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Original article
MicroRNA-200c modulates epithelial-to-mesenchymal transition (EMT) in human colorectal cancer metastasis
  1. Keun Hur1,
  2. Yuji Toiyama1,
  3. Masanobu Takahashi1,
  4. Francesc Balaguer1,
  5. Takeshi Nagasaka2,
  6. Junichi Koike3,
  7. Hiromichi Hemmi4,
  8. Minoru Koi1,
  9. C Richard Boland1,
  10. Ajay Goel1
  1. 1Gastrointestinal Cancer Research Laboratory, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA
  2. 2Department of Gastroenterological Surgery and Surgical Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama, Japan
  3. 3Department of Surgery, Faculty of Medicine, Toho University, Ohta-ku, Tokyo, Japan
  4. 4Department of Molecular Biology, Faculty of Medicine, Toho University, Ohta-ku, Tokyo, Japan
  1. Correspondence to Dr Ajay Goel, Gastrointestinal Cancer Research Laboratory, Baylor University Medical Center, 3500 Gaston Avenue, Suite H-250, Dallas, TX 75246, USA; ajay.goel{at}baylorhealth.edu Dr C Richard Boland, Gastrointestinal Cancer Research Laboratory, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA; rick.boland{at}baylorhealth.edu

Abstract

Objective Distant metastasis is the major cause of cancer-related death in patients with colorectal cancer (CRC). Although the microRNA-200 (miR-200) family is a crucial inhibitor of epithelial-to-mesenchymal transition (EMT) in human cancer, the role of miR-200 members in the pathogenesis of metastatic CRC has not been investigated.

Design Fifty-four pairs of primary CRC and corresponding matched liver metastasis tissue specimens were analysed for expression and methylation status of the miR-200 family members. Functional analysis of miR-200c overexpression was investigated in CRC cell lines, and cells were analysed for proliferation, invasion and migration. Expression of several miR-200c target genes (ZEB1, ETS1 and FLT1) and EMT markers (E-cadherin and vimentin) in CRC cell lines and tissue specimens was validated.

Results Liver metastasis tissues showed higher expression of miR-200c (primary CRC=1.31 vs. liver metastasis=1.59; p=0.0014) and miR-141 (primary CRC=0.14 vs. liver metastasis=0.17; p=0.0234) than did primary CRCs, which was significantly associated with hypomethylation of the promoter region of these miRNAs (primary CRC=61.2% vs. liver metastasis=46.7%; p<0.0001). The invasive front in primary CRC tissues revealed low miR-200c expression by in situ hybridization analysis. Transfection of miR-200c precursors resulted in enhanced cell proliferation but reduced invasion and migration behaviours in CRC cell lines. Overexpression of miR-200c in CRC cell lines caused reduced expression of putative gene targets, and resulted in increased E-cadherin and reduced vimentin expression. The associations between miR-200c, target genes and EMT markers were validated in primary CRCs and matching liver metastasis tissues.

Conclusions miR-200c plays an important role in mediating EMT and metastatic behaviour in the colon. Its expression is epigenetically regulated, and miR-200c may serve as a potential diagnostic marker and therapeutic target for patients with CRC.

  • Colorectal cancer
  • metastasis
  • miR-200c
  • EMT
  • methylation
  • cancer
  • carcinogenesis
  • cell biology
  • gastric cancer
  • cancer genetics
  • cancer syndromes
  • chemotherapy
  • abdominal surgery
  • colorectal antral surgery
  • hepatic surgery
  • DNA microsatellite instability
  • juvenile polyposis
  • HNPCC syndrome
  • familial adenomatous polyposis
  • cancer prevention
  • non-steroidal
  • colon carcinogenesis
  • 5-aminosalicylic acid (5-ASA)
  • molecular genetics

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Footnotes

  • Correction notice This article has been corrected since it was published Online First. Figure 3A has been updated.

  • Funding The present work was supported by grants R01 CA72851 and CA129286 from the National Cancer Institute, National Institutes of Health and funds from the Baylor Research Institute to CRB and AG.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval The study was approved by the institutional review boards of all participating institutions.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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