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MiR-139-5p as a novel serum biomarker for recurrence and metastasis in colorectal cancer.

ABSTRACT: Approximately 30-50% of colorectal cancer (CRC) patients who undergo curative resection subsequently experience tumor recurrence or metastasis. Although microRNAs (miRNAs) are a class of small noncoding RNAs frequently deregulated in various human malignancies, it remains unknown if these can help predict recurrence and metastasis in CRC patients. MiRNAs were initially screened using miRNA-microarray and miRNA-seq datasets with or without recurrence. Candidate miRNAs were then tested in two independent cohorts of 111 stage II/III and 139 stage I-III CRC patients, as well as serum samples and matched primary and metastatic liver tissues. An animal model of peritoneal dissemination was used to assess the oncogenic role of the target miRNA. Four candidate miRNAs were identified during the initial screening, and we subsequently validated upregulation of miR-139-5p in two independent clinical cohorts, wherein it associated with poor recurrence-free survival. Moreover, miR-139-5p were also upregulated in the serum of recurrence-positive CRC patients and yielded significantly shorter recurrence-free survival. Intriguingly, miR-139-5p was upregulated in metastatic liver tissues and negatively correlated with genes associated with epithelial-mesenchymal transition. Lastly, we showed that miR-139-5p overexpression enhanced peritoneal dissemination in a mouse model. In conclusion, we identified miR-139-5p as a novel biomarker for tumor recurrence and metastasis in CRC.

SUBMITTER: Miyoshi J

PROVIDER: S-EPMC5338356 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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MiR-139-5p as a novel serum biomarker for recurrence and metastasis in colorectal cancer.

Miyoshi Jinsei J Toden Shusuke S Yoshida Kazuhiro K Toiyama Yuji Y Alberts Steven R SR Kusunoki Masato M Sinicrope Frank A FA Goel Ajay A

Scientific reports 20170306

Approximately 30-50% of colorectal cancer (CRC) patients who undergo curative resection subsequently experience tumor recurrence or metastasis. Although microRNAs (miRNAs) are a class of small noncoding RNAs frequently deregulated in various human malignancies, it remains unknown if these can help predict recurrence and metastasis in CRC patients. MiRNAs were initially screened using miRNA-microarray and miRNA-seq datasets with or without recurrence. Candidate miRNAs were then tested in two inde ...[more]

PMID: 28262692

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Project description:BACKGROUND:Accumulating evidence indicates that long non-coding RNAs (lncRNAs) acting as crucial regulators in tumorigenesis. However, its biological functions of lncRNAs in colorectal cancer (CRC) have not been systematically clarified. METHODS:An unbiased screening was performed to identify disregulated lncRNAs revealed to be implicated in CRC carcinogenesis according to an online-available data dataset. In situ hybridization (ISH), RT-qPCR and RNA fluorescence in situ hybridization (RNA-FISH) were applied to detect RP11-757G1.5 expression in CRC tissues and cell lines. The associations of RP11-757G1.5 with clinicopathological characteristics were analyzed. Their effects on prognosis were analyzed by the Kaplan-Meier analysis, Log-rank test, Univariate and Multivariate Cox regression analysis. The potential biological function of RP11-757G1.5 in CRC was investigated by Colony formation, Edu cell proliferation, Flow cytometry, Wound healing and Transwell assays. Bioinformatics binding site analysis, Luciferase reporter assay, Ago2 immunoprecipitation assays, RNA pull-down assay, RT-qPCR and Western blotting were utilized to demonstrate the mechanism of RP11-757G1.5 acts as a molecular sponge of miR-139-5p to regulate the expression of YAP1. Finally, we further explore the potential role of RP11-757G1.5 in CRC orthotopic xenografts in vivo. RESULTS:We discovered a novel oncogenic lncRNA RP11-757G1.5, that was overexpressed in CRC tissues, especially in aggressive cases. Moreover, up-regulation of RP11-757G1.5 strongly correlated with poor clinical outcomes of patients with CRC. Functional analyses revealed that RP11-757G1.5 promoted cell proliferation in vitro and in vivo. Furthermore, RP11-757G1.5 stimulated cell migration and invasion in vitro and in vivo. Mechanistic studies illustrated that RP11-757G1.5 regulated the expression of YAP1 through sponging miR-139-5p and inhibiting its activity thereby promoting CRC progression and development. CONCLUSIONS:Altogether, these results reveal a novel RP11-757G1.5/miR-139-5p/YAP1 regulatory axis that participates in CRC carcinogenesis and progression.

Project description:Introduction: Colorectal cancer (CRC) frequently harbors KRAS mutations that result in chemoresistance and metastasis. MicroRNAs (miRNAs) are usually dysregulated and play important regulatory roles in tumor progression. However, the KRAS mutation-responsive miRNA profile in CRC remains uninvestigated.Methods: miR-139-5p was identified and evaluated by small RNA sequencing, qRT-PCR and in situ hybridization. The roles of miR-139-5p in CRC cells with and without KRAS mutation were determined by Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry and transwell assays in vitro and by tumorigenesis and metastasis assays in vivo. Microarrays followed by bioinformatic analyses, luciferase reporter assays and Western blotting were applied for mechanistic studies.Results: miR-139-5p was significantly downregulated in KRAS-mutated CRC cells and tissues compared with their wild-type counterparts. Low miR-139-5p expression was associated with aggressive phenotypes and poor prognosis in CRC patients. miR-139-5p overexpression inhibited CRC cell proliferation, migration and invasion in vitro, sensitized tumors to chemotherapy, and impaired tumor growth and metastasis in vivo. Transcriptomic profiling identified multiple modulators in the Ras (JUN and FOS) and Wnt (CTNNB1 and DVL1) signaling pathways and the epithelial-to-mesenchymal transition (EMT) process (ZEB1) as direct targets of miR-139-5p, and inverse correlations were confirmed in CRC clinical tissues. Aberrantly activated Wnt signaling in KRAS-mutant cells was demonstrated to transcriptionally repress miR-139-5p through TCF4, forming a miR-139-5p/Wnt signaling double-negative feedback loop.Conclusions: We identified miR-139-5p as a KRAS-responsive miRNA and demonstrated its involvement in CRC progression. KRAS mutation disrupted the miR-139-5p/Wnt signaling reciprocal negative feedback mechanism, which might cause miR-139-5p downregulation and derepression of oncogenic signaling pathways and EMT. These results reveal a transcriptional regulatory mode of KRAS-driven malignant transformation and highlight miR-139-5p as a novel regulator of crosstalk between the Ras and Wnt signaling pathways in CRC.

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MiR-139-5p as a novel serum biomarker for recurrence and metastasis in colorectal cancer.

Publications

MiR-139-5p as a novel serum biomarker for recurrence and metastasis in colorectal cancer.

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