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Serum miR-200c Is a Novel Prognostic and Metastasis-Predictive Biomarker in Patients With Colorectal Cancer

Toiyama, Yuji MD, PhD*,†; Hur, Keun PhD*; Tanaka, Koji MD, PhD; Inoue, Yasuhiro MD, PhD; Kusunoki, Masato MD, PhD; Boland, C. Richard MD*; Goel, Ajay PhD*

doi: 10.1097/SLA.0b013e3182a6909d
Original Articles

Objective: To evaluate the ability of epithelial-to-mesenchymal transition–related microRNAs (miRNAs) as serum biomarkers for prognosis and prediction of metastasis in patients with colorectal cancer (CRC).

Background: Epithelial-to-mesenchymal transition–related miRNAs drive CRC progression and metastasis. However, their potential as serum biomarkers in CRC has not been studied.

Methods: This was a 3-phase study using 446 colorectal specimens. In the first phase, we selected candidate miRNAs associated with metastasis by analyzing the expression of 4 miR-200 family members (miR-200b, -200c, -141, and -429) in serum samples from 12 patients with stage I and IV CRC. The second phase involved independent validation of candidate miRNAs in serum from 182 patients with CRC and 24 controls. Finally, we analyzed expression in matched 156 tumor tissues from 182 patients with CRC and an independent set of 20 matched primary CRC and corresponding liver metastases to identify the source of circulating miRNAs.

Results: After initial screening, miR-200c was selected as the candidate serum miRNA best associated with metastasis. Validation analysis revealed that serum miR-200c levels were significantly higher in stage IV than in stage I–III CRCs. High serum miR-200c demonstrated a significant positive correlation with lymph node metastasis, distant metastasis, and prognosis (P = 0.0026, P = 0.0023, and P = 0.0064, respectively). More importantly, serum miR-200c was an independent predictor for lymph node metastasis (odds ratio: 4.81, 95% confidence interval: 1.98–11.7, P = 0.0005) and tumor recurrence (hazard ratio: 4.51, 95% confidence interval: 1.56–13.01, P = 0.005) and emerged as an independent prognostic marker for CRC (hazard ratio: 2.67, 95% confidence interval: 1.28–5.67, P = 0.01).

Conclusions: Serum miR-200c has strong potential to serve as a noninvasive biomarker for CRC prognosis and predicting metastasis.

Supplemental Digital Content is Available in the Text.We demonstrated that serum miR-200c levels increased in a stage-dependent manner and were significantly higher in stage IV patients. Furthermore, high serum miR-200c expression was significantly associated with tumor metastasis (lymph node, liver, or other organs) and emerged as independent factors for reduced disease-free and overall survival. Finally, we provide potential insights into the origin of high serum miR-200c levels in patients with advanced CRC and metastasis.

*Gastrointestinal Cancer Research Laboratory, Division of Gastroenterology, Department of Internal Medicine, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, Dallas, TX

Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie, Japan.

Reprints: Ajay Goel, PhD, Baylor University Medical Center, 3500 Gaston Ave, Gastrointestinal Cancer Research Laboratory, Ste H-250, Dallas, TX 75246. E-mail: ajay.goel@baylorhealth.edu or C. Richard Boland; rickbo@baylorhealth.edu.

Supported by grants R01 CA72851 and CA129286 from the National Cancer Institute, National Institutes of Health, and funds from the Baylor Research Institute to C.R.B. and A.G. This study was also supported by a pilot project grant from the Charles A Sammons Cancer Center, Baylor University Medical Center to A.G.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.annalsofsurgery.com).

Disclosure: The authors have no conflict of interests to disclose.

© 2014 by Lippincott Williams & Wilkins.