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. 2011 Mar 17;6(3):e17745.
doi: 10.1371/journal.pone.0017745.

Circulating plasma MiR-141 is a novel biomarker for metastatic colon cancer and predicts poor prognosis

Hanyin Cheng  1 , Lina Zhang, David E Cogdell, Hong Zheng, Aaron J Schetter, Matti Nykter, Curtis C Harris, Kexin Chen, Stanley R Hamilton, Wei Zhang
Affiliations

Circulating plasma MiR-141 is a novel biomarker for metastatic colon cancer and predicts poor prognosis

Hanyin Cheng et al. PLoS One. .

Abstract

Background: Colorectal cancer (CRC) remains one of the major cancer types and cancer related death worldwide. Sensitive, non-invasive biomarkers that can facilitate disease detection, staging and prediction of therapeutic outcome are highly desirable to improve survival rate and help to determine optimized treatment for CRC. The small non-coding RNAs, microRNAs (miRNAs), have recently been identified as critical regulators for various diseases including cancer and may represent a novel class of cancer biomarkers. The purpose of this study was to identify and validate circulating microRNAs in human plasma for use as such biomarkers in colon cancer.

Methodology/principal findings: By using quantitative reverse transcription-polymerase chain reaction, we found that circulating miR-141 was significantly associated with stage IV colon cancer in a cohort of 102 plasma samples. Receiver operating characteristic (ROC) analysis was used to evaluate the sensitivity and specificity of candidate plasma microRNA markers. We observed that combination of miR-141 and carcinoembryonic antigen (CEA), a widely used marker for CRC, further improved the accuracy of detection. These findings were validated in an independent cohort of 156 plasma samples collected at Tianjin, China. Furthermore, our analysis showed that high levels of plasma miR-141 predicted poor survival in both cohorts and that miR-141 was an independent prognostic factor for advanced colon cancer.

Conclusions/significance: We propose that plasma miR-141 may represent a novel biomarker that complements CEA in detecting colon cancer with distant metastasis and that high levels of miR-141 in plasma were associated with poor prognosis.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Plasma miR-141, miR-21 and miR-92 levels in healthy controls and colon cancer patients.
(A) Each row corresponds to a plasma miRNA and each column corresponds to each sample. Expression levels for each miRNA are normalized across the samples and shaded in colors such that red denotes high expression and green denotes low expression. Spearman correlation shows that miR-141 is highly correlated with stages (r = 0.605, P = 1.17×10−8). (B–G) The relative levels of selected plasma microRNAs were normalized to spike-in control cel-miR-39 and shown as the log10 of the relative quantity (RQ). The Wilcoxon two-sample tests were performed to examine the difference of selected plasma microRNAs between normal controls and colon cancer patients (B–D), or between normal controls and/or colon cancer patients with different clinical stages (E–G).
Figure 2
Figure 2. Higher plasma miR-141 is significantly associated with Stage IV colon cancer in the training set.
(A) Small RNA was isolated from plasma samples and miR-141 was measured by quantitative RT-PCR assays. The Wilcoxon two-sample test was performed to evaluate differences of miR-141 levels between the Stage III and Stage I–II groups. ROC analysis was performed to determine the sensitivity and specificity with the value of AUC in the right panel. The Wilcoxon two-sample tests between (B) Stage IV and Stage I–II, (C) Stage IV and Sage III, and (D) Stage IV and Stage I–III groups were performed to evaluate the association of plasma miR-141 with Stage IV disease status.
Figure 3
Figure 3. Combination of CEA and miR-141 identifies additional Stage IV cases in the training cohort.
Two-parameter (expression of miR-141 and CEA in plasma) classification is used to discriminate distant metastatic colon cancer. The cut-off value for CEA is 5.0 ng/mL, and for miR-141 is 16.77 defined from the ROC curve. The corresponding cut-off values are marked by grey lines.
Figure 4
Figure 4. Higher plasma miR-141 level is associated with Stage IV colon cancer patients in the validation data set.
Small RNA isolation and miR-141 quantitative RT-PCR assays were performed in the same way as for the training cohort. (A) The Wilcoxon two-sample test was performed to compare miR-141 levels between normal controls and/or colon cancer patients with different clinical stages. (B–D) The same analyses were performed to compare miR-141 levels between Stage IV cases and Stage I–II cases (B), between Stage IV and Stage III cases (C), and between Stage IV and Stage I–III cases (D), respectively. ROC analysis was performed to determine the sensitivity and specificity with the value of AUC in the right panel. (E) Combination of CEA and miR-141 identified additional metastatic patients that were missed by either marker alone. See Figure 3 for the definition of the cut-off values for CEA and miR-141.
Figure 5
Figure 5. MiR-141 in tumor tissues is not associated with colon cancer tumor stage.
(A) Total RNA was isolated from tumor tissues of metastatic or non-metastatic patients from the Tianjin cohort, and the miR-141 levels were measured with quantitative RT-PCR using RNU6B as an endogenous control. The Wilcoxon two-sample test was performed to compare miR-141 expression in tumor tissues between these two groups. A P<0.05 is considered significant. (B) The miR-141 expression levels were measured using microRNA profiling data from the Maryland cohort of CRC samples. The Wilcoxon matched-pairs tests were performed to compare the miR-141 levels between tumor tissues and adjacent normal tissues in these CRC patients.
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