miR-224 overexpression is a strong and independent prognosticator of short-term relapse and poor overall survival in colorectal adenocarcinoma

Adamopoulos, Panagiotis G.; Kontos, Christos K.; Rapti, Stamatia-Maria; Papadopoulos, Iordanis N.; Scorilas, Andreas

doi:10.3892/ijo.2014.2775

Cited by 41 publications

(26 citation statements)

References 66 publications

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“…In addition to this discovery step, we analyzed two independent patient cohorts to validate that miR-139-5p is a potential biomarker for CRC recurrence. Supporting these results, several studies have reported that miRNAs such as miR-21, miR-29a, miR-34a, and miR-224 are deregulated during relapse and in metastatic CRC and were able to predict patients with high risk of recurrence28293031. However, these studies had several limitations, including inadequate sample size, lack of systematic and comprehensive discovery approach and lack of a validation patient cohort.…”

Section: Discussionmentioning

confidence: 83%

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

Miyoshi

Toden

Yoshida

et al. 2017

Sci Rep

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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.

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Section: Discussionmentioning

confidence: 83%

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

Miyoshi

Toden

Yoshida

et al. 2017

Sci Rep

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“…The role of miR-224 during CRC initiation and progression remains controversial [15, 16, 17, 18, 19, 20, 21]: MiR-224 is overexpressed in inflammatory bowel disease-associated CRC [21], it promotes CRC tumor growth in mice by repressing PHLPP1 and PHLPP2 [19], and ectopic miR-224 expression decreases the chemoradiosensitivity of CRC [22], all of which suggests an oncogenic function. Yet, reports that methotrexate-resistant colon cancer cells express lower miR-224 [23], and that miR-224 suppresses tumor growth and metastasis in vivo [20] suggest that an opposite role in CRC may be true.…”

Section: Discussionmentioning

confidence: 99%

The clinical and biological significance of MIR-224 expression in colorectal cancer metastasis

Ling

Pickard

Ivan

et al. 2015

Gut

120

106

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Objective MicroRNA (miRNA) expression profile can be used as prognostic marker for human cancers. We aim to explore the significance of miRNAs in colorectal cancer (CRC) metastasis. Design We performed miRNA microarrays using primary CRC tissues from patients with and without metastasis, and validated selected candidates in 85 CRC samples by qRT-PCR. We tested metastatic activity of selected miRNAs, and identified miRNA targets by prediction algorithms, qRT-PCR, western blot and luciferase assays. Clinical outcomes were analyzed in six sets of CRC cases (n=449) including The Cancer Genome Atlas consortium and correlated with miR-224 status. We used the Kaplan-Meier method and log-rank test to assess the difference in survival between patients with low or high levels of miR-224 expression. Results MiR-224 expression increases consistently with tumor burden and microsatellite stable (MSS) status, and miR-224 enhances CRC metastasis in vitro and in vivo. We identified SMAD4 as a miR-224 target, and observed negative correlation (Spearman Rs=−0.44, p<0.0001) between SMAD4 and miR-224 expression in clinical samples. Patients with high miR-224 levels display shorter overall survival in multiple CRC cohorts (p=0.0259, 0.0137, 0.0207, 0.0181, 0.0331 and 0.0037 respectively), and shorter metastasis-free survival (hazard ratio 6.51, 95% CI 1.97-21.51, p=0.0008). In the TCGA set, combined analysis of miR-224 with SMAD4 expression enhanced correlation with survival (hazard ratio 4.12, 95% CI 1.1-15.41, p=0.0175). Conclusion MiR-224 promotes CRC metastasis, at least in part, through the regulation of SMAD4. MiR-224 expression in primary CRC, alone or combined with its targets, may have prognostic value for CRC patient survival.

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“…It has been established that an miRNA can have a predominantly oncogenic role in one type of cancer and a tumor suppressive role in another; for instance, miR-224 was identified to be a tumor suppressor in prostate cancer (30), whereas in other types of malignancy, including gastric (11,31) and colorectal cancer (32), an oncogenic role for miR-224 was described. The ambiguous role of miR-224 was also observed within the SCC histological subtype of NSCLC in the present study.…”

Section: Discussionmentioning

confidence: 99%

Predictive relevance of miR‑34a, miR‑224 and miR‑342 in patients with advanced squamous cell carcinoma of the lung undergoing palliative chemotherapy

et al. 2017

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Abstract. Attributing to their pathophysiological role and stability in biological samples, microRNAs (miRNAs) have the potential to become valuable predictive markers for non-small cell lung cancer (NSCLC). Samples of biopsy tissue constitute suitable material for miRNA profiling with the aim of predicting the effect of palliative chemotherapy. The present study group included 81 patients (74 males, 7 females, all smokers or former smokers) with the squamous cell carcinoma (SCC) histological subtype of NSCLC at a late stage (3B or 4). All patients received palliative chemotherapy based on platinum derivatives in combination with paclitaxel or gemcitabine. The expression of 17 selected miRNAs was measured by reverse transcription-quantitative polymerase chain reaction in tumor tissue macrodissected from formalin-fixed paraffin-embedded (FFPE) tissue samples. To predict the effect of palliative chemotherapy, the association between gene expression levels and overall survival (OS) time was analyzed. From the 17 miRNAs of interest, low expression levels of miR-342 and high expression levels of miR-34a and miR-224 were associated with a reduced OS time in subgroups of patients based on smoking status and treatment modality. Using cluster analysis, associations between combinations of miR-34a, -224 and -342 expression levels with patient survival were identified. The present study revealed that patients with the simultaneous high expression of miR-224 and -342 had a similar prognostic outcome to those with the low expression of miR-224 and -342, which was significantly reduced, compared with patients exhibiting high expression of either miR-224 or miR-342 with low expression of the other. We hypothesize that the effect of a particular miRNA is dependent on the expression level of other members of the miRNA network. This finding appears to complicate survival analyses based on individual miRNAs as markers. In conclusion, the present study provides evidence that specific miRNAs were associated with OS time, which may be candidate predictors for the effectiveness of palliative treatment in SCC lung cancer patients. This objective can be better achieved by combining more markers together than by using individual miRNAs.

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miR-224 overexpression is a strong and independent prognosticator of short-term relapse and poor overall survival in colorectal adenocarcinoma

Cited by 41 publications

References 66 publications

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

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

The clinical and biological significance of MIR-224 expression in colorectal cancer metastasis

Predictive relevance of miR‑34a, miR‑224 and miR‑342 in patients with advanced squamous cell carcinoma of the lung undergoing palliative chemotherapy

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