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Annals of Surgical Oncology

, Volume 22, Issue 8, pp 2649–2655 | Cite as

MiR-92a Promotes Cell Metastasis of Colorectal Cancer Through PTEN-Mediated PI3K/AKT Pathway

  • Tao-Wei Ke
  • Po-Li Wei
  • Ken-Tu Yeh
  • William Tzu-Liang Chen
  • Ya-Wen ChengEmail author
Colorectal Cancer

Abstract

Background

MicroRNAs regulate gene expression at the posttranscriptional level and play important roles in tumor development, progression, and metastasis. The aim of this study was to investigate the role of microRNA-92a (miR-92a) in metastasis of colorectal cancer (CRC).

Methods

One hundred fifty-eight CRC patients were enrolled. The expression of miR-92a, PTEN, and E-cadherin was analyzed by real-time PCR. Univariate (Kaplan–Meier) analysis was used to analyze primary outcomes included 5-year overall survival and tumor recurrence. CRC cell model studies were used to analyze the miR-92a-involved CRC metastasis.

Results

The expression of miR-92a in tumor tissues was significantly positively correlated with lymph node metastasis in CRC patients (p = 0.012). After adjusting for age, sex, and disease differentiation, this correlation remained significant (p = 0.01). In addition, there was a negative correlation between levels of miR-92a and the PTEN gene (p < 0.0001). No any association of miR-92a and E-cadherin was found (p = 0.128). Patients with high miR-92a/low PTEN had poorer overall survival and disease-free survival rates than those with high miR-92a/high PTEN, low miR-92a/high PTEN, and low miR-92a/low PTEN. The association of levels of miR-92a and PTEN with tumor cell migration in CRC was also confirmed in CRC cell models.

Conclusions

We suggest that miR-92a is involved in lymph node metastasis of CRC patients through PTEN-regulated PI3K/AKT signaling pathway.

Keywords

Esophageal Squamous Cell Carcinoma PTEN Expression SW480 Cell Line PTEN Gene Expression High PTEN 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgment

This work was supported by grants from the National Science Council (NSC-100-B-040-012) and Ministry of Health and Welfare (MOHW103-TD-B-111-01 and MOHW103-TDU-B-212-113001) of Taiwan.

Disclosure

The authors declare no conflict of interest.

Supplementary material

10434_2014_4305_MOESM1_ESM.docx (180 kb)
Supplementary material 1 (DOCX 180 kb)

References

  1. 1.
    Jemal A, Siegel R, Xu J, Ward E. Cancer statistics. CA Cancer J Clin. 2010;60:277–300.PubMedCrossRefGoogle Scholar
  2. 2.
    Leslie A, Carey FA, Pratt NR, Steele RJ. The colorectal adenoma–carcinoma sequence. Br J Surg. 2002;89:845–60.PubMedCrossRefGoogle Scholar
  3. 3.
    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.PubMedCrossRefGoogle Scholar
  4. 4.
    Wang H, Wu J, Meng X, et al. MicroRNA-342 inhibits colorectal cancer cell proliferation and invasion by directly targeting DNA methyltransferase 1. Carcinogenesis. 2011;32:1033–42.PubMedCrossRefGoogle Scholar
  5. 5.
    Calin GA, Sevignani C, Dumitru CD, et al. Human micro-RNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A. 2004;101:2999–3004.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Shatseva T, Lee DY, Deng Z, Yang BB. MicroRNA miR-199a-3p regulates cell proliferation and survival by targeting caveolin-2. J Cell Sci. 2011;124:2826–36.PubMedCrossRefGoogle Scholar
  7. 7.
    Hayashita Y, Osada H, Tatematsu Y, et al. A polycistronic microRNA cluster, Mir-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res. 2005;65:9628–32.PubMedCrossRefGoogle Scholar
  8. 8.
    Shigoka M, Tsuchida A, Matsudo T, et al. Deregulation of MiR-92a expression is implicated in hepatocellular carcinoma development. Pathol Int. 2010;60:351–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Chen ZL, Zhao XH, Wang JW, et al. MicroRNA-92a promotes lymph node metastasis of human esophageal squamous cell carcinoma via E-cadherin. J Biol Chem. 2011;286:10725–34.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Lin HY, Chiang CH, Hung WC. STAT3 upregulates MiR-92a to inhibit RECK expression and to promote invasiveness of lung cancer cells. Br J Cancer. 2013;109:731–8.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Zhang G, Zhou H, Xiao H, Liu Z, Tian H, Zhou T. MicroRNA-92a functions as an oncogene in colorectal cancer by targeting PTEN. Dig Dis Sci. 2014;59:98–107.PubMedCrossRefGoogle Scholar
  12. 12.
    Miranda E, Destro A, Malesci A, et al. Genetic and epigenetic changes in primary metastatic and nonmetastatic colorectal cancer. Br J Cancer. 2006;95:1101–7.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Lind GE, Thorstensen L, Løvig T, et al. A Cpg island hypermethylation profile of primary colorectal carcinomas and colon cancer cell lines. Mol Cancer. 2004;3:28.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Hur K, Cejas P, Feliu J, et al. Hypomethylation of long interspersed nuclear element-1 (LINE-1) leads to activation of proto-oncogenes in human colorectal cancer metastasis. Gut. 2014;63:635–46.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Cantley LC, Neel BG. New insights into tumor suppression; PTEN suppresses tumor formation by restraining phosphoinositide 3-kinase/Akt pathway. Proc Natl Acad Sci U S A. 1999;96:4240–5.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Khaleghpour K, Li Y, Banville D, et al. Involvement of PI-3 kinase signaling pathway in progression of colon adenocarcinoma. Carcinogenesis. 2004;25:241–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Stiles B, Gilman V, Khanzenzon N, et al. Essential role of Akt-1/protein kinase B in PTEN-controlled tumorigenesis. Moll Cell Biol. 2002;22:3842–51.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Osaki M, Oshimura M, Ito H, et al. PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis. 2004;9:667–76.PubMedCrossRefGoogle Scholar
  19. 19.
    Colakoglu T, Yildirim S, Kayaselcuk F, et al. Clinicopathological significance of PTEN loss and the phosphoinositide 3-kinase/Akt pathway in sporadic colorectal neoplasms: is PTEN loss predictor of local recurrence? Am J Surg. 2008;195:719–25.PubMedCrossRefGoogle Scholar
  20. 20.
    Tang JM, He QY, Guo RX, et al. Phosphorylated Akt overexpression and loss of PTEN expression in non-small lung cancer confers poor prognosis. Lung Cancer. 2006;51:181–91.PubMedCrossRefGoogle Scholar
  21. 21.
    McMenamin ME, Soung P, Perera S, et al. Loss of PTEN expression in paraffin-embedded primary prostate cancer correlates with high Gleason score and advanced stage. Cancer Res. 1999;59:4291–6.PubMedGoogle Scholar
  22. 22.
    Saal LH, Holm K, Maurer M, et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 2005;65:2554–9.PubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2014

Authors and Affiliations

  • Tao-Wei Ke
    • 1
    • 2
  • Po-Li Wei
    • 4
    • 5
    • 6
    • 7
  • Ken-Tu Yeh
    • 3
  • William Tzu-Liang Chen
    • 2
  • Ya-Wen Cheng
    • 7
    Email author
  1. 1.Institute of MedicineChung-Shan Medical UniversityTaichungTaiwan
  2. 2.Division of Colorectal Surgery, Department of SurgeryChina Medical University HospitalTaichungTaiwan
  3. 3.Department of PathologyChanghua Christian HospitalChanghuaTaiwan
  4. 4.Department of Surgery, College of MedicineTaipei Medical UniversityTaipeiTaiwan
  5. 5.Division of General Surgery, Department of Surgery, Taipei Medical University HospitalTaipei Medical UniversityTaipeiTaiwan
  6. 6.Cancer Center, Taipei Medical University HospitalTaipei Medical UniversityTaipeiTaiwan
  7. 7.Graduate Institute of Cancer Biology and Drug DiscoveryTaipei Medical UniversityTaipeiTaiwan

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