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Digestive Diseases and Sciences

, Volume 59, Issue 7, pp 1452–1460 | Cite as

LPS Induced miR-181a Promotes Pancreatic Cancer Cell Migration via Targeting PTEN and MAP2K4

  • Jianhui Liu
  • Dong Xu
  • Qingguang Wang
  • Datong Zheng
  • Xiuqin Jiang
  • Lijian XuEmail author
Original Article

Abstract

Background

Pancreatic cancer is aggressive; 80–90 % of pancreatic cancer patients have already developed metastatic cancer at the time of diagnosis. Inflammation has been shown to facilitate pancreatic cancer migration. The toll-like receptors (TLRs) pathway is an important inflammatory signal transduction pathway. However, the mechanism of inflammation pathway to induce pancreatic cancer migration is unclear.

Aims

The purpose of this study was to investigate how inflammation affects pancreatic cancer migration.

Methods

RT-PCR was used to detect the TLRs expression files in pancreatic cancer cells and tissues. Pancreatic cancer cells migration was assessed after treatment with TLR4 agonist, lipopolysaccharide (LPS). Moreover, two tumor suppressors, PTEN and MAP2K4, were detected. Then we predicted and proved the miRNA which targeted PTEN and MAP2K4.

Results

We found that the expression of TLR4 was increased in pancreatic cancer cells and tissues. After treatment with LPS, the migration of pancreatic cancer cells was increased and the protein levels of two tumor suppressors, PTEN and MAP2K4, were inhibited. To investigate the possible mechanism, we checked the expression of miR-181a. The result showed that miR-181a was decreased by LPS. Furthermore, we predicted and confirmed that both PTEN and MAP2K4 were miR-181a targets. Pancreatic cancer tissues analysis showed that PTEN and MAP2K4 were all negatively correlated with miR-181a.

Conclusions

These results suggest that the LPS-TLR4-miR-181a signaling pathway plays a significant role in pancreatic cancer invasion and progression.

Keywords

Pancreatic cancer TLR4 MiR-181a PTEN MAP2K4 

Notes

Conflict of interest

None.

References

  1. 1.
    Raimondi S, Maisonneuve P, Lowenfels AB. Epidemiology of pancreatic cancer: an overview. Nat Rev Gastroenterol Hepatol. 2009;6:699–708.PubMedCrossRefGoogle Scholar
  2. 2.
    Barkin JS, Goldstein JA. Diagnostic and therapeutic approach to pancreatic cancer. Biomed Pharmacother. 2000;54:400–409.PubMedCrossRefGoogle Scholar
  3. 3.
    Mantovani A. CANCER inflaming metastasis. Nature. 2009;457:36–37.PubMedCrossRefGoogle Scholar
  4. 4.
    Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–444.PubMedCrossRefGoogle Scholar
  5. 5.
    Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 2009;30:1073–1081.PubMedCrossRefGoogle Scholar
  6. 6.
    Wen F, Shen A, Choi A, Gerner EW, Shi J. Extracellular DNA in pancreatic cancer promotes cell invasion and metastasis. Cancer Res. 2013;73(14):4256–4266. doi: 10.1158/0008-5472.Google Scholar
  7. 7.
    Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801.PubMedCrossRefGoogle Scholar
  8. 8.
    O’Neill LA. How Toll-like receptors signal: what we know and what we don’t know. Curr Opin Immunol. 2006;18:3–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Cook DN, Pisetsky DS, Schwartz DA. Toll-like receptors in the pathogenesis of human disease. Nat Immunol. 2004;5:975–979.PubMedCrossRefGoogle Scholar
  10. 10.
    Goto Y, Arigami T, Kitago M, Nguyen SL, et al. Activation of Tolllike receptors 2, 3, and 4 on human melanoma cells induces inflammatory factors. Mol Cancer Ther. 2008;7:3642–3653.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Kelly MG, Alvero AB, Chen R, Silasi DA, et al. TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer Res. 2006;66:3859–3868.PubMedCrossRefGoogle Scholar
  12. 12.
    Jurk M, Vollmer J. Therapeutic applications of synthetic CpG oligodeoxynucleotides as TLR9 agonists for immune modulation. BioDrugs. 2007;21:387–401.PubMedCrossRefGoogle Scholar
  13. 13.
    West AP, Koblansky AA, Ghosh S. Recognition and signaling by toll-like receptors. Annu Rev Cell Dev Biol. 2006;22:409–437.PubMedCrossRefGoogle Scholar
  14. 14.
    Triantafilou K, Triantafilou M, Dedrick RL. A CD14-independent LPS receptor cluster. Nat Immunol. 2001;4:338–345.CrossRefGoogle Scholar
  15. 15.
    Suzanne LT, Kevin JZ, Seth BC, Ruth SW, Elizabeth SD, Aline BS. Toll-like receptors on human mesenchymal stem cells drive their migration and immunomodulating responses. Stem Cells. 2008;26:99–107.CrossRefGoogle Scholar
  16. 16.
    Ikebe M, Kitaura Y, Nakamura M, Tanaka H, et al. Lipopolysaccharide (LPS) increases the invasive ability of pancreatic cancer cells through the TLR4/MyD88 signaling pathway. J Surg Oncol. 2009;100:725–731.PubMedCrossRefGoogle Scholar
  17. 17.
    Nicoloso MS, Calin GA. MicroRNA involvement in brain tumors: from bench to bedside. Brain Pathol. 2008;18:122–129.PubMedCrossRefGoogle Scholar
  18. 18.
    Wang HW, Mendell JT. MicroRNAs in cell proliferation, cell death and tumorigenesis. Br J Cancer. 2006;94:776–780.CrossRefGoogle Scholar
  19. 19.
    Hulsmans M, Sinnaeve P, Van der Schueren B, Mathieu C, Janssens S, Holvoet P. Decreased miR-181a expression in monocytes of obese patients is associated with the occurrence of metabolic syndrome and coronary artery disease. J Clin Endocrinol Metab. 2012;97:E1213–E1218.PubMedCrossRefGoogle Scholar
  20. 20.
    Bloomston M, Frankel WL, Petrocca F. MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA. 2007;297:1901–1908.PubMedCrossRefGoogle Scholar
  21. 21.
    Zhang Y, Li M, Wang H. Profiling of 95 microRNAs in pancreatic cancer cell lines and surgical specimens by real-time PCR analysis. World J Surg. 2009;33:698–709.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Xie W, Li Z, Li M, Xu N, Zhang Y. miR-181a and inflammation: miRNA homeostasis response to inflammatory stimuli in vivo. Biochem Biophys Res Commun. 2013;430:647–652.PubMedCrossRefGoogle Scholar
  23. 23.
    Luo H, Yang Y, Duan J, Wu P, Jiang Q, Xu C. PTEN-regulated AKT/FoxO3a/Bim signaling contributes to reactive oxygen species-mediated apoptosis in selenite-treated colorectal cancer cells. Cell Death Dis. 2013;7:e481.CrossRefGoogle Scholar
  24. 24.
    Yamada KM, Araki M. Tumor suppressor PTEN: modulator of cell signaling, growth, migration and apoptosis. J Cell Sci. 2001;114:2375–2382.PubMedGoogle Scholar
  25. 25.
    Xin W, Yun KJ, Ricci F, Zahurak M, et al. MAP2K4/MKK4 expression in pancreatic cancer: genetic validation of immunohistochemistry and relationship to disease course. Clin Cancer Res. 2004;10:8516–8520.PubMedCrossRefGoogle Scholar
  26. 26.
    Ishikawa M, Nakayama K, Rahman MT, Rahman M, et al. Functional and clinicopathological analysis of loss of MKK4 expression in endometrial cancer. Oncology. 2010;79:238–246.PubMedCrossRefGoogle Scholar
  27. 27.
    Michaud DS, Izard J, Wilhelm-Benartzi CS, You DH, et al. Plasma antibodies to oral bacteria and risk of pancreatic cancer in a large European prospective cohort study. Gut. 2013;62:1764–1770.Google Scholar
  28. 28.
    Michaud DS. Role of bacterial infections in pancreatic cancer. Carcinogenesis. 2013;34:2193–2197. Google Scholar
  29. 29.
    Price JC, Bromfield JJ, Sheldon IM. Pathogen-associated molecular patterns initiate inflammation and perturb the endocrine function of bovine granulosa cells from ovarian dominant follicles via TLR2 and TLR4 pathways. Endocrinology. 2013;154(9):3377–3386.Google Scholar
  30. 30.
    Zhang JJ, Wu HS, Wang L, Tian Y, Zhang JH, Wu HL. Expression and significance of TLR4 and HIF-1alpha in pancreatic ductal adenocarcinoma. World J Gastroenterol. 2010;16:2881–2888.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Del Pozo JL. Primers on molecular pathways: lipopolysaccharide signaling—potential role in pancreatitis and pancreatic cancer. Pancreatology. 2010;10:114–118.PubMedCrossRefGoogle Scholar
  32. 32.
    Jianwei Z, Fan L, Xiancheng L, Enzhong B, Shuai L, Can L. MicroRNA 181a improves proliferation and invasion, suppresses apoptosis of osteosarcoma cell. Tumour Biol. 2013;34:3331–3337. Google Scholar
  33. 33.
    Taylor MA, Sossey-Alaoui K, Thompson CL, Danielpour D, Schiemann WP. TGF-β upregulates miR-181a expression to promote breast cancer metastasis. J Clin Invest. 2013;123:150–163.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Chu EC, Tarnawski AS. PTEN regulatory functions in tumor suppression and cell biology. Med Sci Monit. 2004;10: RA235–RA2341.Google Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Jianhui Liu
    • 1
  • Dong Xu
    • 2
  • Qingguang Wang
    • 1
  • Datong Zheng
    • 3
  • Xiuqin Jiang
    • 3
  • Lijian Xu
    • 1
    Email author
  1. 1.Department of General SurgeryThe Second Affiliated Hospital of Nanjing Medical UniversityNanjingPeople’s Republic of China
  2. 2.Department of General SurgeryGaochun People’s HospitalNanjingPeople’s Republic of China
  3. 3.Central LaboratoryThe Second Affiliated Hospital of Nanjing Medical UniversityNanjingPeople’s Republic of China

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