Skip to main content
SpringerLink
Log in

Notch4 promotes gastric cancer growth through activation of Wnt1/β-catenin signaling

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Gastric cancer (GC) is one of the most common cancers and lethal malignancies in the world. Discovering novel biomarkers that correlate with GC may provide opportunities to reduce the severity of GC. As one of Notch receptor family members in mammals, Notch4 plays an important role in carcinogenesis of several tumors. However, the precise function and mechanism of Notch4 in GC remain undefined. To address this question, we investigated whether Notch4 could be involved in GC progression. We found that Notch4 was activated by overexpressing exogenous intracellular domain of Notch4 (ICN4), and Notch4 activation promoted GC growth in vitro and in vivo, while Notch4 inhibition using ICN4 siRNA had opposite effects. In addition, Notch4 activation induced expression and activation of Wnt1, β-catenin and downstream target genes, c-Myc and cyclin D1, in GC cells, while Notch4 inhibition had opposite effects. Moreover, β-catenin depletion by siRNA attenuated cell proliferation induced by Notch4 activation. Therefore, our results revealed that Notch4 activates Wnt1/β-catenin signaling to regulate GC growth.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90

    Article  PubMed  Google Scholar 

  2. Karimi P, Islami F, Anandasabapathy S, Freedman ND, Kamangar F (2014) Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention. Cancer Epidemiol Biomarkers Prev 23(5):700–713

    Article  PubMed  Google Scholar 

  3. Sehdev A, Catenacci DV (2013) Gastroesophageal cancer: focus on epidemiology, classification, and staging. Discov Med 16(87):103–111

    PubMed  Google Scholar 

  4. Pancewicz J, Nicot C (2011) Current views on the role of Notch signaling and the pathogenesis of human leukemia. BMC Cancer 11:502

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Nagase H, Nakayama K (2013) γ-Secretase-regulated signaling typified by Notch signaling in the immune system. Curr Stem Cell Res Ther 8(5):341–356

    Article  CAS  PubMed  Google Scholar 

  6. Yan M (2011) Therapeutic promise and challenges of targeting DLL4/NOTCH1. Vasc Cell 3:17

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Klusza S, Deng WM (2011) At the crossroads of differentiation and proliferation: precise control of cell-cycle changes by multiple signaling pathways in Drosophila follicle cells. BioEssays 33(2):124–134

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Ntziachristos P, Lim JS, Sage J, Aifantis I (2014) From fly wings to targeted cancer therapies: a centennial for notch signaling. Cancer Cell 25(3):318–334

    Article  CAS  PubMed  Google Scholar 

  9. Sasnauskienė A, Jonušienė V, Krikštaponienė A, Butkytė S, Dabkevičienė D, Kanopienė D, Kazbarienė B, Didžiapetrienė J (2014) NOTCH1, NOTCH3, NOTCH4, and JAG2 protein levels in human endometrial cancer. Medicina (Kaunas) 50(1):14–18

    Article  Google Scholar 

  10. Nagamatsu I, Onishi H, Matsushita S, Kubo M, Kai M, Imaizumi A, Nakano K, Hattori M, Oda Y, Tanaka M, Katano M (2014) NOTCH4 is a potential therapeutic target for triple-negative breast cancer. Anticancer Res 34(1):69–80

    CAS  PubMed  Google Scholar 

  11. Hardy KM, Kirschmann DA, Seftor EA, Margaryan NV, Postovit LM, Strizzi L, Hendrix MJ (2010) Regulation of the embryonic morphogen Nodal by Notch4 facilitates manifestation of the aggressive melanoma phenotype. Cancer Res 70(24):10340–10350

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Hidaka Y, Mitomi H, Saito T, Takahashi M, Lee SY, Matsumoto K, Yao T, Watanabe S (2013) Alteration in the Wnt/β-catenin signaling pathway in gastric neoplasias of fundic gland (chief cell predominant) type. Hum Pathol 44(11):2438–2448

    Article  CAS  PubMed  Google Scholar 

  13. Ju X, Ishikawa TO, Naka K, Ito K, Ito Y, Oshima M (2014) Context-dependent activation of Wnt signaling by tumor suppressor RUNX3 in gastric cancer cells. Cancer Sci 105(4):418–424

    Article  CAS  PubMed  Google Scholar 

  14. Chigita S, Sugiura T, Abe M, Kobayashi Y, Shimoda M, Onoda M, Shirasuna K (2012) CD82 inhibits canonical Wnt signalling by controlling the cellular distribution of β-catenin in carcinoma cells. Int J Oncol 41(6):2021–2028

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Koehler A, Schlupf J, Schneider M, Kraft B, Winter C, Kashef J (2013) Loss of Xenopus cadherin-11 leads to increased Wnt/β-catenin signaling and up-regulation of target genes c-myc and cyclin D1 in neural crest. Dev Biol 383(1):132–145

    Article  CAS  PubMed  Google Scholar 

  16. Huang J, Xiao D, Li G, Ma J, Chen P, Yuan W, Hou F, Ge J, Zhong M, Tang Y, Xia X, Chen Z (2014) EphA2 promotes epithelial-mesenchymal transition through the Wnt/β-catenin pathway in gastric cancer cells. Oncogene 33(21):2737–2747

    Article  CAS  PubMed  Google Scholar 

  17. Sun Q, Wang R, Luo J, Wang P, Xiong S, Liu M, Cheng B (2014) Notch1 promotes hepatitis B virus X protein-induced hepatocarcinogenesis via Wnt/β-catenin pathway. Int J Oncol 45(4):1638–1648

    CAS  PubMed  Google Scholar 

  18. Gu B, Watanabe K, Sun P, Fallahi M, Dai X (2013) Chromatin effector Pygo2 mediates Wnt-notch crosstalk to suppress luminal/alveolar potential of mammary stem and basal cells. Cell Stem Cell 13(1):48–61

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Li H, Mo J, Jia G, Liu C, Luan Z, Guan Y (2013) Activation of Wnt signaling inhibits the pro-apoptotic role of Notch in gastric cancer cells. Mol Med Rep 7(6):1751–1756

    CAS  PubMed  Google Scholar 

  20. Ding LC, She L, Zheng DL, Huang QL, Wang JF, Zheng FF, Lu YG (2010) Notch-4 contributes to the metastasis of salivary adenoid cystic carcinoma. Oncol Rep 24(2):363–368

    CAS  PubMed  Google Scholar 

  21. Yao W, Li K, Zheng S, Xiao X, Ma Y, Zhai X (2013) Knockdown of β-catenin expression inhibits neuroblastoma cell growth in vitro and in vivo. J Pediatr Surg 48(12):2466–2473

    Article  PubMed  Google Scholar 

  22. Song P, Zheng JX, Liu JZ, Xu J, Wu LY, Liu C, Zhu Q, Wang Y (2014) Effect of the Wnt1/β-catenin signalling pathway on human embryonic pulmonary fibroblasts. Mol Med Rep 10(2):1030–1036

    CAS  PubMed  Google Scholar 

  23. Chung HW, Lim JB (2014) Role of the tumor microenvironment in the pathogenesis of gastric carcinoma. World J Gastroenterol 20(7):1667–1680

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Yang W, Raufi A (1846) Klempner SJ (2014) Targeted therapy for gastric cancer: Molecular pathways and ongoing investigations. Biochim Biophys Acta 1:232–237

    Google Scholar 

  25. Lobry C, Oh P, Mansour MR, Look AT, Aifantis I (2014) Notch signaling: switching an oncogene to a tumor suppressor. Blood 123(16):2451–2459

    Article  CAS  PubMed  Google Scholar 

  26. Wu WK, Cho CH, Lee CW, Fan D, Wu K, Yu J, Sung JJ (2010) Dysregulation of cellular signaling in gastric cancer. Cancer Lett 295(2):144–153

    Article  CAS  PubMed  Google Scholar 

  27. Soutto M, Peng D, Katsha A, Chen Z, Piazuelo MB, Washington MK, Belkhiri A, Correa P, El-Rifai W (2014) Activation of β-catenin signalling by TFF1 loss promotes cell proliferation and gastric tumorigenesis. Gut pii. doi:10.1136/gutjnl-2014-307191

    Google Scholar 

  28. Casás-Selves M, Kim J, Zhang Z, Helfrich BA, Gao D, Porter CC, Scarborough HA, Bunn PA Jr, Chan DC, Tan AC, DeGregori J (2012) Tankyrase and the canonical Wnt pathway protect lung cancer cells from EGFR inhibition. Cancer Res 72(16):4154–4164

    Article  PubMed Central  PubMed  Google Scholar 

  29. Wang A, Wang J, Ren H, Yang F, Sun L, Diao K, Zhao Z, Song M, Cui Z, Wang E, Wei M, Mi X (2014) TRAF4 participates in Wnt/β-catenin signaling in breast cancer by upregulating β-catenin and mediating its translocation to the nucleus. Mol Cell Biochem 395(1–2):211–219

    Article  CAS  PubMed  Google Scholar 

  30. Niehrs C (2012) The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol 13(12):767–779

    Article  CAS  PubMed  Google Scholar 

  31. Baryawno N, Sveinbjörnsson B, Eksborg S, Chen CS, Kogner P, Johnsen JI (2010) Small-molecule inhibitors of phosphatidylinositol 3-kinase/Akt signaling inhibit Wnt/beta-catenin pathway cross-talk and suppress medulloblastoma growth. Cancer Res 70(1):266–276

    Article  CAS  PubMed  Google Scholar 

  32. Naylor RW, Jones EA (2009) Notch activates Wnt-4 signalling to control medio-lateral patterning of the pronephros. Development 136(21):3585–3595

    Article  CAS  PubMed  Google Scholar 

  33. Bhatt T, Rizvi A, Batta SP, Kataria S, Jamora C (2013) Signaling and mechanical roles of E-cadherin. Cell Commun Adhes 20(6):189–199

    Article  CAS  PubMed  Google Scholar 

  34. Cong N, Du P, Zhang A, Shen F, Su J, Pu P, Wang T, Zjang J, Kang C, Zhang Q (2013) Downregulated microRNA-200a promotes EMT and tumor growth through the wnt/β-catenin pathway by targeting the E-cadherin repressors ZEB1/ZEB2 in gastric adenocarcinoma. Oncol Rep 29(4):1579–1587

    CAS  PubMed  Google Scholar 

  35. Zeljko M, Pecina-Slaus N, Martic TN, Kusec V, Beros V, Tomas D (2011) Molecular alterations of E-cadherin and beta-catenin in brain metastases. Front Biosci (Elite Ed) 3:616–624

    Article  Google Scholar 

  36. Mao J, Fan S, Ma W, Fan P, Wang B, Zhang J, Wang H, Tang B, Zhang Q, Yu X, Wang L, Song B, Li L (2014) Roles of Wnt/β-catenin signaling in the gastric cancer stem cells proliferation and salinomycin treatment. Cell Death Dis 5:e1039

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Qiu HB, Zhang LY, Ren C, Zeng ZL, Wu WJ, Luo HY, Zhou ZW, Xu RH (2013) Targeting CDH17 suppresses tumor progression in gastric cancer by downregulating Wnt/β-catenin signaling. PLoS ONE 8(3):e56959

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from Zhejiang Provincial Natural Science Foundation (nos. LY14H160036 and Q15H160016), Science and Technology Plans of Taizhou City (no. 1301KY39), Science and Technology Plans of Jiaojiang District of Taizhou City (no. 132061), and National Innovation and Entrepreneurship Training Project for University Students (no. 201410350020).

Author information

Authors and Affiliations

  1. Institute of Tumor, School of Medicine, Taizhou University, Taizhou, Zhejiang Province, People’s Republic of China

    Cuijuan Qian, Fuqiang Liu, Yong Liang & Jun Yao

  2. Department of Gastroenterology, Taizhou Municipal Hospital, Taizhou, Zhejiang Province, People’s Republic of China

    Bei Ye & Xin Zhang

Authors
  1. Cuijuan Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fuqiang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bei Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yong Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jun Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yong Liang or Jun Yao.

Additional information

Cuijuan Qian and Fuqiang Liu contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qian, C., Liu, F., Ye, B. et al. Notch4 promotes gastric cancer growth through activation of Wnt1/β-catenin signaling. Mol Cell Biochem 401, 165–174 (2015). https://doi.org/10.1007/s11010-014-2304-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-014-2304-z

Keywords

Search

Navigation