Skip to main content

Advertisement

SpringerLink
Log in

MiR-126 suppresses colon cancer cell proliferation and invasion via inhibiting RhoA/ROCK signaling pathway

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

Abstract

Recent data strongly suggests the profound role of miRNAs in cancer progression. Here, we showed miR-126 expression was much lower in HCT116, SW620 and HT-29 colon cancer cells with highly metastatic potential and miR-126 downregulation was more frequent in colorectal cancers with metastasis. Restored miR-126 expression inhibited HT-29 cell growth, cell-cycle progression and invasion. Mechanically, microarray results combined with bioinformatic and experimental analysis demonstrated miR-126 exerted cancer suppressor role via inhibiting RhoA/ROCK signaling pathway. These results suggest miR-126 function as a potential tumor suppressor in colon cancer progression and miR-126/RhoA/ROCK may be a novel candidate for developing rational therapeutic strategies.

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

Similar content being viewed by others

References

  1. Alwan A (2007) World Health Organization. Disaster Med Public Health Prep 1:7–8

    Article  PubMed  Google Scholar 

  2. Siegel R, Naishadham D, Jemal A (2012) Cancer statistics, 2012. CA Cancer J Clin 62:10–29

    Article  PubMed  Google Scholar 

  3. Din FV, Theodoratou E, Farrington SM, Tensa A, Barnetson RA, Cetnarskyj R, Stark L, Porteous ME, Campbell H, Dumlop MG (2010) Effect of aspirin and NSAIDs on risk and survival from colorectal cancer. Gut 59:1670–1679

    Article  CAS  PubMed  Google Scholar 

  4. Ambros V (2003) MicroRNA pathways in flies and worms: growth, death, fat, stress and timing. Cell 113:673–676

    Article  CAS  PubMed  Google Scholar 

  5. Brennecke J, Hipfner AS, Russell RB, Cohen SM (2003) Bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in drosophila. Cell 113:25–36

    Article  CAS  PubMed  Google Scholar 

  6. Chen C, Li L, Lodish HF, Bartel DP (2004) MicroRNAs modulate hematopoietic lineage differentiation. Science 303:83–86

    Article  CAS  PubMed  Google Scholar 

  7. Croce CM, Calin GA (2005) miRNAs, cancer and stem cell division. Cell 122:6–7

    Article  CAS  PubMed  Google Scholar 

  8. Zhang B, Pan X, Cobb GP, Anderson TA (2007) MicroRNAs as oncogenes and tumor suppressors. Dev Biol 302:1–12

    Article  CAS  PubMed  Google Scholar 

  9. Iorio MV, Croce CM (2009) MicroRNAs in cancer: small molecules with a huge impact. J Clin Oncol 27:5848–5856

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Schetter AJ, Leung SY, Sohn JJ, Zanetti KA, Bowman ED, Yanaihara N, Yune ST, Chan TL, Kwong DL, Au GK, Liu CG, Calin GA, Croce CM, Harris CC (2008) MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 299:425–436

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, Prueitt RL, Yanaihara N, Lanza G, Scarpa A, Vecchione A, Negrini M, Harris CC, Croce CM (2006) A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 103:2257–2261

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Wang XY, Wu MH, Liu F, Li Y, Li N, Li GY, Shen SR (2010) Differential miRNA expression and their target genes between NGX6-positive and negative colon cancer cells. Mol Cell Biochem 345:283–290

    Article  CAS  PubMed  Google Scholar 

  13. Wang S, Aurora AB, Jonason BA, Qi X, McAnally J, Hill JA, Richardson JA, Bassel-Duby R, Olson EN (2008) The endothelial specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev Cell 15:261–271

    Article  PubMed Central  PubMed  Google Scholar 

  14. Tavazoie SF, Alarcón C, Oskarsson T, Padua D, Wang Q, Bos PD, Gerald WL, Massagué J (2008) Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451:147–152

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, Stephens RM, Okamoto A, Yokota J, Tanaka T, Calin GA, Liu CG, Croce CM, Harris CC (2006) Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9:189–198

    Article  CAS  PubMed  Google Scholar 

  16. Cho WC, Chow AS, Au JS (2009) Restoration of tumour suppressor hsa-miR-145 inhibits cancer cell growth in lung adenocarcinoma patients with epidermal growth factor receptor mutation. Eur J Cancer 45:2197–2206

    Article  CAS  PubMed  Google Scholar 

  17. Feng R, Chen X, Yu Y, Su L, Yu B, Li J, Cai Q, Yan M, Liu B, Zhu Z (2010) miR-126 functions as a tumour suppressor in human gastric cancer. Cancer Lett 298:50–63

    Article  CAS  PubMed  Google Scholar 

  18. Wang X, Tang S, Le SY, Lu R, Rader JS, Meyers C, Zheng ZM (2008) Aberrant expression of oncogenic and tumor-suppressive microRNAs in cervical cancer is required for cancer cell growth. PLoS One 3:e2557

    Article  PubMed Central  PubMed  Google Scholar 

  19. Saito Y, Friedman JM, Chihara Y, Egger G, Chuang JC, Liang G (2009) Epigenetic therapy up-regulates the tumor suppressor microRNA-126 and its host gene EGFL7 in human cancer cells. Biochem Biophys Res Commun 379:726–731

    Article  CAS  PubMed  Google Scholar 

  20. Sahai E, Marshall CJ (2002) RHO-GTPases and cancer. Nat Rev Cancer 2:133–142

    Article  PubMed  Google Scholar 

  21. Schee K, Boye K, Abrahamsen TW, Fodstad Ø, Flatmark K (2012) Clinical relevance of microRNA miR-21, miR-31, miR-92a, miR-101, miR-106a and miR-145 in colorectal cancer. BMC Cancer 12:505

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Vega FM, Ridley AJ (2008) Rho GTPases in cancer cell biology. FEBS Lett 582(14):2093

    Article  CAS  PubMed  Google Scholar 

  23. Tang Y, Olufemi L, Wang MT, Nie D (2008) Role of Rho GTPases in breast cancer. Front Biosci 13:759–776

    Article  CAS  PubMed  Google Scholar 

  24. Cheng KW, Agarwal R, Mills GB (2009) Ras-superfamily GTPases in ovarian cancer. Cancer Treat Res 149:229–240

    Article  CAS  PubMed  Google Scholar 

  25. Grise F, Bidaud A, Moreau V (2009) Rho GTPases in hepatocellular carcinoma. Biochim Biophys Acta 1795(2):137–151

    CAS  PubMed  Google Scholar 

  26. Struckhoff AP, Rana MK, Worthylake RA (2011) RhoA can lead the way in tumor cell invasion and metastasis. Front Biosci 1:1915–1926

    Article  Google Scholar 

  27. Chang YW, Marlin JW, Chance TW, Jakobi R (2006) RhoA mediates cyclooxygenase-2 signaling to disrupt the formation of adherens junctions and increase cell motility. Cancer Res 66:11700–11708

    Article  CAS  PubMed  Google Scholar 

  28. Cavallaro U, Christofori G (2004) Cell adhesion and signaling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer 4:118–132

    Article  CAS  PubMed  Google Scholar 

  29. Fagan-Solis KD, Schneider SS, Pentecost BT, Bentley BA, Otis CN, Gierthy JF, Arcaro KF (2012) The ras homolog gene family, member A (RhoA) pathway mediates MMP-2 and MMP-9-independent invasive behavior in a triple-negative breast cancer cell line. J Cell Biochem 17:1002

    Google Scholar 

  30. Olson MF (2008) Applications for ROCK kinase inhibition. Curr Opin Cell Biol 20:242–248

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Amano M, Chihara K, Kimura K, Fukata Y, Nakamura N, Matsuura Y, Kaibuchi K (1997) Formation of actin stress fibers and focal adhesions enhanced by Rho-kinase. Science 275:1308–1311

    Article  CAS  PubMed  Google Scholar 

  32. Matsuoka T, Yashiro M, Kato Y, Shinto O, Kashiwagi S, Hirakawa K (2011) RhoA/ROCK signaling mediates plasticity of scirrhous gastric carcinoma motility. Clin Exp Metastasis 28:627–636

    Article  CAS  PubMed  Google Scholar 

  33. Lane J, Martin TA, Watkins G, Mansel RE, Jiang WG (2008) The expression and prognostic value of ROCK I and ROCK II and their role in human breast cancer. Int J Oncol 33:585–593

    CAS  PubMed  Google Scholar 

  34. Kamai T, Tsujii T, Arai K, Takagi K, Asami H, Ito Y, Oshima H (2003) Significant association of Rho/ROCK pathway with invasion and metastasis of bladder cancer. Clin Cancer Res 9:2632–2641

    CAS  PubMed  Google Scholar 

  35. Li B, Zhao WD, Tan ZM, Fang WG, Zhu L, Chen YH (2006) Involvement of Rho/ROCK signalling in small cell lung cancer migration through human brain microvascular endothelial cells. FEBS Lett 580:4252–4260

    Article  CAS  PubMed  Google Scholar 

  36. Joshi B, Strugnell SS, Goetz JG, Kojic LD, Cox ME, Griffith OL, Chan SK, Jones SJ, Leung SP, Masoudi H, Leung S, Wiseman SM, Nabi IR (2008) Phosphorylated caveolin-1 regulates Rho/ROCK-dependent focal adhesion dynamics and tumor cell migration and invasion. Cancer Res 68:8210–8820

    Article  CAS  PubMed  Google Scholar 

  37. Cardone RA, Bagorda A, Bellizzi A, Busco G, Guerra L, Paradiso A, Casavola V, Zaccolo M, Reshkin SJ (2005) Protein kinase A gating of a pseudopodial-located RhoA/ROCK/p38/NHE1 signal module regulates invasion in breast cancer cell lines. Mol Biol Cell 16:3117–3127

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Kitzing TM, Sahadevan AS, Brandt DT, Knieling H, Hannemann S, Fackler OT, Grosshans J, Grosse R (2007) Positive feedback between Dia1, LARG, and RhoA regulates cell morphology and invasion. Genes Dev 21:1478–1483

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Jiang W, Wang Q, Chen S, Song L, Liu P, Huang W (2013) Influenza A virus NS1 induces G0/G1 cell cycle arrest by inhibiting the expression and activity of RhoA protein. J Virol 87(6):3039–3052

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Lee MH, Cho YS, Han YM (2007) Simvastatin suppresses self-renewal of mouse embryonic stem cells by inhibiting RhoA geranylgeranylation. Stem Cells 25:1654–1663

    Article  CAS  PubMed  Google Scholar 

  41. Benitah SA, Valerón PF, van Aelst L, Marshall CJ, Lacal JC (2004) Rho GTPases in human cancer: an unresolved link to upstream and downstream transcriptional regulation. Biochim Biophys Acta 1705:121–132

    CAS  PubMed  Google Scholar 

  42. Li Y, Chen Y, Tao Y, Xu J, Chen M (2010) RhoA protein is generally distributed in the nuclei of cancer cells. Oncol Rep 24:1005–1009

    CAS  PubMed  Google Scholar 

  43. Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL (2011) Cyclin D as a therapeutic target in cancer. Nat Rev Cancer 11:558–572

    Article  CAS  PubMed  Google Scholar 

  44. Cock-Rada AM, Medjkane S, Janski N, Yousfi N, Perichon M, Chaussepied M, Chluba J, Langsley G, Weitzman JB (2012) SMYD3 promotes cancer invasion by epigenetic upregulation of the metalloproteinase MMP-9. Cancer Res 72:810–820

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Nalbant P, Chang YC, Birkenfeld J, Chang ZF, Bokoch GM (2009) Guanine nucleotide exchange factor-H1 regulates cell migration via localized activation of RhoA at the leading edge. Mol Biol Cell 20:4070–4082

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Furukawa K, Kumon Y, Harada H, Kohno S, Nagato S, Teraola M, Fujiwara S, Nakagawa K, Hamada K, Ohnishi T (2006) PTEN gene transfer suppresses the invasive potential of human malignant gliomas by regulating cell invasion-related molecules. Int J Oncol 29(1):73–81

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from National Natural Science Foundation (No. 81272736), Natural Science Foundation of Hunan Province (No. 09JJ3066), Science and Technology of Hunan Province (No. 2009FJ3086), and Innovative Project of Science and Technology of Hunan Province (No. 2011TT2020).

Author information

Author notes

  1. Shuo Huang

    Present address: Department of Infection, Xiangtan People’s Hospital, Xiangtan, Hunan, People’s Republic of China

  2. Zeng Li

    Present address: Department of Gastroenterology, The Xiangtan Central Hospital, Xiangtan, Hunan, People’s Republic of China

Authors and Affiliations

  1. Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Tongzhipo Road 138#, Changsha, Hunan, People’s Republic of China

    Nan Li, Anliu Tang, Shuo Huang, Zeng Li, Xiayu Li, Shourong Shen & Xiaoyan Wang

  2. Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, People’s Republic of China

    Nan Li, Anliu Tang, Xiayu Li, Shourong Shen, Jian Ma & Xiaoyan Wang

  3. Cancer Research Institute, Central South University, Changsha, Hunan, People’s Republic of China

    Jian Ma

  4. Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, People’s Republic of China

    Jian Ma

  5. Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, People’s Republic of China

    Jian Ma

Authors
  1. Nan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anliu Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shuo Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zeng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiayu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shourong Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jian Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiaoyan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiaoyan Wang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, N., Tang, A., Huang, S. et al. MiR-126 suppresses colon cancer cell proliferation and invasion via inhibiting RhoA/ROCK signaling pathway. Mol Cell Biochem 380, 107–119 (2013). https://doi.org/10.1007/s11010-013-1664-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-013-1664-0

Keywords

Search

Navigation