Digestive Diseases and Sciences

, Volume 63, Issue 12, pp 3348–3358 | Cite as

Retinoic Acid Receptor α Knockdown Suppresses the Tumorigenicity of Esophageal Carcinoma via Wnt/β-catenin Pathway

  • Xiao-Mei Mao
  • Hua Li
  • Xiao-Yun Zhang
  • Pan Zhou
  • Qi-Rui Fu
  • Qian-En Chen
  • Jin-Xing Shen
  • Yu Liu
  • Qing-Xi ChenEmail author
  • Dong-Yan ShenEmail author
Original Article



Aberrant expression of retinoic acid receptor α (RARα) was correlated with diverse carcinomas such as acute promyelocytic leukemia and colorectal carcinoma. Nevertheless, the function and mechanism of RARα in esophageal carcinoma (EC) remain unclear.


To investigate the expression of RARα in EC and its effect in the tumorigenesis of EC.

Methods and Results

In immunohistochemistry study, RARα was overexpressed in human EC tissues, and its overexpression was closely related to the pathological differentiation, lymph node metastasis, and clinical stages in EC patients. Functionally, RARα knockdown suppressed the proliferation and metastasis of EC cells through downregulating the expression of PCNA, Ki67, MMP7, and MMP9, as well as enhanced drug susceptibility of EC cells to 5-fluorouracil and cisplatin. Mechanistically, RARα knockdown inhibited the activity of Wnt/β-catenin pathway through reducing the phosphorylation level of GSK3β at Ser-9 and inducing phosphorylation level at Tyr-216, which resulted in downregulation of its downstream targets such as MMP7, MMP9, and P-gP.


Our results demonstrated that RARα knockdown suppressed the tumorigenicity of EC via Wnt/β-catenin pathway. RARα might be a potential molecular target for EC clinical therapy.


Retinoic acid receptor α Esophageal carcinoma Proliferation Metastasis Drug susceptibility Wnt/β-catenin pathway 



This study was supported by the National Natural Science Foundation of China (Grant No. 81572394); Project of Natural Science Foundation of Science and Technology Department, Fujian, China (Grant No. 2015J01545); and Special fund of Marine economic development in Xiamen (Grant No. 17GYY011HJ05).

Author’s contribution

XMM and HL wrote the manuscript and were involved in data collection. PZ and QRF were involved in the creation of the figures. XYZ, JXS, and YL analyzed the data. QXC and DYS conceived and revised the manuscript. All authors edited the manuscript and have approved its final version.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no competing financial interests related to this work.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institute Research Ethics Committee of the First Affiliated Hospital of Xiamen University.


  1. 1.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.CrossRefGoogle Scholar
  2. 2.
    Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115–132.CrossRefGoogle Scholar
  3. 3.
    Arnold M, Soerjomataram I, Ferlay J, Forman D. Global incidence of oesophageal cancer by histological subtype in 2012. Gut. 2015;64:381–387.CrossRefGoogle Scholar
  4. 4.
    Garg AX, McArthur E, Lentine KL, Donor Nephrectomy Outcomes Research (DONOR) Network. Gestational hypertension and preeclampsia in living kidney donors. N Engl J Med. 2015;372:1469–1470.CrossRefGoogle Scholar
  5. 5.
    Reid BJ, Li X, Galipeau PC, Vaughan TL. Barrett’s oesophagus and oesophageal adenocarcinoma: time for a new synthesis. Nat Rev Cancer. 2010;10:87–101.CrossRefGoogle Scholar
  6. 6.
    Gronemeyer H, Gustafsson JA, Laudet V. Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov. 2004;3:950–964.CrossRefGoogle Scholar
  7. 7.
    di Masi A, Leboffe L, De Marinis E, et al. Retinoic acid receptors: from molecular mechanisms to cancer therapy. Mol Asp Med. 2015;41:1–115.CrossRefGoogle Scholar
  8. 8.
    Redner RLRE, Faas S, et al. The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion. Blood. 1996;87:882–886.PubMedGoogle Scholar
  9. 9.
    Deng FYZK, Cui WL, Liu D, Ma YQ. Clinicopathological significance of wnt/β-catenin signaling pathway in esophageal squamous cell carcinoma. Int J Clin Exp Pathol. 2015;8:3045–3053.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Qiao F, Yao F, Chen L, et al. Kruppel-like factor 9 was down-regulated in esophageal squamous cell carcinoma and negatively regulated beta-catenin/TCF signaling. Mol Carcinog. 2016;55:280–291.CrossRefGoogle Scholar
  11. 11.
    Li S, Qin X, Guo X, et al. Dickkopf-1 is oncogenic and involved in invasive growth in non small cell lung cancer. PLoS ONE. 2013;8:e84944.CrossRefGoogle Scholar
  12. 12.
    Ge XS, Ma HJ, Zheng XH, et al. HOTAIR, a prognostic factor in esophageal squamous cell carcinoma, inhibits WIF-1 expression and activates Wnt pathway. Cancer Sci. 2013;104:1675–1682.CrossRefGoogle Scholar
  13. 13.
    Golpich M, Amini E, Hemmati F, et al. Glycogen synthase kinase-3 beta (GSK-3beta) signaling: implications for Parkinson’s disease. Pharmacol Res. 2015;97:16–26.CrossRefGoogle Scholar
  14. 14.
    Wu D, Pan W. GSK3: a multifaceted kinase in Wnt signaling. Trends Biochem Sci. 2010;35:161–168.CrossRefGoogle Scholar
  15. 15.
    Yook JI, Li XY, Ota I, et al. A Wnt–Axin2–GSK3beta cascade regulates Snail1 activity in breast cancer cells. Nat Cell Biol. 2006;8:1398–1406.CrossRefGoogle Scholar
  16. 16.
    Huang GL, Zhang W, Ren HY, et al. Oncogenic retinoic acid receptor alpha promotes human colorectal cancer growth through simultaneously regulating p21 transcription and GSK3beta/beta-catenin signaling. Cancer Lett. 2017;388:118–129.CrossRefGoogle Scholar
  17. 17.
    Ren HY, Liu F, Huang GL, et al. Positive feedback loop of IL-1β/Akt/RARα/Akt signaling mediates oncogenic property of RARα in gastric carcinoma. Oncotarget. 2016;8:6718–6729.PubMedCentralGoogle Scholar
  18. 18.
    Huang GL, Shen DY, Cai CF, Zhang QY, Ren HY, Chen QX. β-escin reverses multidrug resistance through inhibition of the GSK3β/β-catenin pathway in cholangiocarcinoma. World J Gastroenterol. 2015;21:1148–1157.CrossRefGoogle Scholar
  19. 19.
    Ghaus S, Neumann H, Muhammad H, Tontini GE, Ishaq S. Diagnosis and surveillance of Barrett’s esophagus: addressing the transatlantic divide. Dig Dis Sci. 2016;61:2185–2193.CrossRefGoogle Scholar
  20. 20.
    Longo KA, Kennell JA, Ochocinska MJ, Ross SE, Wright WS, MacDougald OA. Wnt signaling protects 3T3-L1 preadipocytes from apoptosis through induction of insulin-like growth factors. J Biol Chem. 2002;277:38239–38244.CrossRefGoogle Scholar
  21. 21.
    Huang GL, Luo Q, Rui G, et al. Oncogenic activity of retinoic acid receptor gamma is exhibited through activation of the Akt/NF-kappaB and Wnt/beta-catenin pathways in cholangiocarcinoma. Mol Cell Biol. 2013;33:3416–3425.CrossRefGoogle Scholar
  22. 22.
    Johansson HJ, Sanchez BC, Mundt F, et al. Retinoic acid receptor alpha is associated with tamoxifen resistance in breast cancer. Nat Commun. 2013;4:2175.CrossRefGoogle Scholar
  23. 23.
    Hua S, Kittler R, White KP. Genomic antagonism between retinoic acid and estrogen signaling in breast cancer. Cell. 2009;137:1259–1271.CrossRefGoogle Scholar
  24. 24.
    Yu VZ, Wong VC, Dai W, et al. Nuclear localization of DNAJB6 is associated with survival of patients with esophageal cancer and reduces AKT signaling and proliferation of cancer cells. Gastroenterology. 2015;149:1825–1836.CrossRefGoogle Scholar
  25. 25.
    Molnár JEH, Hohmann J, Molnár P, et al. Reversal of multidrug resistance by natural substances from plants. Curr Top Med Chem. 2010;10:1757–1768.CrossRefGoogle Scholar
  26. 26.
    Zhang S, Cao W, Yue M, et al. Caveolin-1 affects tumor drug resistance in esophageal squamous cell carcinoma by regulating expressions of P-gp and MRP1. Tumour Biol. 2016;37:9189–9196.CrossRefGoogle Scholar
  27. 27.
    Gan SY, Zhong XY, Xie SM, Li SM, Peng H, Luo F. Expression and significance of tumor drug resistance related proteins and catenin in esophageal squamous cell carcinoma. Chin J Cancer. 2009;29:300–305.CrossRefGoogle Scholar
  28. 28.
    Mukai FIK, Sano Y. Alternative splicing isoform of tau protein kinase I/glycogen synthase kinase 3beta. J Neurochem. 2002;81:1073–1083.CrossRefGoogle Scholar
  29. 29.
    Ruel LBM, Heitzler P. Drosophila shaggy kinase and rat glycogen synthase kinase-3 have conserved activities and act downstream of Notch. Nature. 1993;362:557–560.CrossRefGoogle Scholar
  30. 30.
    Asuni AA, Hooper C, Reynolds CH, Lovestone S, Anderton BH, Killick R. GSK3alpha exhibits beta-catenin and tau directed kinase activities that are modulated by Wnt. Eur J Neurosci. 2006;24:3387–3392.CrossRefGoogle Scholar
  31. 31.
    Gupta K, Gulen F, Sun L, et al. GSK3 is a regulator of RAR-mediated differentiation. Leukemia. 2012;26:1277–1285.CrossRefGoogle Scholar
  32. 32.
    Kisoh K, Hayashi H, Itoh T, et al. Involvement of GSK-3beta phosphorylation through PI3-K/Akt in cerebral ischemia-induced neurogenesis in rats. Mol Neurobiol. 2017;54:7917–7927.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Xiao-Mei Mao
    • 1
  • Hua Li
    • 2
  • Xiao-Yun Zhang
    • 3
  • Pan Zhou
    • 1
  • Qi-Rui Fu
    • 1
  • Qian-En Chen
    • 1
  • Jin-Xing Shen
    • 3
  • Yu Liu
    • 3
  • Qing-Xi Chen
    • 1
    Email author
  • Dong-Yan Shen
    • 3
    Email author
  1. 1.Key Lab of the Ministry of Education for Coastal and Wetland Ecosystems, School of Life SciencesXiamen UniversityXiamenChina
  2. 2.Department of GastroenterologyThe First Affiliated Hospital of Xiamen UniversityXiamenChina
  3. 3.Department of BiobankThe First Affiliated Hospital of Xiamen UniversityXiamenChina

Personalised recommendations