Skip to main content
SpringerLink
Log in

MAGI1 mediates tumor metastasis through c-Myb/miR-520h/MAGI1 signaling pathway in renal cell carcinoma

  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Renal cell carcinoma (RCC) is the third most common urological cancer with highly metastatic potential. MAGI1 plays an important role in stabilization of the adherens junctions and has been confirmed to suppress invasiveness and metastasis in multiple cancers in clinic. However, its expression and anti-metastatic ability in RCC are still unclear. In this study, we demonstrated that MAGI1 was markedly decreased in the RCC and indicated poor survival. Furthermore, we found that MAGI1 suppressed the invasion and migration of human RCC cells. Mechanistic investigations revealed that MAGI1 stabilized the PTEN/MAGI1/β-catenin complex to inhibit β-catenin signaling pathway. Moreover, MAGI1 was targeted by miR-520h which was transcriptionally activated by c-Myb. Collectively, our findings suggested that MAGI1mediated tumor metastasis through c-Myb/miR-520h/MAGI1 signaling pathway in RCC.

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

Similar content being viewed by others

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424

    Article  Google Scholar 

  2. Barata PC, Rini BI (2017) Treatment of renal cell carcinoma: current status and future directions. CA Cancer J Clin 67(6):507–524

    Article  Google Scholar 

  3. Dabestani S, Thorstenson A, Lindblad P, Harmenberg U, Ljungberg B, Lundstam S (2016) Renal cell carcinoma recurrences and metastases in primary non-metastatic patients: a population-based study. World J Urol 34(8):1081–1086

    Article  Google Scholar 

  4. Lalani AA, McGregor BA, Albiges L, Choueiri TK, Motzer R, Powles T et al (2019) Systemic treatment of metastatic clear cell renal cell carcinoma in 2018: current paradigms, use of immunotherapy, and future directions. Eur Urol 75(1):100–110

    Article  Google Scholar 

  5. Hakimi AA, Voss MH, Kuo F, Sanchez A, Liu M, Nixon BG et al (2019) Transcriptomic profiling of the tumor microenvironment reveals distinct subgroups of clear cell renal cell cancer: data from a randomized phase III trial. Cancer Discov 9(4):510–525

    Article  CAS  Google Scholar 

  6. Knights AJ, Funnell AP, Crossley M, Pearson RC (2012) Holding tight: cell junctions and cancer spread. Trends Cancer Res 8:861–869

    Google Scholar 

  7. Friedl P, Mayor R (2017) Tuning collective cell migration by cell-cell junction regulation. Cold Spring Harb Perspect Biol 9(4):a029199

    Article  Google Scholar 

  8. Woodcock SA, Rooney C, Liontos M, Connolly Y, Zoumpourlis V, Whetton AD et al (2009) Src-induced disassembly of adherens junctions requires localized phosphorylation and degradation of the rac activator Tiam1. Mol Cell 33(5):639–653

    Article  CAS  Google Scholar 

  9. Abe JI, Ko KA, Kotla S, Wang Y, Paez-Mayorga J, Shin IJ et al (2019) MAGI1 as a link between endothelial activation and ER stress drives atherosclerosis. JCI Insight 4(7):e125570

    Article  Google Scholar 

  10. Feng X, Jia S, Martin TA, Jiang WG (2014) Regulation and involvement in cancer and pathological conditions of MAGI1, a tight junction protein. Anticancer Res 34(7):3251–3256

    CAS  PubMed  Google Scholar 

  11. Zhang G, Wang Z (2011) MAGI1 inhibits cancer cell migration and invasion of hepatocellular carcinoma via regulating PTEN. Zhong Nan Da Xue Xue Bao Yi Xue Ban 36(5):381–385

    CAS  PubMed  Google Scholar 

  12. Zaric J, Joseph JM, Tercier S, Sengstag T, Ponsonnet L, Delorenzi M et al (2012) Identification of MAGI1 as a tumor-suppressor protein induced by cyclooxygenase-2 inhibitors in colorectal cancer cells. Oncogene 31(1):48–59

    Article  CAS  Google Scholar 

  13. Jia S, Lu J, Qu T, Feng Y, Wang X, Liu C et al (2017) MAGI1 inhibits migration and invasion via blocking MAPK/ERK signaling pathway in gastric cancer. Chin J Cancer Res 29(1):25–35

    Article  Google Scholar 

  14. Kotelevets L, van Hengel J, Bruyneel E, Mareel M, van Roy F, Chastre E (2005) Implication of the MAGI-1b/PTEN signalosome in stabilization of adherens junctions and suppression of invasiveness. FASEB J 19(1):115–117

    Article  CAS  Google Scholar 

  15. Wen JL, Wen XF, Li RB, Jin YC, Wang XL, Zhou L et al (2015) UBE3C promotes growth and metastasis of renal cell carcinoma via activating Wnt/beta-catenin pathway. PLoS ONE 10(2):e0115622

    Article  Google Scholar 

  16. Buttrick GJ, Wakefield JG (2008) PI3-K and GSK-3: Akt-ing together with microtubules. Cell Cycle 7(17):2621–2625

    Article  CAS  Google Scholar 

  17. Wu D, Pan W (2010) GSK3: a multifaceted kinase in Wnt signaling. Trends Biochem Sci 35(3):161–168

    Article  CAS  Google Scholar 

  18. Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M et al (2004) Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 6(10):931–940

    Article  CAS  Google Scholar 

  19. Mittal V (2018) Epithelial mesenchymal transition in tumor metastasis. Annu Rev Pathol 13:395–412

    Article  CAS  Google Scholar 

  20. Choueiri TK, Motzer RJ (2017) Systemic therapy for metastatic renal-cell carcinoma. N Engl J Med 376(4):354–366

    Article  CAS  Google Scholar 

  21. Nguyen MM, Nguyen ML, Caruana G, Bernstein A, Lambert PF, Griep AE (2003) Requirement of PDZ-containing proteins for cell cycle regulation and differentiation in the mouse lens epithelium. Mol Cell Biol 23(24):8970–8981

    Article  CAS  Google Scholar 

  22. Ghimire K, Zaric J, Alday-Parejo B, Seebach J, Bousquenaud M, Stalin J et al (2019) MAGI1 mediates eNOS activation and NO production in endothelial cells in response to fluid shear stress. Cells 8(5):388

    Article  Google Scholar 

  23. Sakurai A, Fukuhara S, Yamagishi A, Sako K, Kamioka Y, Masuda M et al (2006) MAGI-1 is required for Rap1 activation upon cell-cell contact and for enhancement of vascular endothelial cadherin-mediated cell adhesion. Mol Biol Cell 17(2):966–976

    Article  CAS  Google Scholar 

  24. Ma J, Guo X, Zhang J, Wu D, Hu X, Li J et al (2017) PTEN gene induces cell invasion and migration via regulating AKT/GSK-3beta/beta-catenin signaling pathway in human gastric cancer. Dig Dis Sci 62(12):3415–3425

    Article  CAS  Google Scholar 

  25. Lu Z, Ghosh S, Wang Z, Hunter T (2003) Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion. Cancer Cell 4(6):499–515

    Article  CAS  Google Scholar 

  26. Liu H, Yin J, Wang H, Jiang G, Deng M, Zhang G et al (2015) FOXO3a modulates WNT/beta-catenin signaling and suppresses epithelial-to-mesenchymal transition in prostate cancer cells. Cell Signal 27(3):510–518

    Article  CAS  Google Scholar 

  27. Wang Y, Bu F, Royer C, Serres S, Larkin JR, Soto MS et al (2014) ASPP2 controls epithelial plasticity and inhibits metastasis through beta-catenin-dependent regulation of ZEB1. Nat Cell Biol 16(11):1092–1104

    Article  CAS  Google Scholar 

  28. Gurtan AM, Sharp PA (2013) The role of miRNAs in regulating gene expression networks. J Mol Biol 425(19):3582–3600

    Article  CAS  Google Scholar 

  29. Pencheva N, Tavazoie SF (2013) Control of metastatic progression by microRNA regulatory networks. Nat Cell Biol 15(6):546–554

    Article  CAS  Google Scholar 

  30. Liao R, Sun J, Zhang L, Lou G, Chen M, Zhou D et al (2008) MicroRNAs play a role in the development of human hematopoietic stem cells. J Cell Biochem 104(3):805–817

    Article  CAS  Google Scholar 

  31. Zhang J, Liu W, Shen F, Ma X, Liu X, Tian F et al (2018) The activation of microRNA-520h-associated TGF-beta1/c-Myb/Smad7 axis promotes epithelial ovarian cancer progression. Cell Death Dis 9(9):884

    Article  Google Scholar 

  32. Su CM, Wang MY, Hong CC, Chen HA, Su YH, Wu CH et al (2016) miR-520h is crucial for DAPK2 regulation and breast cancer progression. Oncogene 35(9):1134–1142

    Article  CAS  Google Scholar 

  33. Wang F, Xue X, Wei J, An Y, Yao J, Cai H et al (2010) hsa-miR-520h downregulates ABCG2 in pancreatic cancer cells to inhibit migration, invasion, and side populations. Br J Cancer 103(4):567–574

    Article  CAS  Google Scholar 

  34. Ding M, Lu X, Wang C, Zhao Q, Ge J, Xia Q et al (2018) The E2F1-miR-520/372/373-SPOP axis modulates progression of renal carcinoma. Cancer Res 78(24):6771–6784

    Article  CAS  Google Scholar 

  35. Ramsay RG, Gonda TJ (2008) MYB function in normal and cancer cells. Nat Rev Cancer 8(7):523–534

    Article  CAS  Google Scholar 

  36. Li Y, Jin K, van Pelt GW, van Dam H, Yu X, Mesker WE et al (2016) c-Myb enhances breast cancer Invasion and metastasis through the Wnt/beta-Catenin/Axin2 pathway. Cancer Res 76(11):3364–3375

    Article  CAS  Google Scholar 

  37. Chen RX, Xia YH, Xue TC, Ye SL (2010) Transcription factor c-Myb promotes the invasion of hepatocellular carcinoma cells via increasing osteopontin expression. J Exp Clin Cancer Res 29:172

    Article  CAS  Google Scholar 

  38. Lan T, Yuan K, Yan X, Xu L, Liao H, Hao X et al (2019) LncRNA SNHG10 facilitates hepatocarcinogenesis and metastasis by modulating its homolog SCARNA13 via a positive feedback loop. Cancer Res. https://doi.org/10.1158/0008-5472.can-18-4044

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The work was supported by grant from the National Natural Science Foundation of China (Grant No. 21300005131323).

Author information

Authors and Affiliations

  1. Department of Pathology, Qilu Hospital, Shandong University, Jinan, Shandong, China

    Wei Wang & Tingguo Zhang

  2. Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China

    Wei Wang, Shihong Shao & Shasha Hu

  3. Department of Pathology, Qingdao Municipal Hospital, Qingdao, Shandong, China

    Yanhua Yang

  4. Department of Pathology, Qingdao Central Hospital, Qingdao, Shandong, China

    Xinyi Chen

  5. Department of Pathology, The Second Affiliated Hospital of Qingdao University Medical College, Qingdao, Shandong, China

    Xinyi Chen

  6. Department of Pathology, School of Basic Medical Sciences, Shandong University, NO. 44, Wenhuaxi Road, Jinan, Shandong, China

    Tingguo Zhang

Authors
  1. Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yanhua Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xinyi Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shihong Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shasha Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tingguo Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

WW and TZ conceived and designed the experiments; WW, YY and XC performed the experiments; WW, SS and SH analyzed the data; WW and TZ wrote the paper.

Corresponding author

Correspondence to Tingguo Zhang.

Ethics declarations

Conflict of interest

The authors confirm that there is no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 109 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, W., Yang, Y., Chen, X. et al. MAGI1 mediates tumor metastasis through c-Myb/miR-520h/MAGI1 signaling pathway in renal cell carcinoma. Apoptosis 24, 837–848 (2019). https://doi.org/10.1007/s10495-019-01562-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-019-01562-8

Keywords

Search

Navigation