Tumor Biology

, Volume 33, Issue 6, pp 1863–1870

miR-143 inhibits the metastasis of pancreatic cancer and an associated signaling pathway

  • Yongjun Hu
  • Yanglu Ou
  • Kemin Wu
  • Yuxiang Chen
  • Weijia Sun
Research Article

Abstract

Pancreatic cancer is characterized by early metastasis and high mortality. In this study, the role of miR-143 in invasion and metastasis was investigated in pancreatic cancer cells. miR-143 expression was established by an adenovirus-carried miR-143 expression cassette. mRNA and protein levels of gene expression were examined by RT-PCR and Western blot assay, respectively. Rho GTPases activity was measured by the pull down assay. The role of miR-143 in migration and invasion of Panc-1 cells was tested in vitro. The antimetastatic effect of miR-143 was tested in a liver metastasis model, while its antitumor growth effect was tested in a xenograft Panc-1 tumor model. Results demonstrated that ARHGEF1 (GEF1), ARHGEF2 (GEF2), and K-RAS genes are the targets of miR-143. miR-143 expression significantly decreased mRNA and protein levels of GEF1, GEF2, and K-RAS genes; lowered the constitutive activities of RhoA, Rac1, and Cdc42 GTPases; decreased the protein levels of MMP-2 and MMP-9; but significantly increased the protein level of E-cadherin. miR-143 expression also significantly inhibited the migration and invasion of Panc-1 cells in vitro, liver metastasis, and xenograft tumor growth in vivo. Our study suggested that miR-143 plays a central role in the invasion and metastasis of pancreatic cancer and miR-143 is a potential target for pancreatic cancer therapy.

Keywords

microRNA miR-143 Rho GTPase GEF E-cadherin Pancreatic cancer 

References

  1. 1.
    Spratlin JL, Mulder KE. Looking to the future: biomarkers in the management of pancreatic adenocarcinoma. Int J Mol Sci. 2011;12:5895–907.PubMedCrossRefGoogle Scholar
  2. 2.
    Arora S, Bhardwaj A, Srivastava SK, Singh S, McClellan S, Wang B, Singh AP. Honokiol arrests cell cycle, induces apoptosis, and potentiates the cytotoxic effect of gemcitabine in human pancreatic cancer cells. PLoS One. 2011;6:e21573.PubMedCrossRefGoogle Scholar
  3. 3.
    Singh P, Srinivasan R, Wig JD. Major molecular markers in pancreatic ductal adenocarcinoma and their roles in screening, diagnosis, prognosis, and treatment. Pancreas. 2011;40:644–52.PubMedCrossRefGoogle Scholar
  4. 4.
    Cohenuram M, Saif MW. Epidermal growth factor receptor inhibition strategies in pancreatic cancer: past, present and the future. JOP. 2007;8:4–15.PubMedGoogle Scholar
  5. 5.
    Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2002;2:563–72.PubMedCrossRefGoogle Scholar
  6. 6.
    Brown DM, Ruoslahti E. Metadherin, a cell surface protein in breast tumors that mediates lung metastasis. Cancer Cell. 2004;5:365–74.PubMedCrossRefGoogle Scholar
  7. 7.
    Fukata M, Kaibuchi K. Rho-family GTPases in cadherin-mediated cell-cell adhesion. Nat Rev Mol Cell Biol. 2001;2:887–97.PubMedCrossRefGoogle Scholar
  8. 8.
    Billadeau DD. Cell growth and metastasis in pancreatic cancer: is Vav the Rho'd to activation? Int J Gastrointest Cancer. 2002;31:5–13.PubMedCrossRefGoogle Scholar
  9. 9.
    Lazer G, Katzav S. Guanine nucleotide exchange factors for RhoGTPases: good therapeutic targets for cancer therapy? Cell Signal. 2011;23:969–79.PubMedCrossRefGoogle Scholar
  10. 10.
    Makrodouli E, Oikonomou E, Koc M, Andera L, Sasazuki T, Shirasawa S, Pintzas A. BRAF and RAS oncogenes regulate Rho GTPase pathways to mediate migration and invasion properties in human colon cancer cells: a comparative study. Mol Cancer. 2011;10:118.PubMedCrossRefGoogle Scholar
  11. 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. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 2006;103:2257–61.PubMedCrossRefGoogle Scholar
  12. 12.
    Yang Y, Chaerkady R, Kandasamy K, Huang TC, Selvan LD, Dwivedi SB, Kent OA, Mendell JT, Pandey A. Identifying targets of miR-143 using a SILAC-based proteomic approach. Mol Biosyst. 2010;26:187318–82.Google Scholar
  13. 13.
    Kent OA, Chivukula RR, Mullendore M, Wentzel EA, Feldmann G, Lee KH, Liu S, Leach SD, Maitra A, Mendell JT. Repression of the miR-143/145 cluster by oncogenic Ras initiates a tumor-promoting feed-forward pathway. Genes Dev. 2010;24:2754–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Ali S, Ahmad A, Aboukameel A, Bao B, Padhye S, Philip PA, Sarkar FH. Increased Ras GTPase activity is regulated by miRNAs that can be attenuated by CDF treatment in pancreatic cancer cells. Cancer Lett. 2012;319:173–81.PubMedCrossRefGoogle Scholar
  15. 15.
    Pramanik D, Campbell NR, Karikari C, Chivukula R, Kent OA, Mendell JT, Maitra A. Restitution of tumor suppressor microRNAs using a systemic nanovector inhibits pancreatic cancer growth in mice. Mol Cancer Ther. 2011;10:1470–80.PubMedCrossRefGoogle Scholar
  16. 16.
    Zhang X, Kon T, Wang H, Li F, Huang Q, Rabbani ZN, Kirkpatrick JP, Vujaskovic Z, Dewhirst MW, Li CY. Enhancement of hypoxia-induced tumor cell death in vitro and radiation therapy in vivo by use of small interfering RNA targeted to hypoxia-inducible factor-1alpha. Cancer Res. 2004;64:8139–42.PubMedCrossRefGoogle Scholar
  17. 17.
    Yamada T, Sato K, Komachi M, Malchinkhuu E, Tobo M, Kimura T, Kuwabara A, Yanagita Y, Ikeya T, Tanahashi Y, Ogawa T, Ohwada S, Morishita Y, Ohta H, Im DS, Tamoto K, Tomura H, Okajima F. Lysophosphatidic acid (LPA) in malignant ascites stimulates motility of human pancreatic cancer cells through LPA1. J Biol Chem. 2004;279:6595–605.PubMedCrossRefGoogle Scholar
  18. 18.
    Komachi M, Tomura H, Malchinkhuu E, Tobo M, Mogi C, Yamada T, Kimura T, Kuwabara A, Ohta H, Im DS, Kurose H, Takeyoshi I, Sato K, Okajima F. LPA1 receptors mediate stimulation, whereas LPA2 receptors mediate inhibition, of migration of pancreatic cancer cells in response to lysophosphatidic acid and malignant ascites. Carcinogenesis. 2009;30:457–65.PubMedCrossRefGoogle Scholar
  19. 19.
    Mi J, Sarraf-Yazdi S, Zhang X, Cao Y, Dewhirst MW, Kontos CD, Li CY, Clary BM. A comparison of antiangiogenic therapies for the prevention of liver metastases. J Surg Res. 2006;131:97–104.PubMedCrossRefGoogle Scholar
  20. 20.
    Deer EL, González-Hernández J, Coursen JD, Shea JE, Ngatia J, Scaife CL, Firpo MA, Mulvihill SJ. Phenotype and genotype of pancreatic cancer cell lines. Pancreas. 2010;39:425–35.PubMedCrossRefGoogle Scholar
  21. 21.
    Asnaghi L, Vass WC, Quadri R, Day PM, Qian X, Braverman R, Papageorge AG, Lowy DR. E-cadherin negatively regulates neoplastic growth in non-small cell lung cancer: role of Rho GTPases. Oncogene. 2010;29:2760–71.PubMedCrossRefGoogle Scholar
  22. 22.
    Szarvas T, vom Dorp F, Ergün S, Rübben H. Matrix metalloproteinases and their clinical relevance in urinary bladder cancer. Nat Rev Urol. 2011;8:241–54.PubMedCrossRefGoogle Scholar
  23. 23.
    Bar N, Dikstein R. miR-22 forms a regulatory loop in PTEN/AKT pathway and modulates signaling kinetics. PLoS One. 2010;5:e10859.PubMedCrossRefGoogle Scholar
  24. 24.
    Nagakawa Y, Aoki T, Kasuya K, Tsuchida A, Koyanagi Y. Histologic features of venous invasion, expression of vascular endothelial growth factor and matrix metalloproteinase-2 and matrix metalloproteinase-9, and the relation with liver metastasis in pancreatic cancer. Pancreas. 2002;24:169–78.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2012

Authors and Affiliations

  • Yongjun Hu
    • 1
  • Yanglu Ou
    • 1
  • Kemin Wu
    • 1
  • Yuxiang Chen
    • 2
  • Weijia Sun
    • 1
  1. 1.Department of General Surgery, Xiangya HospitalCentral South UniversityChangshaPR China
  2. 2.Hepatobiliary and Enteric Surgery Research Center, Xiangya HospitalCentral South UniversityChangshaPR China

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