respir J. 18:e46–e47. 2011. View Article : Google Scholar : PubMed/NCBI
5	Hill RP, Marie-Egyptienne DT and Hedley DW: Cancer stem cells, hypoxia and metastasis. Semin Radiat Oncol. 19:106–111. 2009. View Article : Google Scholar : PubMed/NCBI
6	Adams JM, Difazio LT, Rolandelli RH, Luján JJ, Haskó G, Csóka B, Selmeczy Z and Németh ZH: HIF-1: A key mediator in hypoxia. Acta Physiol Hung. 96:19–28. 2009. View Article : Google Scholar : PubMed/NCBI
7	Joseph JV, Conroy S, Pavlov K, Sontakke P, Tomar T, Eggens-Meijer E, Balasubramaniyan V, Wagemakers M, den Dunnen WF and Kruyt FA: Hypoxia enhances migration and invasion in glioblastoma by promoting a mesenchymal shift mediated by the HIF1α-ZEB1 axis. Cancer Lett. 359:107–116. 2015. View Article : Google Scholar : PubMed/NCBI
8	Wu K, Ning Z, Zeng J, Fan J, Zhou J, Zhang T, Zhang L, Chen Y, Gao Y, Wang B, et al: Silibinin inhibits β-catenin/ZEB1 signaling and suppresses bladder cancer metastasis via dual-blocking epithelial-mesenchymal transition and stemness. Cell Signal. 25:2625–2633. 2013. View Article : Google Scholar : PubMed/NCBI
9	Kenney PA, Wszolek MF, Rieger-Christ KM, Neto BS, Gould JJ, Harty NJ, Mosquera JM, Zeheb R, Loda M, Darling DS, et al: Novel ZEB1 expression in bladder tumorigenesis. BJU Int. 107:656–663. 2011. View Article : Google Scholar : PubMed/NCBI
10	Zhang T, Fan J, Wu K, Zeng J, Sun K, Guan Z, Wang X, Hiesh JT and He D: Roles of HIF-1α in a novel optical orthotopic spontaneous metastatic bladder cancer animal model. Urol Oncol. 30:928–935. 2012. View Article : Google Scholar : PubMed/NCBI
11	Karam JA, Huang S, Fan J, Stanfield J, Schultz RA, Pong RC, Sun X, Mason RP, Xie XJ, Niu G, et al: Upregulation of TRAG3 gene in urothelial carcinoma of the bladder. Int J Cancer. 128:2823–2832. 2011. View Article : Google Scholar : PubMed/NCBI
12	Witjes JA, Compérat E, Cowan NC, De Santis M, Gakis G, Lebret T, Ribal MJ, Van der Heijden AG and Sherif A; European Association of Urology, : EAU guidelines on muscle-invasive and metastatic bladder cancer: Summary of the 2013 guidelines. Eur Urol. 65:778–792. 2014. View Article : Google Scholar : PubMed/NCBI
13	Schned AR, Andrew AS, Marsit CJ, Kelsey KT, Zens MS and Karagas MR: Histological classification and stage of newly diagnosed bladder cancer in a population-based study from the Northeastern United States. Scand J Urol Nephrol. 42:237–242. 2008. View Article : Google Scholar : PubMed/NCBI
14	Murai T, Yamada S, Fuchs BC, Fujii T, Nakayama G, Sugimoto H, Koike M, Fujiwara M, Tanabe KK and Kodera Y: Epithelial-to-mesenchymal transition predicts prognosis in clinical gastric cancer. J Surg Oncol. 109:684–689. 2014. View Article : Google Scholar : PubMed/NCBI
15	Pouysségur J, Dayan F and Mazure NM: Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature. 441:437–443. 2006. View Article : Google Scholar : PubMed/NCBI
16	Denko NC: Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer. 8:705–713. 2008. View Article : Google Scholar : PubMed/NCBI
17	Krishnamachary B, Zagzag D, Nagasawa H, Rainey K, Okuyama H, Baek JH and Semenza GL: Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B. Cancer Res. 66:2725–2731. 2006. View Article : Google Scholar : PubMed/NCBI
18	Rohwer N, Lobitz S, Daskalow K, Jöns T, Vieth M, Schlag PM, Kemmner W, Wiedenmann B, Cramer T and Höcker M: HIF-1alpha determines the metastatic potential of gastric cancer cells. Br J Cancer. 100:772–781. 2009. View Article : Google Scholar : PubMed/NCBI
19	Deniz H, Karakök M, Yagci F and Güldür ME: Evaluation of relationship between HIF-1alpha immunoreactivity and stage, grade, angiogenic profile and proliferative index in bladder urothelial carcinomas. Int Urol Nephrol. 42:103–107. 2010. View Article : Google Scholar : PubMed/NCBI
20	Meng X, Kong DH, Li N, Zong ZH, Liu BQ, Du ZX, Guan Y, Cao L and Wang HQ: Knockdown of BAG3 induces epithelial-mesenchymal transition in thyroid cancer cells through ZEB1 activation. Cell Death Dis. 5:e10922014. View Article : Google Scholar : PubMed/NCBI
21	Wu K, Fan J, Zhang L, Ning Z, Zeng J, Zhou J, Li L, Chen Y, Zhang T, Wang X, et al: PI3K/Akt to GSK3β/β-catenin signaling cascade coordinates cell colonization for bladder cancer bone metastasis through regulating ZEB1 transcription. Cell Signal. 24:2273–2282. 2012. View Article : Google Scholar : PubMed/NCBI