Tumor Biology

, Volume 37, Issue 1, pp 463–471 | Cite as

MiR-375 targets KLF4 and impacts the proliferation of colorectal carcinoma

  • Qiqi Mao
  • Tao Quan
  • Bin Luo
  • Xuefeng Guo
  • Lei Liu
  • Qinghui Zheng
Original Article


MiR-375 has been identified as oncogenes or tumor suppressor genes which has the potential to the development and growth of cancers. However, the limited information concerning the expression and role of miR-375 in colorectal cancer (CRC) is available. In this work, we provide evidence for a function of miR-375 in the inhibition of CRC proliferation. Here, we showed that miR-375, down-modulated in human colorectal cancer tissues compared with normal human colon tissues, including several colorectal cancer cell lines. Subsequently, using the luciferase reporter assays, we found that the KLF4 untranslated region (3′UTR) carries the direct binding site of miR-375. In terms of function in vitro, CCK-8 assay, colony formation assay, and cell cycle assay demonstrated that the overexpression of miR-375 suppressed CRC cell proliferation. Inhibition of KLF4 performed similar effects with miR-375 overexpression on CRC cells, and overexpression of KLF4 could significantly reverse the tumor suppressive effects of miR-375 on CRC cells. Furthermore, we found overexpressed miR-375 effectively repressed tumor growth via KLF4 in xenograft animal experiment. Taken together, these results illustrated that miR-375 depresses proliferation of CRC through regulating 3′UTR of KLF4 mRNA, which might be a promising therapeutic target for treating colorectal cancers.


MiR-375 KLF4 Colorectal cancer Proliferation 




Conflicts of interest



  1. 1.
    Bartel DP. Micrornas: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.CrossRefPubMedGoogle Scholar
  2. 2.
    Bartel DP, Chen CZ. Micromanagers of gene expression: the potentially widespread influence of metazoan micrornas. Nat Rev Genet. 2004;5:396–400.CrossRefPubMedGoogle Scholar
  3. 3.
    Luo D, Wilson JM, Harvel N, Liu J, Pei L, Huang S, et al. A systematic evaluation of miRNA:mRNA interactions involved in the migration and invasion of breast cancer cells. J Transl Med. 2013;11:57.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Wu X, Ajani JA, Gu J, Chang DW, Tan W, Hildebrandt MA, et al. Microrna expression signatures during malignant progression from Barrett’s esophagus to esophageal adenocarcinoma. Cancer Prev Res (Phila). 2013;6:196–205.CrossRefGoogle Scholar
  5. 5.
    Xu Y, Deng Y, Yan X, Zhou T. Targeting miR-375 in gastric cancer. Expert Opin Ther Targets. 2011;15:961–72.CrossRefPubMedGoogle Scholar
  6. 6.
    Szczyrba J, Nolte E, Wach S, Kremmer E, Stohr R, Hartmann A, et al. Downregulation of sec23a protein by miRNA-375 in prostate carcinoma. Mol Cancer Res. 2011;9:791–800.CrossRefPubMedGoogle Scholar
  7. 7.
    Luo J, Wu J, Li Z, Qin H, Wang B, Wong TS, et al. MiR-375 suppresses IGF1R expression and contributes to inhibition of cell progression in laryngeal squamous cell carcinoma. BioMed Res Int. 2014;2014:374598.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Chang Y, Yan W, He X, Zhang L, Li C, Huang H, et al. MiR-375 inhibits autophagy and reduces viability of hepatocellular carcinoma cells under hypoxic conditions. Gastroenterology. 2012;143:177–87. e178.CrossRefPubMedGoogle Scholar
  9. 9.
    Liu Y, Xing R, Zhang X, Dong W, Zhang J, Yan Z, et al. MiR-375 targets the p53 gene to regulate cellular response to ionizing radiation and etoposide in gastric cancer cells. DNA Repair (Amst). 2013;12:741–50.CrossRefGoogle Scholar
  10. 10.
    Faltejskova P, Svoboda M, Srutova K, Mlcochova J, Besse A, Nekvindova J, et al. Identification and functional screening of microRNAs highly deregulated in colorectal cancer. J Cell Mol Med. 2012;16:2655–66.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.CrossRefPubMedGoogle Scholar
  12. 12.
    Wang L, Qian L, Li X, Yan J. MicroRNA-195 inhibits colorectal cancer cell proliferation, colony-formation and invasion through targeting CARMA3. Mol Med Rep. 2014;10:473–8.PubMedGoogle Scholar
  13. 13.
    Wang Q, Huang Z, Guo W, Ni S, Xiao X, Wang L, et al. MicroRNA-202-3p inhibits cell proliferation by targeting ADP-ribosylation factor-like 5a in human colorectal carcinoma. Clin Cancer Res. 2014;20:1146–57.CrossRefPubMedGoogle Scholar
  14. 14.
    Xin C, Zhang H, Liu Z. MiR-154 suppresses colorectal cancer cell growth and motility by targeting TLR2. Mol Cell Biochem. 2014;387:271–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Reczko M, Maragkakis M, Alexiou P, Grosse I, Hatzigeorgiou AG. Functional microRNA targets in protein coding sequences. Bioinformatics. 2012;28:771–6.CrossRefPubMedGoogle Scholar
  16. 16.
    He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004;5:522–31.CrossRefPubMedGoogle Scholar
  17. 17.
    Hwang HW, Mendell JT. MicroRNAs in cell proliferation, cell death, and tumorigenesis. Br J Cancer. 2006;94:776–80.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Shen Y, Tang D, Yao R, Wang M, Wang Y, Yao Y, et al. MicroRNA expression profiles associated with survival, disease progression, and response to gefitinib in completely resected non-small-cell lung cancer with EGFR mutation. Med Oncol. 2013;30:750.CrossRefPubMedGoogle Scholar
  19. 19.
    Yi B, Piazza GA, Su X, Xi Y. MicroRNA and cancer chemoprevention. Cancer Prev Res (Phila). 2013;6:401–9.CrossRefGoogle Scholar
  20. 20.
    Shen ZY, Zhang ZZ, Liu H, Zhao EH, Cao H. MiR-375 inhibits the proliferation of gastric cancer cells by repressing ERBB2 expression. Exp Ther Med. 2014;7:1757–61.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Jung HM, Patel RS, Phillips BL, Wang H, Cohen DM, Reinhold WC, et al. Tumor suppressor miR-375 regulates myc expression via repression of CIP2A coding sequence through multiple miRNA-mRNA interactions. Mol Biol Cell. 2013;24:1638–48. S1631–1637.Google Scholar
  22. 22.
    Wang Y, Tang Q, Li M, Jiang S, Wang X. MicroRNA-375 inhibits colorectal cancer growth by targeting PIK3CA. Biochem Biophys Res Commun. 2014;444:199–204.CrossRefPubMedGoogle Scholar
  23. 23.
    Ge X, Zheng L, Huang M, Wang Y, Bi F. Microrna expression profiles associated with acquired gefitinibresistance in human lung adenocarcinoma cells. Mol Med Rep. 2014.Google Scholar
  24. 24.
    Chai J, Feng R, Shi H, Ren M, Zhang Y, Wang J. Bioinformatic identification and expression analysis of banana microRNAs and their targets. PLoS One. 2015;10:e0123083.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Tiwari N, Meyer-Schaller N, Arnold P, Antoniadis H, Pachkov M, van Nimwegen E, et al. Klf4 is a transcriptional regulator of genes critical for EMT, including Jnk1 (Mapk8). PLoS One. 2013;8:e57329.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Zheng X, Li A, Zhao L, Zhou T, Shen Q, Cui Q, et al. Key role of microRNA-15a in the KLF4 suppressions of proliferation and angiogenesis in endothelial and vascular smooth muscle cells. Biochem Biophys Res Commun. 2013;437:625–31.CrossRefPubMedGoogle Scholar
  27. 27.
    Wei D, Gong W, Kanai M, Schlunk C, Wang L, Yao JC, et al. Drastic down-regulation of Kruppel-like factor 4 expression is critical in human gastric cancer development and progression. Cancer Res. 2005;65:2746–54.CrossRefPubMedGoogle Scholar
  28. 28.
    Meza-Sosa KF, Perez-Garcia EI, Camacho-Concha N, Lopez-Gutierrez O, Pedraza-Alva G, Perez-Martinez L. MiR-7 promotes epithelial cell transformation by targeting the tumor suppressor KLF4. PLoS One. 2014;9:e103987.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Medical Scientific Research CentreGuangxi Medical UniversityNanningPeople’s Republic of China
  2. 2.Department of Gastrointestinal SurgeryFirst Affiliated Hospital of Guangxi Medical UniversityNanningPeople’s Republic of China
  3. 3.Department of Gastrointestinal SurgeryAffiliated Tumor Hospital of Guangxi Medical UniversityNanningPeople’s Republic of China

Personalised recommendations