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LncRNA ZEB2-AS1 contributes to the tumorigenesis of gastric cancer via activating the Wnt/β-catenin pathway

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Abstract

Studies have shown that long noncoding RNA Zinc finger E-box-binding homeobox 2 antisense RNA 1 (ZEB2-AS1) is involved in the progression of lung cancer, bladder cancer, and hepatocellular carcinoma. However, its role in the pathogenesis of gastric cancer remains unknown. The Wnt/β-catenin pathway contributes to the development of gastric cancer. ZEB2-AS1 expression was firstly detected in the gastric carcinoma tissue samples as well as in gastric cancer cells. Knockdown of ZEB2-AS1 was performed by ZEB2-AS1-shRNA, and the viability, migration, invasion, and apoptosis of gastric cancer cells were determined by CCK-8, scratch assay, transwell, and flow cytometry, respectively. Furthermore, levels of Ki-67, PCNA, VEGF, MMP9, epithelial–mesenchymal transition (EMT) markers (E-cadherin, Vimentin and ZEB2), cleaved caspase 3/8/9 and PARP, active β-catenin, c-Myc, cyclinD1, and AXIN2 were assayed by Western blot or real-time PCR. Additionally, the role and mechanism of ZEB2-AS1 were confirmed in a xenograft nude mouse model. We found ZEB2-AS1 expression was increased in gastric carcinoma samples, and it was correlated with tumor progression. Also, its expression was elevated in gastric cancer cells. Knockdown of ZEB2-AS1 reduced the proliferation, migration, invasion, and EMT, but increased the apoptosis of gastric carcinoma cells. Furthermore, ZEB2-AS1 downregulation remarkably suppressed the expression of Ki-67, PCNA, VEGF and MMP9, and the activation of Wnt/β-catenin signaling, whereas elevated the levels of cleaved caspase 3/8/9 and PARP in gastric cancer cells. And ZEB2 overexpression reversed the effects of ZEB2-AS1 downregulation on the proliferation, EMT and inactivation of Wnt/β-catenin signaling. Additionally, ZEB2-AS1 knockdown inhibited tumor growth, Ki-67 staining, and the expression of VEGF, MMP9, active β-catenin, c-Myc, cyclinD1, and AXIN2 in mice. In conclusion, ZEB2-AS1 promotes the tumorigenesis of gastric carcinoma that is related to the upregulation of ZEB2 and the activation of the Wnt/β-catenin pathway.

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References

  1. Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66:7–30. https://doi.org/10.3322/caac.21332

    Article  PubMed  Google Scholar 

  2. Saka M, Morita S, Fukagawa T, Katai H (2011) Present and future status of gastric cancer surgery. Jpn J Clin Oncol 41:307–313. https://doi.org/10.1093/jjco/hyq240

    Article  PubMed  Google Scholar 

  3. Allum WH, Blazeby JM, Griffin SM, Cunningham D, Jankowski JA, Wong R (2011) Guidelines for the management of oesophageal and gastric cancer. Gut 60:1449–1472. https://doi.org/10.1136/gut.2010.228254

    Article  CAS  PubMed  Google Scholar 

  4. Terracciano D, Terreri S, de Nigris F, Costa V, Calin GA, Cimmino A (2017) The role of a new class of long noncoding RNAs transcribed from ultraconserved regions in cancer. Biochim Biophys Acta 1868:449–455. https://doi.org/10.1016/j.bbcan.2017.09.001

    Article  CAS  Google Scholar 

  5. Yang W, Ma J, Zhou W, Cao B, Zhou X, Yang Z, Zhang H, Zhao Q, Fan D, Hong L (2017) Molecular mechanisms and theranostic potential of miRNAs in drug resistance of gastric cancer. Expert Opin Ther Targets 21:1063–1075. https://doi.org/10.1080/14728222.2017.1389900

    Article  CAS  PubMed  Google Scholar 

  6. Rong D, Sun H, Li Z, Liu S, Dong C, Fu K, Tang W, Cao H (2017) An emerging function of circRNA–miRNAs–mRNA axis in human diseases. Oncotarget 8:73271–73281. https://doi.org/10.18632/oncotarget.19154

    Article  PubMed  PubMed Central  Google Scholar 

  7. Zhu H, Yu J, Guo Y, Feng S (2017) Identification of key lncRNAs in colorectal cancer progression based on associated protein–protein interaction analysis. World J Surg Oncol 15:153. https://doi.org/10.1186/s12957-017-1211-7

    Article  PubMed  PubMed Central  Google Scholar 

  8. He X, Ou C, Xiao Y, Han Q, Li H, Zhou S (2017) LncRNAs: key players and novel insights into diabetes mellitus. Oncotarget 8:71325–71341. https://doi.org/10.18632/oncotarget.19921

    Article  PubMed  PubMed Central  Google Scholar 

  9. Zhang Q, Chen B, Liu P, Yang J (2018) XIST promotes gastric cancer (GC) progression through TGF-beta1 via targeting miR-185. J Cell Biochem 119:2787–2796. https://doi.org/10.1002/jcb.26447

    Article  CAS  PubMed  Google Scholar 

  10. Yang F, Xue X, Bi J, Zheng L, Zhi K, Gu Y, Fang G (2013) Long noncoding RNA CCAT1, which could be activated by c-Myc, promotes the progression of gastric carcinoma. J Cancer Res Clin Oncol 139:437–445. https://doi.org/10.1007/s00432-012-1324-x

    Article  CAS  PubMed  Google Scholar 

  11. Zhang K, Han X, Zhang Z, Zheng L, Hu Z, Yao Q, Cui H, Shu G, Si M, Li C, Shi Z, Chen T, Han Y, Chang Y, Yao Z, Han T, Hong W (2017) The liver-enriched lnc-LFAR1 promotes liver fibrosis by activating TGFbeta and Notch pathways. Nat Commun 8:144. https://doi.org/10.1038/s41467-017-00204-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sun L, Jiang C, Xu C, Xue H, Zhou H, Gu L, Liu Y, Xu Q (2017) Down-regulation of long non-coding RNA RP11-708H21.4 is associated with poor prognosis for colorectal cancer and promotes tumorigenesis through regulating AKT/mTOR pathway. Oncotarget 8:27929–27942. https://doi.org/10.18632/oncotarget.15846

    Article  PubMed  PubMed Central  Google Scholar 

  13. Liao B, Chen R, Lin F, Mai A, Chen J, Li H, Xu Z, Dong S (2018) Long noncoding RNA HOTTIP promotes endothelial cell proliferation and migration via activation of the Wnt/beta-catenin pathway. J Cell Biochem 119:2797–2805. https://doi.org/10.1002/jcb.26448

    Article  CAS  PubMed  Google Scholar 

  14. Mei D, Song H, Wang K, Lou Y, Sun W, Liu Z, Ding X, Guo J (2013) Up-regulation of SUMO1 pseudogene 3 (SUMO1P3) in gastric cancer and its clinical association. Med Oncol 30:709. https://doi.org/10.1007/s12032-013-0709-2

    Article  CAS  PubMed  Google Scholar 

  15. Zhu S, Mao J, Shao Y, Chen F, Zhu X, Xu D, Zhang X, Guo J (2015) Reduced expression of the long non-coding RNA AI364715 in gastric cancer and its clinical significance. Tumour Biol 36:8041–8045. https://doi.org/10.1007/s13277-015-3543-7

    Article  CAS  PubMed  Google Scholar 

  16. Lan T, Chang L, Wu L, Yuan Y (2016) Downregulation of ZEB2-AS1 decreased tumor growth and metastasis in hepatocellular carcinoma. Mol Med Rep 14:4606–4612. https://doi.org/10.3892/mmr.2016.5836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Guo Y, Hu Y, Hu M, He J, Li B (2018) Long non-coding RNA ZEB2-AS1 promotes proliferation and inhibits apoptosis in human lung cancer cells. Oncol Lett 15:5220–5226. https://doi.org/10.3892/ol.2018.7918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wu X, Yan T, Wang Z, Wu X, Cao G, Zhang C (2017) LncRNA ZEB2-AS1 promotes bladder cancer cell proliferation and inhibits apoptosis by regulating miR-27b. Biomed Pharmacother 96:299–304. https://doi.org/10.1016/j.biopha.2017.08.060

    Article  CAS  PubMed  Google Scholar 

  19. Jiang Y, Wang Y, Liang L, Gao Y, Chen J, Sun Y, Cheng Y, Xu Y (2015) IL-37 mediates the antitumor activity in renal cell carcinoma. Med Oncol 32:250. https://doi.org/10.1007/s12032-015-0695-7

    Article  CAS  PubMed  Google Scholar 

  20. Ko GH, Go SI, Lee WS, Lee JH, Jeong SH, Lee YJ, Hong SC, Ha WS (2017) Prognostic impact of Ki-67 in patients with gastric cancer-the importance of depth of invasion and histologic differentiation. Medicine (Baltimore) 96:e7181. https://doi.org/10.1097/MD.0000000000007181

    Article  CAS  Google Scholar 

  21. Mondal J, Samadder A, Khuda-Bukhsh AR (2016) Psorinum 6 × triggers apoptosis signals in human lung cancer cells. J Integr Med 14:143–153. https://doi.org/10.1016/S2095-4964(16)60230-3

    Article  PubMed  Google Scholar 

  22. Liu Z, Wang Y, Dou C, Xu M, Sun L, Wang L, Yao B, Li Q, Yang W, Tu K, Liu Q (2018) Hypoxia-induced up-regulation of VASP promotes invasiveness and metastasis of hepatocellular carcinoma. Theranostics 8:4649–4663. https://doi.org/10.7150/thno.26789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Liu N, Zhou N, Chai N, Liu X, Jiang H, Wu Q, Li Q (2016) Helicobacter pylori promotes angiogenesis depending on Wnt/beta-catenin-mediated vascular endothelial growth factor via the cyclooxygenase-2 pathway in gastric cancer. BMC Cancer 16:321. https://doi.org/10.1186/s12885-016-2351-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Qi S, Song Y, Peng Y, Wang H, Long H, Yu X, Li Z, Fang L, Wu A, Luo W, Zhen Y, Zhou Y, Chen Y, Mai C, Liu Z, Fang W (2012) ZEB2 mediates multiple pathways regulating cell proliferation, migration, invasion, and apoptosis in glioma. PLoS ONE 7:e38842. https://doi.org/10.1371/journal.pone.0038842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhou DD, Wang X, Wang Y, Xiang XJ, Liang ZC, Zhou Y, Xu A, Bi CH, Zhang L (2016) MicroRNA-145 inhibits hepatic stellate cell activation and proliferation by targeting ZEB2 through Wnt/beta-catenin pathway. Mol Immunol 75:151–160. https://doi.org/10.1016/j.molimm.2016.05.018

    Article  CAS  PubMed  Google Scholar 

  26. Huang T, Liu HW, Chen JQ, Wang SH, Hao LQ, Liu M, Wang B (2017) The long noncoding RNA PVT1 functions as a competing endogenous RNA by sponging miR-186 in gastric cancer. Biomed Pharmacother 88:302–308. https://doi.org/10.1016/j.biopha.2017.01.049

    Article  CAS  PubMed  Google Scholar 

  27. Na K, Li K, Sang T, Wu K, Wang Y, Wang X (2017) Anticarcinogenic effects of water extract of sporoderm-broken spores of Ganoderma lucidum on colorectal cancer in vitro and in vivo. Int J Oncol 50:1541–1554. https://doi.org/10.3892/ijo.2017.3939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wakiyama K, Kitajima Y, Tanaka T, Kaneki M, Yanagihara K, Aishima S, Nakamura J, Noshiro H (2017) Low-dose YC-1 combined with glucose and insulin selectively induces apoptosis in hypoxic gastric carcinoma cells by inhibiting anaerobic glycolysis. Sci Rep 7:12653. https://doi.org/10.1038/s41598-017-12929-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Liu QQ, Zhang FF, Wang F, Qiu JH, Luo CH, Zhu GY, Liu YF (2015) TIPE2 inhibits lung cancer growth attributing to promotion of apoptosis by regulating some apoptotic molecules expression. PLoS ONE 10:e0126176. https://doi.org/10.1371/journal.pone.0126176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Xu Y, Gao CC, Pan ZG, Zhou CW (2018) Irigenin sensitizes TRAIL-induced apoptosis via enhancing pro-apoptotic molecules in gastric cancer cells. Biochem Biophys Res Commun 496:998–1005. https://doi.org/10.1016/j.bbrc.2018.01.003

    Article  CAS  PubMed  Google Scholar 

  31. Keleg S, Buchler P, Ludwig R, Buchler MW, Friess H (2003) Invasion and metastasis in pancreatic cancer. Mol Cancer 2:14

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ru GQ, Wang HJ, Xu WJ, Zhao ZS (2011) Upregulation of Twist in gastric carcinoma associated with tumor invasion and poor prognosis. Pathol Oncol Res 17:341–347. https://doi.org/10.1007/s12253-010-9332-0

    Article  CAS  PubMed  Google Scholar 

  33. Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23:1011–1027. https://doi.org/10.1200/JCO.2005.06.081

    Article  CAS  PubMed  Google Scholar 

  34. Mercurio AM, Bachelder RE, Bates RC, Chung J (2004) Autocrine signaling in carcinoma: VEGF and the alpha6beta4 integrin. Semin Cancer Biol 14:115–122. https://doi.org/10.1016/j.semcancer.2003.09.016

    Article  CAS  PubMed  Google Scholar 

  35. Lichtenberger BM, Tan PK, Niederleithner H, Ferrara N, Petzelbauer P, Sibilia M (2010) Autocrine VEGF signaling synergizes with EGFR in tumor cells to promote epithelial cancer development. Cell 140:268–279. https://doi.org/10.1016/j.cell.2009.12.046

    Article  CAS  PubMed  Google Scholar 

  36. Akkoc A, Nak D, Demirer A, Simsek G (2017) Immunocharacterization of matrix metalloproteinase-2 and matrix metalloproteinase-9 in canine transmissible venereal tumors. Biotech Histochem 92:100–106. https://doi.org/10.1080/10520295.2016.1259500

    Article  CAS  PubMed  Google Scholar 

  37. Zhuang J, Lu Q, Shen B, Huang X, Shen L, Zheng X, Huang R, Yan J, Guo H (2015) TGFbeta1 secreted by cancer-associated fibroblasts induces epithelial-mesenchymal transition of bladder cancer cells through lncRNA-ZEB2NAT. Sci Rep 5:11924. https://doi.org/10.1038/srep11924

    Article  PubMed  PubMed Central  Google Scholar 

  38. Trautmann M, Sievers E, Aretz S, Kindler D, Michels S, Friedrichs N, Renner M, Kirfel J, Steiner S, Huss S, Koch A, Penzel R, Larsson O, Kawai A, Tanaka S, Sonobe H, Waha A, Schirmacher P, Mechtersheimer G, Wardelmann E, Buttner R, Hartmann W (2014) SS18-SSX fusion protein-induced Wnt/beta-catenin signaling is a therapeutic target in synovial sarcoma. Oncogene 33:5006–5016. https://doi.org/10.1038/onc.2013.443

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by Si miao Plan of Shaanxi Provincial Natural Science Foundation (No. 2016ZDKF19).

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Authors and Affiliations

  1. Department of Clinical Laboratory, Chang’an Hospital, Xi’an, 710016, Shaanxi, People’s Republic of China

    Feixia Wang & Ruili Yang

  2. Department of Clinical Laboratory, Ankang Municipality of Traditional Chinese Medicine Hospital, No. 47, East Bashan Road, Ankang, 725000, Shaanxi, People’s Republic of China

    Wu Zhu, Wanhua Xie & Daojun Wang

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  1. Feixia Wang
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Correspondence to Daojun Wang.

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Wang, F., Zhu, W., Yang, R. et al. LncRNA ZEB2-AS1 contributes to the tumorigenesis of gastric cancer via activating the Wnt/β-catenin pathway. Mol Cell Biochem 456, 73–83 (2019). https://doi.org/10.1007/s11010-018-03491-7

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