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Circulating microRNA-203 predicts prognosis and metastasis in human colorectal cancer.

ABSTRACT: Distant metastasis is a major cause of deaths in patients with colorectal cancer (CRC), which is partly due to lack of robust metastasis-predictive biomarkers. In spite of the important function of microRNA (miR)-203 in cancer metastasis, its clinical significance in CRC metastasis remains unknown. Here, we evaluated the potential role of serum miR-203 as a non-invasive biomarker for CRC metastasis.MiR-203 expression was quantified by quantitative reverse-transcription PCR in 58 pairs of primary CRC (pCRC) and corresponding matched liver metastasis (LM), as well as 186 serum and 154 matched tissue specimens from patients with CRC in cohort 1. Next, we performed validation of miR-203 levels in serum from 144 patients with CRC in an independent cohort (cohort 2). Mouse models of CRC-associated metastases were established to identify the source of circulating miR-203. Expression patterns of miR-203 in tissues were determined by in situ hybridisation.MiR-203 expression was significantly upregulated in LM compared with matched pCRC tissues. Serum miR-203 levels were significantly upregulated in a stage-dependent manner, and high miR-203 expression was associated with poor survival in patients with CRC in both patient cohorts. Increased miR-203 levels in serum indicated high risk for poor prognosis (HR=2.1), as well as metastasis to lymph nodes (OR=2.5), liver (OR=6.2), peritoneum (OR=7.2) and distant organs (OR=4.4). Serum miR-203 levels were significantly higher in animals with liver or systemic metastasis compared with controls.High levels of serum miR-203 associate with poor survival and metastasis, suggesting it to be a promising non-invasive prognostic and metastasis-predictive biomarker in patients with CRC.

SUBMITTER: Hur K

PROVIDER: S-EPMC4919275 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Circulating microRNA-203 predicts prognosis and metastasis in human colorectal cancer.

Hur Keun K Toiyama Yuji Y Okugawa Yoshinaga Y Ide Shozo S Imaoka Hiroki H Boland C Richard CR Goel Ajay A

Gut 20151223 4

<h4>Background and aims</h4>Distant metastasis is a major cause of deaths in patients with colorectal cancer (CRC), which is partly due to lack of robust metastasis-predictive biomarkers. In spite of the important function of microRNA (miR)-203 in cancer metastasis, its clinical significance in CRC metastasis remains unknown. Here, we evaluated the potential role of serum miR-203 as a non-invasive biomarker for CRC metastasis.<h4>Methods</h4>MiR-203 expression was quantified by quantitative reve ...[more]

PMID: 26701878

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Project description:BackgroundMetastasis is the most frequent cause of treatment failure and death in colorectal cancer. Early detection of tumors and metastases is crucial for improving treatment strategies and patient outcome. Development of reliable biomarkers and simple tests routinely applicable in the clinic for detection, prognostication, and therapy monitoring is of special interest. We recently identified the novel gene Metastasis-Associated in Colon Cancer 1 (MACC1), a key regulator of the HGF/Met-pathway. MACC1 is a strong prognostic biomarker for colon cancer metastasis and allows identification of high-risk subjects in early stages, when determined in patients' primary tumors. To overcome the limitation of a restricted number of molecular analyses in tumor tissue, the establishment of a non-invasive blood test for early identification of high-risk cancer patients, for monitoring disease course and therapy response is strongly needed.Methodology/principal findingsFor the first time, we describe a non-invasive assay for quantification of circulating MACC1 transcripts in blood of more than 300 colorectal cancer patients. MACC1 transcript levels are increased in all disease stages of the cancer patients compared to tumor-free volunteers. Highest MACC1 levels were determined in individuals with metastases (all P<0.05). Importantly, high MACC1 levels correlate with unfavorable survival (P<.0001). Combining MACC1 with circulating transcripts of the metastasis gene S100A4, a transcriptional target of the Wnt/?-catenin-pathway, improves survival prediction for newly diagnosed cancer patients.Conclusion/significanceThis blood-based assay for circulating MACC1 transcripts, which can be quantitated on a routine basis, is clinically applicable for diagnosis, prognosis, and therapeutic monitoring of cancer patients. Here we demonstrate the diagnostic and prognostic value of circulating MACC1 transcripts in patient plasma for metastasis and survival. Since MACC1 represents a promising target for anti-metastatic therapies, circulating MACC1 transcripts may prove to be an ideal read-out for monitoring therapeutic response of future interventions targeting MACC1-induced metastasis in cancer patients.

Project description:Distant metastasis is the major cause of mortality in colorectal cancer (CRC). We performed a systemic, comprehensive discovery for expression patterns of metastasis-specific microRNAs (miRNAs) by directly comparing primary CRCs (pCRCs) and matched liver metastases (LMs) and evaluated the feasibility of their clinical application as metastasis-specific biomarkers. CRC metastasis-specific miRNA profiles were generated by analyzing nine pairs of pCRC and LM tissues, followed by quantitative validation in an independent cohort of 58 pairs of matched pCRC and LM tissues. We evaluated associations between miRNA expression and patient survival and ability to predict metastasis in another 84 patients with CRC. Subsequently, associations were quantitatively validated in 175 CRC tissues and 169 serum samples. Kaplan-Meier, Cox regression, and logistic regression analyses were used. All statistical tests were two-sided. Twenty-three miRNAs were identified that were differentially expressed between pCRC and LM (P < .001; FDR < .5). Four miRNAs downregulated in LM (let-7i, miR-10b, miR-221, and miR-320a) and one upregulated miR (miR-885-5p) were quantitatively validated in pCRC (P < .0001). Low let-7i expression in pCRC tissue predicted worsened prognosis (hazard ratio [HR] = 5.0, 95% confidence interval [CI] = 1.0 to 24.4, P = .0479) as well as distant metastasis (odds ratio [OR] = 5.5, 95% CI = 1.1 to 26.8, P = .0334). High miR-10b expression in pCRC tissue independently predicted distant metastasis (OR = 4.9, 95% CI = 1.2 to 19.7, P = .0248). High serum miR-885-5p expression independently predicted prognosis (HR = 2.9, 95% CI = 1.1 to 7.5, P = .0323), LN metastasis (OR = 3.0, 95% CI = 1.3 to 7.2, P = .0116), and distant metastasis (OR = 3.1, 95% CI = 1.0 to 10.0, P = .0456), whereas tissue miR-885-5p expression did not. Expression patterns of miRNAs were confirmed by in situ hybridization. We discovered a metastasis-specific miRNA signature in pCRCs and discovered novel tissue- and serum-based CRC metastasis-specific miRNA biomarkers through intensive validation. These unique miRNAs may be clinically applicable to predict prognosis and distant metastasis in CRC.

Project description:BackgroundSarcopenia frequently occurs in metastatic cancer patients. Emerging evidence has revealed that various secretory products from metastatic tumours can influence host organs and promote sarcopenia in patients with malignancies. Furthermore, the biological functions of microRNAs in cell-to-cell communication by incorporating into neighbouring or distal cells, which have been gradually elucidated in various diseases, including sarcopenia, have been elucidated.MethodsWe evaluated psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC) using pre-operative computed tomography imaging in 183 colorectal cancer (CRC) patients. miR-203 expression levels in CRC tissues and pre-operative serum were evaluated using quantitative polymerase chain reaction. Functional analysis of miR-203 overexpression was investigated in human skeletal muscle cells (SkMCs), and cells were analysed for proliferation and apoptosis. Expressions of several putative miR-203 target genes (CASP3, CASP10, BIRC5, BMI1, BIRC2, and BIRC3) in SKMCs were validated.ResultsA total of 183 patients (108 men and 75 women) were included. The median age of enrolled patients at diagnosis was 68.0 years (range 35-89 years). High IMAC status significantly correlated with female gender (P = 0.004) and older age (P = 0.0003); however, no other clinicopathological factors correlated with IMAC status in CRC patients. In contrast, decreased PMI significantly correlated with female gender (P = 0.006) and all well-established disease development factors, including advanced T stage (P = 0.035), presence of venous invasion (P = 0.034), lymphovascular invasion (P = 0.012), lymph node (P = 0.001), distant metastasis (P = 0.002), and advanced Union for International Cancer Control tumour-node-metastasis stage classification (P = 0.0004). Although both high IMAC status and low PMI status significantly correlated with poor overall survival (IMAC: P = 0.0002; PMI: P < 0.0001; log-rank test) and disease-free survival (IMAC: P = 0.0003; PMI: P = 0.0002; log-rank test), multivariate Cox's regression analysis revealed that low PMI was an independent prognostic factor for both overall survival (hazard ratio: 4.69, 95% confidence interval (CI): 2.19-10, P = 0.0001) and disease-free survival (hazard ratio: 2.33, 95% CI: 1.14-4.77, P = 0.021) in CRC patients. Serum miR-203 expression negatively correlated with pre-operative PMI level (P = 0.0001, ρ = -0.25), and multivariate logistic regression analysis revealed that elevated serum miR-203 was an independent risk factor for myopenia (low PMI) in CRC patients (odds ratio: 5.16, 95% CI: 1.8-14.8, P = 0.002). Overexpression of miR-203 inhibited cell proliferation and induced apoptosis via down-regulation of BIRC5 (survivin) expression in human SkMC line.ConclusionsAssessment of serum miR-203 expression could be used for risk assessment of myopenia, and miR-203 might be a novel therapeutic target for inhibition of myopenia in CRC.

Dataset Information

Circulating microRNA-203 predicts prognosis and metastasis in human colorectal cancer.

Publications

Circulating microRNA-203 predicts prognosis and metastasis in human colorectal cancer.

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