Dataset Information

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

ABSTRACT: 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 quantitative real-time PCR (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 analysed in six sets of CRC cases (n=449), including The Cancer Genome Atlas (TCGA) 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 tumour burden and microsatellite stable 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 (HR 6.51, 95% CI 1.97 to 21.51, p=0.0008). In the TCGA set, combined analysis of miR-224 with SMAD4 expression enhanced correlation with survival (HR 4.12, 95% CI 1.1 to 15.41, p=0.0175). CONCLUSIONS: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 survival of patients with CRC.

SUBMITTER: Ling H

PROVIDER: S-EPMC4581915 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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

Ling Hui H Pickard Karen K Ivan Cristina C Isella Claudio C Ikuo Mariko M Mitter Richard R Spizzo Riccardo R Bullock Marc M Braicu Cornelia C Pileczki Valentina V Vincent Kimberly K Pichler Martin M Stiegelbauer Verena V Hoefler Gerald G Almeida Maria I MI Hsiao Annie A Zhang Xinna X Primrose John J Packham Graham G Liu Kevin K Bojja Krishna K Gafà Roberta R Xiao Lianchun L Rossi Simona S Song Jian H JH Vannini Ivan I Fanini Francesca F Kopetz Scott S Zweidler-McKay Patrick P Wang Xuemei X Ionescu Calin C Irimie Alexandru A Fabbri Muller M Lanza Giovanni G Hamilton Stanley R SR Berindan-Neagoe Ioana I Medico Enzo E Mirnezami Alex A Calin George A GA Calin George A GA Nicoloso Milena S MS

Gut 20150324 6

<h4>Objective</h4>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.<h4>Design</h4>We performed miRNA microarrays using primary CRC tissues from patients with and without metastasis, and validated selected candidates in 85 CRC samples by quantitative real-time PCR (qRT-PCR). We tested metastatic activity of selected miRNAs and identified miRNA targets by prediction algorithms, ...[more]

PMID: 25804630

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Project description:BackgroundAt present, there is a lack of novel biomarkers for the early diagnosis and targeted therapy of colorectal cancer (CRC). The current study investigated the expression of miR-17-5p in colorectal tumors and adjacent tissues, and examined the effects of miR-17-5p on the cellular growth of the colon cancer cell line HCT-116.MethodsA total of 30 paired tissue specimens were obtained from patients with CRC who were admitted to the Department of General Surgery V of the First Affiliated Hospital, Gannan Medical College between December 2019 and January 2021. The clinical information for the corresponding patients was collated. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) was performed to detect the expression of miR-17-5p in tumor tissues and the paracancerous tissues. The relationship between miR-17-5p and clinicopathology was analyzed. The CRC cell line HCT-116 was transfected with miR-17-5p mimics and inhibitors using liposomes. The effects of miR-17-5p on cell proliferation, invasion and migration, and apoptosis were determined using colon formation assays, transwell and scratch assays, and flow cytometry, respectively. The effects of miR-17-5p on CD44 (homing cell adhesion molecule), MMP2 (matrix metalloproteinase 2), BCL2 (B-cell lymphoma-2), BAX (BCL2-associated X), and E-cadherin protein and gene expression were investigated using Western blot and RT-qPCR, respectively.ResultsMiR-17-5p expression was higher in tumor tissues compared to the normal adjacent tissues. While miR-17-5p expression levels were unrelated to age nor gender, they were related to the degree of differentiation, stage, lymph node metastasis, and tumor size in patients with CRC. Upregulation of miR-17-5p promoted CRC cell proliferation, metastasis, and invasion, while inhibiting apoptosis. However, downregulation of miR-17-5p had the opposite effect. Furthermore, miR-17-5p upregulation increased E-cadherin, CD44, MMP2, and BCL2 expression while decreasing BAX expression, whereas miR-17-5p downregulation had the opposite effect.ConclusionsMiR-17-5p is highly expressed in tumor tissues and correlates with increased proliferation, invasion, and migration, as well as reduced apoptosis in HCT-116 cells. Indeed, miR-17-5p may be a potential indicator for the early diagnosis of CRC and may guide clinical targeted therapy.

Project description:Purpose: This study aimed to identify a novel biomarker or a target of treatment for colorectal cancer (CRC). Experimental Design: The expression profiles of cancer cells in 104 patients with CRC were examined using laser microdissection and oligonucleotide microarray analysis. Overexpression in CRC cells especially in patients with distant metastasis was a prerequisite to select candidate genes. The mRNA expression of candidate gene was investigated by quantitative reversetranscription polymerase chain reaction (RT-PCR) in 77 patients as a validation study. We analyzed the protein expression and localization of the candidate gene by immunohistochemical study, and investigated the relationship between the expression and the clinicopathological feature in 274 CRC patients. Results: We identified 6 genes as candidates related to distant metastasis in CRC patients by microarray analysis. Among these genes, Osteoprotegerin (OPG) is known to have an association with aggressiveness in several cancers through inhibiting apoptosis by neutralizing the function of tumor necrosis factor related apoptosis inducing ligand (TRAIL). The mRNA expression of OPG in cancer tissues was significantly higher in patients with distant metastasis than those without metastasis. The overexpression of OPG protein was significantly associated with worse overall survival and relapse free survival (RFS). Moreover, the overexpression of OPG protein was an independent risk factor for recurrence of CRC. Conclusion: The overexpression of OPG would be a predictive biomarker of recurrence and a target of the treatment for CRC. Total of 148 microarray datasets obtained from LCM and homogenized tissues of colorectal cancer patients were normalized using robust multi-array average (RMA) method under R 2.6.2 statistical software with affy package from BioConductor. Normalization was separately performed for LCM dataset and homogenized tissue dataset. The normalized gene expression levels were presented as log2-transformed values by RMA.

Project description:BackgroundThe outcomes of immune checkpoint inhibitors in cancer patients with liver metastases are poor, which may be related to a different tumor microenvironment in liver metastases from primary tumors. This study was aimed to analyze PD-L1 expression and the immune microenvironment status in liver metastases and compare the differences of PD-L1 expression between primary tumors and liver metastases of colorectal cancer.Methods74 cases of pathologically confirmed colorectal cancer with liver metastasis underwent resection from our hospital were included. Tissue microarrays were used for the interpretation of PD-L1 expression, cluster of differentiation 4 (CD4) and CD8 density by immunohistochemistry. We evaluated the disparity between primary tumor and liver metastasis in PD-L1 expression, CD4 and CD8 density and analyzed the factors associated with obvious PD-L1 disparity.ResultsThe expression of PD-L1 was positively related to the density of CD4 and CD8 in liver metastases. The expression of PD-L1 in liver metastases was higher than in primary tumors in certain subgroups, including patients with concurrent liver metastases (n?=?63, p?=?0.05), patients receiving concurrent resection of primary and metastatic tumors (n?=?56, p?=?0.04). The two subgroups generally reflected those without inconsistent external influences, such as treatment and temporal factors, between primary tumors and liver metastases. In these subgroups, the intrinsic differences of microenvironment between primary tumors and liver metastases could be identified. Furthermore, tumor differentiation [moderate vs. poor: OR?=?0.23, 95% CI: 0.03-0.99, p?=?0.05)] were demonstrated to be associated with obvious discordance of PD-L1 expression between primary tumors and liver metastases.ConclusionsThe expression of PD-L1 in liver metastases was higher than in primary tumors in subgroups, reflecting intrinsic microenvironment differences between primary and metastatic tumors. Obvious discordance of PD-L1 expression between primary tumor and liver metastasis was significantly related to the tumor differentiation.

Dataset Information

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

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

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