Skip to main content
SpringerLink
Log in

FHOD3 promotes carcinogenesis by regulating RhoA/ROCK1/LIMK1 signaling pathway in medulloblastoma

  • Research Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Purpose

Medulloblastoma (MB) is a malignant brain disease in young children. The overall survival of MB patients is disappointing due to absence of effective therapeutics and this could be attributed to the lack of molecular mechanism underlying MB. FHOD3 was an important gene during cardio-genesis and was reported to promote cell migration in cancer. However, its role in MB is not clear to date.

Methods

RT-qPCR and IHC analysis were used to determine expression of FHOD3. Survival curve was drawn by K–M analysis. FHOD3 was knocked down by RNAi technology. The effects of FHOD3 on medulloblastoma cells were determined by CCK-8 assay, colony formation assay, transwell assay and FACs analysis.

Results

FHOD3 expression increased by 1.5 fold in tumor tissues compared to the control and IHC analysis further confirmed strong expression of FHOD3 in medulloblastoma tissues. Then higher FHOD3 expression was associated with shorter survival time in MB patients (13.0 months versus 43.8 months). In medulloblastoma cells such as Daoy and D283med, FHOD3 also displayed abundant expression. When FHOD3 was knocked down, the ability of cell proliferation and colony formation was reduced over greatly. The capability of cell migration and invasion was also inhibited significantly. However, cell apoptotic rate increased significantly reversely. Mechanistically, the phosphorylation level of RhoA, ROCK1, and LIMK1 was decreased when FHOD3 was knocked down but increased reversely when FHOD3 was over-expressed in Daoy cells.

Conclusions

FHOD3 was associated with overall survival time in medulloblastoma patients and was essential to cell proliferation, growth and survival in medulloblastoma and might regulates activation of RhoA/ROCK1/LIMK1 signaling pathway.

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
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Katoh M, Katoh M. Identification and characterization of human FHOD3 gene in silico. Int J Mol Med. 2004;13:615–20.

    CAS  PubMed  Google Scholar 

  2. Taniguchi K, Takeya R, Suetsugu S, Kan-O M, Narusawa M, Shiose A, et al. Mammalian formin fhod3 regulates actin assembly and sarcomere organization in striated muscles. J Biol Chem. 2009;284:29873–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Kan-O M, Takeya R, Abe T, Kitajima N, Nishida M, Tominaga R, et al. MammalianforminFhod3 plays an essential role in cardiogenesis by organizing myofibrillogenesis. Biol Open. 2012;1:889–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Dwyer J, Pluess M, Iskratsch T, Dos Remedios CG, Ehler E. The formin FHOD1 in cardiomyocytes. Ant Rec (Hoboken). 2014;297:1560–70.

    CAS  Google Scholar 

  5. Wooten EC, Hebl VB, Wolf MJ, Greytak SR, Orr NM, Draper I, et al. Formin homology 2 domain containing 3 variants associated with hypertrophic cardiomyopathy. Circ Cardiovasc Genet. 2013;6:10–8.

    CAS  PubMed  Google Scholar 

  6. Zhou Q, Wei SS, Wang H, Wang Q, Li W, Li G, et al. Crucial role of ROCK2-mediated phosphorylation and upregulation of FHOD3 in the pathogenesis of angiotensin II-induced cardiac hypertrophy. Hypertension. 2017;69:1070–83.

    CAS  PubMed  Google Scholar 

  7. Ochoa JP, Sabater-Molina M, Garcia-Pinilla JM, Mogensen J, Restrepo-Cordoba A, Palomino-Doza J, et al. Formin homology 2 domain containing 3 (FHOD3) is a genetic basis for hypertrophic cardiomyopathy. J Am Coll Cardiol. 2018;72:2457–67.

    CAS  PubMed  Google Scholar 

  8. Huang S, Pu T, Wei W, Xu R, Wu Y. Exome sequencing identifies a FHOD3 p.S527del mutation in a Chinese family with hypertrophic cardiomyopathy. J Gene Med. 2019;19:e3146.

    Google Scholar 

  9. French D, Yang W, Cheng C, Raimondi SC, Mullighan CG, Downing JR, et al. Acquired variation outweighs inherited variation in whole genome analysis of methotrexate polyglutamate accumulation in leukemia. Blood. 2009;113:4512–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Paul NR, Allen JL, Chapman A, Morlan-Mairal M, Zindy E, Jacquemet G, et al. α5β1 integrin recycling promotes Arp2/3-independent cancer cell invasion via the formin FHOD3. J Cell Biol. 2015;210:1013–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Hetmanski JH, Zindy E, Schwartz JM, Caswell PT. A MAPK-driven feedback loop suppresses rac activity to promote rhoa-driven cancer cell invasion. PLoS Comput Biol. 2016;12:e1004909.

    PubMed  PubMed Central  Google Scholar 

  12. Chai L, Li J, Lv Z. An integrated analysis of cancer genes in thyroid cancer. Oncol Rep. 2016;35:962–70.

    CAS  PubMed  Google Scholar 

  13. Monzo P, Chong YK, Guetta-Terrier C, Krishnasamy A, Sathe SR, Yim EK, et al. Mechanical confinement triggers glioma linear migration dependent on formin FHOD3. Mol Biol Cell. 2016;27:1246–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Millard NE, De Braganca KC. Medulloblastoma. J Child Neurol. 2016;31:1341–53.

    PubMed  Google Scholar 

  15. Quinlan A, Rizzolo D. Understanding medulloblastoma. JAAPA. 2017;30:30–6.

    PubMed  Google Scholar 

  16. Massimino M, et al. Childhood medulloblastoma. Crit Rev Oncol Hematol. 2016;105:35–51.

    PubMed  Google Scholar 

  17. Massimino M, Biassoni V, Gandola L, Garre ML, Gatta G, Giangaspero F, et al. Childhood medulloblastoma. Crit Rev Oncol Hematol. 2016;105:35–51.

    PubMed  Google Scholar 

  18. Bowers DC, Gargan L, Weprin B, Mulne A, Elterman RD, Munoz L, et al. Impact of site of tumor recurrence upon survival for children with recurrent or progressive medulloblastoma. J Neuro Surg. 2007;107(1 Suppl):5–10.

    Google Scholar 

  19. Kline CN, Joseph NM, Grenert JP, van Ziffle J, Talevich E, Onodera C, et al. Targeted next-generation sequencing of pediatric neuro-oncology patients improves diagnosis, identifies pathogenic germline mutations, and directs targeted therapy. Neuro Oncol. 2017;19:699–709.

    CAS  PubMed  Google Scholar 

  20. Cavalli FMG, Remke M, Rampasek L, Peacock J, Shih DJH, Luu B, et al. Intertumoral heterogeneity within medulloblastoma subgroups. Cancer Cell. 2017;31:737–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantative PCR and the 2-△△CT method. Methods. 2001;25:402–8.

    CAS  PubMed  Google Scholar 

  22. Hu CP, Zhou HY, Liu YL, Huang JB, Liu WY, Zhang Q, et al. ROCK1 promotes migration and invasion of non-small-cell lung cancer cells through the PTEN/PI3K/FAK pathway. Int J Oncol. 2019;55:833–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhou WD, Wang X, Sun XZ, Hu J, Zhang RR, Hong Z. Actein induces apoptosis in leukemia cells through suppressing RhoA/ROCK1 signaling pathway. Int J Oncol. 2017;51:1831–41.

    CAS  PubMed  Google Scholar 

  24. Guo D, Li Y, Chen Y, Zhang D, Wang X, Lu G, et al. DANCR promotes HCC progression and regulates EMT by sponging miR-27a-3p via ROCK1/LIMK1/COFILIN1 pathway. Cell Prolif. 2019;51:e12628.

    Google Scholar 

  25. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD1 antibody in cancer. N Engl J Med. 2012;366:2443–544.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang ZG, Wu ZQ, Liu Y, Han WD. New development in CAR-T cell therapy. J Hematol Oncol. 2017;10:53.

    PubMed  PubMed Central  Google Scholar 

  27. McGranahan N, Swanton C. Clonal heterogeneity and tumor evolution: past, present, and the future. Cell. 2017;168:613–28.

    CAS  PubMed  Google Scholar 

  28. Degllnnocenti A, di Leo N, Ciofani G. Genetic hallmarks and heterogeneity of glioblastoma in the single-cell omics era. Adv Ther (Weinh). 2020. https://doi.org/10.1002/adtp.201900152.

    Article  Google Scholar 

  29. Wang SY, Liechty B, Patel S, et al. Programmed death ligand 1 expression and tumor infiltrating lymphocytes in neurofibromatosis type 1 and 2 associated tumors. J Neuro oncol. 2018;138:183–90.

    CAS  Google Scholar 

  30. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    CAS  PubMed  Google Scholar 

  31. Yeh HW, Lee SS, Chang CY, Lang YD, Jou YS. A new switch for TGFβ in cancer. Cancer Res. 2019;79:3797–805.

    CAS  PubMed  Google Scholar 

  32. Kuhn S, Geyer M. Formins as effector proteins of Rho GTPases. Small GTPases. 2014;5:e29513.

    PubMed  PubMed Central  Google Scholar 

  33. Haga RB, Ridley AJ. Rho GTPases: regulation and roles in cancer cell biology. Small GTPases. 2016;7:207–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Etienne-Manneville S, Hall A. Rho GTPases in cell biology. Nature. 2002;420:629–35.

    CAS  PubMed  Google Scholar 

  35. Heasman SJ, Ridley AJ. Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol. 2008;9:690–701.

    CAS  PubMed  Google Scholar 

  36. Hayes MN, McCarthy K, Jin A, Oliveira ML, Iyer S, Garcia SP, et al. Vangl2/RhoA signaling pathway regulates stem cell self-renewal programs and growth in rhabdomyosarcoma. Cell St Cell. 2018;22:414–27.

    CAS  Google Scholar 

  37. Zhang GY, Yang WH, Chen Z. Upregulated STAT3 and RhoA signaling in colorectal cancer (CRC) regulate the invasion and migration of CRC cells. Eur Rev Med Pharmacol Sci. 2016;20:20208–2037.

    Google Scholar 

  38. Zhang G, Zhu F, Han G, Li Z, Yu Q, Li Z, et al. Silencing of URG11 expression inhibits the proliferation and epithelial-mesenchymal transition in benign prostatic hyperplasia cells via the RhoA/ROCK1 pathway. Mol Med Rep. 2018;18:391–8.

    CAS  PubMed  Google Scholar 

  39. Yin M, Lu Q, Liu X, Wang T, Liu Y, Chen L. Silencing Drp1 inhibits glioma cells proliferation and invasion by RHOA/ROCK1 pathway. Biochem Biophys Res Commun. 2016;478:663–8.

    CAS  PubMed  Google Scholar 

  40. Scott RW, Olson MF. LIM kinases: function, regulation and association with human disease. J Mol Med (Berl). 2007;85:555–68.

    CAS  Google Scholar 

  41. Lee MH, Kundu JK, Chae JI, Shim JH. Targeting ROCK/LIMK/cofilin signaling pathway in cancer. Arch Pharm Res. 2019;42:481–91.

    CAS  PubMed  Google Scholar 

  42. Yu JZ, Li H. The expression of FAT1 is associated with overall survival in children with medulloblastoma. Tumori J. 2017;103:44–52.

    CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the Shanghai Municipal Health and Family Planning Commission (NSFS No. 20164Y0086) and Shanghai Anticancer Association EYAS PROJECT (SACA-CY1C03).

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Children’s Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China

    J. Yu, W. Shi, R. Zhao, W. Shen & H. Li

Authors
  1. J. Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W. Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W. Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H. Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H. Li.

Ethics declarations

Conflict of interests

All authors declare that they have no conflict of interest.

Ethical statement

All human studies have been approved by the appropriate ethics committee and have, therefore, been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Informed consent

All persons gave their informed consent prior to their inclusion in the study.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yu, J., Shi, W., Zhao, R. et al. FHOD3 promotes carcinogenesis by regulating RhoA/ROCK1/LIMK1 signaling pathway in medulloblastoma. Clin Transl Oncol 22, 2312–2323 (2020). https://doi.org/10.1007/s12094-020-02389-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-020-02389-5

Keywords

Search

Navigation