Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Wingless modulates activator protein-1-mediated tumor invasion

Oncogene volume 38, pages 3871–3885 (2019)Cite this article

Subjects

Abstract

Metastasis begins with a subset of local tumor cells acquiring the potential to invade into surrounding tissues, and remains to be a major obstacle for cancer treatments. More than 90% of cancer patients died from tumor metastasis, instead of primary tumor growth. The canonical Wnt/β-catenin pathway plays essential roles in promoting tumor formation, yet its function in regulating tumor metastasis and the underlying mechanisms remain controversial. Here we employed well-established Drosophila tumor models to investigate the regulating mechanism of Wingless (Wg) pathway in tumor invasion. Our results showed that Wg signaling is necessary and sufficient for cell polarity disruption-induced cell migration and molecular changes reminiscent of epithelial-mesenchymal transition (EMT). Moreover, reducing Wg signaling suppressed lgl−/−/RasV12-induced tumor invasion, and cooperation between Arm and RasV12 is sufficient to induce tumor invasion. Mechanistically, we found that cell polarity disruption activates JNK signaling, which in turn upregulate wg expression through transcription factor activator protein-1 (AP-1). We identified a consensus AP-1 binding site located in the 2nd intron of wg, and confirmed that it is essential for AP-1 induced wg transcription both in vitro and in vivo. Lastly, we confirmed that the transcriptional activation of WNT by AP-1 is conserved in human cancer cells. These evidences reveal a positive role of Wnt/β-catenin pathway in tumor invasion, and provide a conserved mechanism that connects JNK and Wnt signaling in regulating tumor progression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30.

    Article  Google Scholar 

  2. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.

    Article  CAS  Google Scholar 

  3. Hunter KW, Crawford NP, Alsarraj J. Mechanisms of metastasis. Breast Cancer Res. 2008;10(Suppl 1):S2.

    Article  Google Scholar 

  4. Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011;147:275–92.

    Article  CAS  Google Scholar 

  5. Clevers H, Nusse R. Wnt/beta-catenin signaling and disease. Cell. 2012;149:1192–205.

    Article  CAS  Google Scholar 

  6. Anastas JN, Moon RT. WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer. 2013;13:11–26.

    Article  CAS  Google Scholar 

  7. MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17:9–26.

    Article  CAS  Google Scholar 

  8. Nusse R. Wnt signaling in disease and in development. Cell Res. 2005;15:28–32.

    Article  CAS  Google Scholar 

  9. Miller JR. The Wnts. Genome Biol. 2002;3:REVIEWS3001.

    PubMed  Google Scholar 

  10. Swarup S, Verheyen EM. Wnt/Wingless signaling in Drosophila. Cold Spring Harb Perspect Biol. 2012;4:a007930.

    Article  Google Scholar 

  11. van Amerongen R, Nusse R. Towards an integrated view of Wnt signaling in development. Development. 2009;136:3205–14.

    Article  Google Scholar 

  12. Cadigan KM, Nusse R. Wnt signaling: a common theme in animal development. Genes & Dev. 1997;11:3286–305.

    Article  CAS  Google Scholar 

  13. Zhang S, Chen C, Wu C, Yang Y, Li W, Xue L. The canonical Wg signaling modulates Bsk-mediated cell death in Drosophila. Cell Death Dis. 2015;6:e1713.

    Article  CAS  Google Scholar 

  14. Zhang S, Guo X, Chen C, Chen Y, Li J, Sun Y, et al. dFoxO promotes Wingless signaling in Drosophila. Sci Rep. 2016;6:22348.

    Article  CAS  Google Scholar 

  15. Liu L, Zhu XD, Wang WQ, Shen Y, Qin Y, Ren ZG, et al. Activation of beta-catenin by hypoxia in hepatocellular carcinoma contributes to enhanced metastatic potential and poor prognosis. Clin Cancer Res. 2010;16:2740–50.

    Article  CAS  Google Scholar 

  16. Zulehner G, Mikula M, Schneller D, van Zijl F, Huber H, Sieghart W, et al. Nuclear beta-catenin induces an early liver progenitor phenotype in hepatocellular carcinoma and promotes tumor recurrence. Am J Pathol. 2010;176:472–81.

    Article  CAS  Google Scholar 

  17. Jung A, Schrauder M, Oswald U, Knoll C, Sellberg P, Palmqvist R, et al. The invasion front of human colorectal adenocarcinomas shows co-localization of nuclear beta-catenin, cyclin D1, and p16INK4A and is a region of low proliferation. Am J Pathol. 2001;159:1613–7.

    Article  CAS  Google Scholar 

  18. Zi X, Guo Y, Simoneau AR, Hope C, Xie J, Holcombe RF, et al. Expression of Frzb/secreted Frizzled-related protein 3, a secreted Wnt antagonist, in human androgen-independent prostate cancer PC-3 cells suppresses tumor growth and cellular invasiveness. Cancer Res. 2005;65:9762–70.

    Article  CAS  Google Scholar 

  19. Fu L, Zhang C, Zhang LY, Dong SS, Lu LH, Chen J, et al. Wnt2 secreted by tumour fibroblasts promotes tumour progression in oesophageal cancer by activation of the Wnt/beta-catenin signalling pathway. Gut. 2011;60:1635–43.

    Article  CAS  Google Scholar 

  20. Bachmann IM, Straume O, Puntervoll HE, Kalvenes MB, Akslen LA. Importance of P-cadherin, beta-catenin, and Wnt5a/frizzled for progression of melanocytic tumors and prognosis in cutaneous melanoma. Clin Cancer Res. 2005;11(24 Pt 1):8606–14.

    Article  CAS  Google Scholar 

  21. Chien AJ, Moore EC, Lonsdorf AS, Kulikauskas RM, Rothberg BG, Berger AJ, et al. Activated Wnt/beta-catenin signaling in melanoma is associated with decreased proliferation in patient tumors and a murine melanoma model. Proc Natl Acad Sci USA. 2009;106:1193–8.

    Article  CAS  Google Scholar 

  22. Arozarena I, Bischof H, Gilby D, Belloni B, Dummer R, Wellbrock C. In melanoma, beta-catenin is a suppressor of invasion. Oncogene. 2011;30:4531–43.

    Article  CAS  Google Scholar 

  23. Ulivieri A, Lavra L, Dominici R, Giacomelli L, Brunetti E, Sciacca L, et al. Frizzled-1 is down-regulated in follicular thyroid tumours and modulates growth and invasiveness. J Pathol. 2008;215:87–96.

    Article  CAS  Google Scholar 

  24. Qiang YW, Walsh K, Yao L, Kedei N, Blumberg PM, Rubin JS, et al. Wnts induce migration and invasion of myeloma plasma cells. Blood. 2005;106:1786–93.

    Article  CAS  Google Scholar 

  25. Rubin GM, Lewis EB. A brief history of Drosophila’s contributions to genome research. Science. 2000;287:2216–8.

    Article  CAS  Google Scholar 

  26. Gonzalez C. Drosophila melanogaster: a model and a tool to investigate malignancy and identify new therapeutics. Nat Rev Cancer. 2013;13:172–83.

    Article  CAS  Google Scholar 

  27. Pagliarini RA, Xu T. A genetic screen in Drosophila for metastatic behavior. Science. 2003;302:1227–31.

    Article  CAS  Google Scholar 

  28. Brumby AM, Richardson HE. scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila. EMBO J. 2003;22:5769–79.

    Article  CAS  Google Scholar 

  29. Vidal M, Larson DE, Cagan RL. Csk-deficient boundary cells are eliminated from normal Drosophila epithelia by exclusion, migration, and apoptosis. Dev Cell. 2006;10:33–44.

    Article  CAS  Google Scholar 

  30. Cordero JB, Macagno JP, Stefanatos RK, Strathdee KE, Cagan RL, Vidal M. Oncogenic Ras diverts a host TNF tumor suppressor activity into tumor promoter. Dev Cell. 2010;18:999–1011.

    Article  CAS  Google Scholar 

  31. Ma X, Shao Y, Zheng H, Li M, Li W, Xue L. Src42A modulates tumor invasion and cell death via Ben/dUev1a-mediated JNK activation in Drosophila. Cell Death Dis. 2013;4:e864.

    Article  CAS  Google Scholar 

  32. Ma X, Li W, Yu H, Yang Y, Li M, Xue L, et al. Bendless modulates JNK-mediated cell death and migration in Drosophila. Cell Death Differ. 2014;21:407–15.

    Article  CAS  Google Scholar 

  33. Jung HY, Fattet L, Yang J. Molecular pathways: linking tumor microenvironment to epithelial-mesenchymal transition in metastasis. Clin Cancer Res. 2015;21:962–8.

    Article  CAS  Google Scholar 

  34. Bilder D. Epithelial polarity and proliferation control: links from the Drosophila neoplastic tumor suppressors. Genes Dev. 2004;18:1909–25.

    Article  CAS  Google Scholar 

  35. Zhao M, Szafranski P, Hall CA, Goode S. Basolateral junctions utilize warts signaling to control epithelial-mesenchymal transition and proliferation crucial for migration and invasion of Drosophila ovarian epithelial cells. Genetics. 2008;178:1947–71.

    Article  CAS  Google Scholar 

  36. Yamben IF, Rachel RA, Shatadal S, Copeland NG, Jenkins NA, Warming S, et al. Scrib is required for epithelial cell identity and prevents epithelial to mesenchymal transition in the mouse. Dev Biol. 2013;384:41–52.

    Article  CAS  Google Scholar 

  37. Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest. 2009;119:1429–37.

    Article  CAS  Google Scholar 

  38. Morin X, Daneman R, Zavortink M, Chia W. A protein trap strategy to detect GFP-tagged proteins expressed from their endogenous loci in Drosophila. Proc Natl Acad Sci USA. 2001;98:15050–5.

    Article  CAS  Google Scholar 

  39. Pastor-Pareja JC, Xu T. Shaping cells and organs in Drosophila by opposing roles of fat body-secreted Collagen IV and perlecan. Dev Cell. 2011;21:245–56.

    Article  CAS  Google Scholar 

  40. Nieto MA. The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol. 2002;3:155–66.

    Article  CAS  Google Scholar 

  41. Yook JI, Li XY, Ota I, Fearon ER, Weiss SJ. Wnt-dependent regulation of the E-cadherin repressor snail. J Biol Chem. 2005;280:11740–8.

    Article  CAS  Google Scholar 

  42. Igaki T, Pagliarini RA, Xu T. Loss of cell polarity drives tumor growth and invasion through JNK activation in Drosophila. Curr Biol. 2006;16:1139–46.

    Article  CAS  Google Scholar 

  43. Uhlirova M, Bohmann D. JNK- and Fos-regulated Mmp1 expression cooperates with Ras to induce invasive tumors in Drosophila. EMBO J. 2006;25:5294–304.

    Article  CAS  Google Scholar 

  44. Ma X, Chen Y, Zhang S, Xu W, Shao Y, Yang Y, et al. Rho1-Wnd signaling regulates loss-of-cell polarity-induced cell invasion in Drosophila. Oncogene. 2016;35:846–55.

    Article  CAS  Google Scholar 

  45. Zecca M, Basler K, Struhl G. Direct and long-range action of a wingless morphogen gradient. Cell. 1996;87:833–44.

    Article  CAS  Google Scholar 

  46. Neumann CJ, Cohen SM. Long-range action of Wingless organizes the dorsal-ventral axis of the Drosophila wing. Development. 1997;124:871–80.

    CAS  PubMed  Google Scholar 

  47. Gerlitz O, Basler K. Wingful, an extracellular feedback inhibitor of Wingless. Genes Dev. 2002;16:1055–9.

    Article  CAS  Google Scholar 

  48. Eferl R, Wagner EF. AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer. 2003;3:859–68.

    Article  CAS  Google Scholar 

  49. Weston CR, Davis RJ. The JNK signal transduction pathway. Curr Opin Cell Biol. 2007;19:142–9.

    Article  CAS  Google Scholar 

  50. Rallis A, Moore C, Ng J. Signal strength and signal duration define two distinct aspects of JNK-regulated axon stability. Dev Biol. 2010;339:65–77.

    Article  CAS  Google Scholar 

  51. Ma X, Wang H, Ji J, Xu W, Sun Y, Li W, et al. Hippo signaling promotes JNK-dependent cell migration. Proc Natl Acad Sci USA. 2017;114:1934–9.

    Article  CAS  Google Scholar 

  52. Agnes F, Suzanne M, Noselli S. The Drosophila JNK pathway controls the morphogenesis of imaginal discs during metamorphosis. Development. 1999;126:5453–62.

    CAS  PubMed  Google Scholar 

  53. Wang A, Wang J, Ren H, Yang F, Sun L, Diao K, et al. TRAF4 participates in Wnt/beta-catenin signaling in breast cancer by upregulating beta-catenin and mediating its translocation to the nucleus. Mol Cell Biochem. 2014;395:211–9.

    Article  CAS  Google Scholar 

  54. Yang J, Wei D, Wang W, Shen B, Xu S, Cao Y. TRAF4 enhances oral squamous cell carcinoma cell growth, invasion and migration by Wnt-beta-catenin signaling pathway. Int J Clin Exp Pathol. 2015;8:11837–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Ma X, Yang L, Yang Y, Li M, Li W, Xue L. dUev1a modulates TNF-JNK mediated tumor progression and cell death in Drosophila. Dev Biol. 2013;380:211–21.

    Article  CAS  Google Scholar 

  56. Wang X, Wang Z, Chen Y, Huang X, Hu Y, Zhang R, et al. FoxO mediates APP-induced AICD-dependent cell death. Cell Death Dis. 2014;5:e1233.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Bloomington Drosophila Stock Center, Vienna Drosophila RNAi Center, Fly Stocks of National Institute of Genetics, the Core Facility of Drosophila Resource and Technology at SIBCB of CAS, Developmental Studies Hybridoma Bank, Dr. Jose´ Carlos Pastor-Pareja and Dr. Haiyun Song for fly stocks and antibodies. We thank Drs. Zhihua Liu, Ru Zhang, Fan Zhang and Jian Fei for cell lines and plasmids. We thank Dr. Mark Peifer and other lab members for discussion and critical comments. This work is founded by National Natural Science Foundation of China (31571516, 31701278 and 31771595), and Shanghai Committee of Science and Technology (18430711600, 18140900400, 09DZ2260100).

Author contributions

Shiping Zhang, Xiaowei Guo and Lei Xue conceived the study. Shiping Zhang, Xiaowei Guo, Honggui Wu, Ying Sun, Xianjue Ma, Jikai Li, Chenxi Wu and Qiwen Li performed all the experiments. Shiping Zhang, Xiaowei Guo, Cizhong Jiang, Wenzhe Li, Margaret S. Ho, Zhongwei Lv and Lei Xue analyzed the data. Ying Sun and Qian Xu helped design and analyze the statistics. Shiping Zhang, Xiaowei Guo and Lei Xue wrote the manuscript, and all authors approved the final version.

Author information

Author notes

  1. These authors contributed equally: Shiping Zhang, Xiaowei Guo

Authors and Affiliations

  1. Institute of Intervention Vessel, Shanghai 10th People’s Hospital, Shanghai Key Laboratory of Signaling and Diseases Research, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai, 200092, China

    Shiping Zhang, Xiaowei Guo, Honggui Wu, Ying Sun, Xianjue Ma, Jikai Li, Chenxi Wu, Qiwen Li, Cizhong Jiang, Wenzhe Li, Zhongwei Lv & Lei Xue

  2. School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China

    Shiping Zhang & Margaret S. Ho

  3. Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT, 06519, USA

    Xianjue Ma

  4. Institute of Integrated Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, 1 Qiu Yang Road, Fuzhou, 350122, China

    Qian Xu

  5. College of Traditional Chinese Medicine, North China University of Science and Technology, 21 Bohai Road, Tangshan, 063210, China

    Chenxi Wu

  6. Center of Intervention Radiology, Zhuhai People’s Hospital, Zhuhai, 519000, China

    Lei Xue

Authors
  1. Shiping Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaowei Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Honggui Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ying Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xianjue Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jikai Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qian Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chenxi Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Qiwen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Cizhong Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Wenzhe Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Margaret S. Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Zhongwei Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Lei Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lei Xue.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, S., Guo, X., Wu, H. et al. Wingless modulates activator protein-1-mediated tumor invasion. Oncogene 38, 3871–3885 (2019). https://doi.org/10.1038/s41388-018-0629-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-018-0629-x

This article is cited by

Search

Advanced search

Quick links