Log in

Upregulation of ROCK2 in gastric cancer cell promotes tumor cell proliferation, metastasis and invasion

  • Original Article
  • Published:
Clinical and Experimental Medicine Aims and scope Submit manuscript

Abstract

Rho-associated coiled-coil-containing protein kinase 2 (ROCK2) has been known as an effector for the small GTPase Rho and plays an important role in tumor progression and metastasis. However, the effect of ROCK2 in gastric cancer (GC) has not been identified. This study showed that ROCK2 expression significantly increased in clinical GC tissues compared with adjacent non-cancer tissues. Immunohistochemistrical analysis showed that high expression of ROCK2 was correlated with tumor grade, tumor–node–metastasis stage, infiltration depth, lymph node invasion and Ki-67, and predicted poor prognosis in 135 gastric cancer specimens. In addition, we found that upregulated ROCK2 promoted proliferation, metastasis and invasion of GC cells, while ROCK2 knockdown led to the opposite results in vitro by Cell Counting Kit-8 (CCK-8) assay, colony formation assays, flow cytometric analysis and trans-well assays. Our findings supported that ROCK2 was a significant protein in the progress of GC and would provide a novel promising therapeutic strategy against human GC.

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

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Hironaka S, Sugimoto N, Yamaguchi K, Moriwaki T, Komatsu Y, Nishina T, et al. S-1 plus leucovorin versus S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer: a randomised, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17(1):99–108. doi:10.1016/S1470-2045(15)00410-6.

    Article  CAS  PubMed  Google Scholar 

  2. Lee YC, Chiang TH, Chou CK, Tu YK, Liao WC, Wu MS, et al. Association between helicobacter pylori eradication and gastric cancer incidence: a systematic review and meta-analysis. Gastroenterology. 2016;. doi:10.1053/j.gastro.2016.01.028.

    Google Scholar 

  3. Wang L, Yin J, Wang X, Shao M, Duan F, Wu W, et al. C-Type lectin-Like receptor 2 suppresses AKT signaling and invasive activities of gastric cancer cells by blocking expression of phosphoinositide 3-Kinase subunits. Gastroenterology. 2016;. doi:10.1053/j.gastro.2016.01.034.

    Google Scholar 

  4. Fujitani K, Yang HK, Mizusawa J, Kim YW, Terashima M, Han SU, et al. Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor (REGATTA): a phase 3, randomised controlled trial. Lancet Oncol. 2016;17(3):309–18. doi:10.1016/S1470-2045(15)00553-7.

    Article  CAS  PubMed  Google Scholar 

  5. Van Cutsem E, Ducreux M. Colorectal and gastric cancer in 2015: the development of new agents and molecular classifications. Nat Rev Clin Oncol. 2016;13(2):69–70. doi:10.1038/nrclinonc.2015.217.

    Article  PubMed  Google Scholar 

  6. Kalaji R, Wheeler AP, Erasmus JC, Lee SY, Endres RG, Cramer LP, et al. ROCK1 and ROCK2 regulate epithelial polarisation and geometric cell shape. Biol Cell. 2012;104(8):435–51. doi:10.1111/boc.201100093.

    Article  CAS  PubMed  Google Scholar 

  7. Goetsch KP, Snyman C, Myburgh KH, Niesler CU. ROCK-2 is associated with focal adhesion maturation during myoblast migration. J Cell Biochem. 2014;115(7):1299–307. doi:10.1002/jcb.24784.

    Article  CAS  PubMed  Google Scholar 

  8. Julian L, Olson MF. Rho-associated coiled-coil containing kinases (ROCK): structure, regulation, and functions. Small GTPases. 2014;5:e29846. doi:10.4161/sgtp.29846.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Vigil D, Kim TY, Plachco A, Garton AJ, Castaldo L, Pachter JA, et al. ROCK1 and ROCK2 are required for non-small cell lung cancer anchorage-independent growth and invasion. Cancer Res. 2012;72(20):5338–47. doi:10.1158/0008-5472.CAN-11-2373.

    Article  CAS  PubMed  Google Scholar 

  10. Wong CC, Wong CM, Tung EK, Man K, Ng IO. Rho-kinase 2 is frequently overexpressed in hepatocellular carcinoma and involved in tumor invasion. Hepatology. 2009;49(5):1583–94. doi:10.1002/hep.22836.

    Article  CAS  PubMed  Google Scholar 

  11. Qiu Y, Yuan R, Zhang S, Chen L, Huang D, Hao H, et al. Rock2 stabilizes beta-catenin to promote tumor invasion and metastasis in colorectal cancer. Biochem Biophys Res Commun. 2015;467(4):629–37. doi:10.1016/j.bbrc.2015.10.103.

    Article  CAS  PubMed  Google Scholar 

  12. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics. CA Cancer J Clin. 2014;64(1):9–29. doi:10.3322/caac.21208.

    Article  PubMed  Google Scholar 

  13. Zhang J, He X, Ma Y, Liu Y, Shi H, Guo W, et al. Overexpression of ROCK1 and ROCK2 inhibits human laryngeal squamous cell carcinoma. Int J Clin Exp Pathol. 2015;8(1):244–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Wan C, Gong C, Zhang H, Hua L, Li X, Chen X, et al. beta2-adrenergic receptor signaling promotes pancreatic ductal adenocarcinoma (PDAC) progression through facilitating PCBP2-dependent c-myc expression. Cancer Lett. 2016;373(1):67–76. doi:10.1016/j.canlet.2016.01.026.

    Article  CAS  PubMed  Google Scholar 

  15. Wang J, Yu JC, Kang WM, Ma ZQ. Treatment strategy for early gastric cancer. Surg Oncol. 2012;21(2):119–23. doi:10.1016/j.suronc.2010.12.004.

    Article  CAS  PubMed  Google Scholar 

  16. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. doi:10.3322/caac.20107.

    Article  PubMed  Google Scholar 

  17. Cao Y, DePinho RA, Ernst M, Vousden K. Cancer research: past, present and future. Nat Rev Cancer. 2011;11(10):749–54. doi:10.1038/nrc3138.

    Article  CAS  PubMed  Google Scholar 

  18. Zhang C, Zhang S, Zhang Z, He J, Xu Y, Liu S. ROCK has a crucial role in regulating prostate tumor growth through interaction with c-Myc. Oncogene. 2014;33(49):5582–91. doi:10.1038/onc.2013.505.

    Article  CAS  PubMed  Google Scholar 

  19. Rossman KL, Der CJ, Sondek J. GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nat Rev Mol Cell Biol. 2005;6(2):167–80. doi:10.1038/nrm1587.

    Article  CAS  PubMed  Google Scholar 

  20. Patel RA, Forinash KD, Pireddu R, Sun Y, Sun N, Martin MP, et al. RKI-1447 is a potent inhibitor of the Rho-associated ROCK kinases with anti-invasive and antitumor activities in breast cancer. Cancer Res. 2012;72(19):5025–34. doi:10.1158/0008-5472.CAN-12-0954.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Oellers P, Schroer U, Senner V, Paulus W, Thanos S. ROCKs are expressed in brain tumors and are required for glioma-cell migration on myelinated axons. Glia. 2009;57(5):499–509. doi:10.1002/glia.20777.

    Article  PubMed  Google Scholar 

  22. Lochhead PA, Wickman G, Mezna M, Olson MF. Activating ROCK1 somatic mutations in human cancer. Oncogene. 2010;29(17):2591–8. doi:10.1038/onc.2010.3.

    Article  CAS  PubMed  Google Scholar 

  23. Liu X, Choy E, Hornicek FJ, Yang S, Yang C, Harmon D, et al. ROCK1 as a potential therapeutic target in osteosarcoma. J Orthop Res. 2011;29(8):1259-66. doi:10.1002/jor.21403

    Article  CAS  Google Scholar 

  24. Montalvo J, Spencer C, Hackathorn A, Masterjohn K, Perkins A, Doty C, et al. ROCK1 & 2 perform overlap** and unique roles in angiogenesis and angiosarcoma tumor progression. Curr Mol Med. 2013;13(1):205–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by Nantong University innovation project (No.YKC15077, No.YKC15076); the National Natural Science Foundation of China (No. 81541052); the Science and Technology Project Foundation of Nantong City (No. MS22015092, No. BK2014084, No. MS22015005); the Medical Scientific Research Projects of Jiangsu Provincial Bureau of Health (No. 201455); Six Talent Peaks Project in Jiangsu Province; and Health Bureau Youth Science Foundation of Nantong Grant (No. WQ2015056).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Bojun Bao or Hua Huang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Manhua Li and **g Ke have contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, M., Ke, J., Wang, Q. et al. Upregulation of ROCK2 in gastric cancer cell promotes tumor cell proliferation, metastasis and invasion. Clin Exp Med 17, 519–529 (2017). https://doi.org/10.1007/s10238-016-0444-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10238-016-0444-z

Keywords

Navigation