Expression and prognostic significance of miR-375 and miR-221 in liver cancer.
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ABSTRACT:
SUBMITTER: Xie D
PROVIDER: S-EPMC5530117 | biostudies-other | 2017 Aug
REPOSITORIES: biostudies-other
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Project description:Increasing evidence has demonstrated that microRNAs (miRNAs) are involved in colon cancer initiation and progression, and may serve as diagnostic and prognostic biomarkers for colon cancer. Here, we investigated the levels of miR-9-1, miR-203-3p, miR-221-3p, miR-342-3p, miR-491-5p and miR-503-5p in 90 pairs of colon cancer and adjacent normal tissues, and explored the relationship between their expression and clinical outcome of colon cancer. Five miRNAs (miR-203-3p, miR-221-3p, miR-342-3p, miR-491-5p and miR-503-5p) were dysregulated in colon cancer tissue (P < 0.05). The levels of miR-503-5p in larger tumors (? 6 cm) were higher than those in smaller ones (< 6 cm) (P = 0.031), while the levels of miR-203-3p and miR-491-5p in patients aged 70 years and older were higher than those in patients aged younger than 70 years (P = 0.019 and 0.049, respectively). The high levels of miR-221-3p (HR = 2.416, 95% CI 1.314-4.445, P = 0.005), miR-342-3p (HR = 1.807, 95% CI 1.003-3.253, P = 0.049) and miR-491-5p (HR = 1.868, 95% CI 1.032-3.384, P = 0.039) were significantly associated with worse survival time. Moreover, combination analysis of miR-221-3p, miR-342-3p and miR-491-5p expression revealed that patients with 3 highly expressed miRNAs had lower survival rates compared with those with zero-to-two highly expressed miRNAs (HR = 2.100, 95% CI 1.157-3.813, P = 0.015), especially those with TNM stages I and II (HR = 4.204,95% CI 1.762-10.030, P = 0.001). Our results suggest that the three-miRNA signature may help doctors better predict prognosis and guide treatment decisions for colon cancer.
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Project description:Background: A wealth of evidence has shown that microRNAs (miRNAs) can modulate specific genes, increasing our knowledge on the fine-tuning regulation of protein expression. miR-221 and miR-222 have been frequently identified as deregulated across different cancer types; however, their prognostic significance in cancer remains controversial. In view of these considerations, we performed an updated systematic review and meta-analysis of published data investigating the effects of miR-221/222 on overall survival (OS) and other secondary outcomes among cancer patients. A systematic search of PubMed, Web of Knowledge, and Cochrane Library databases was performed. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were used to assess the strength of association. Results: Fifty studies, analyzing 6086 patients, were included in the systematic review. Twenty-five studies for miR-221 and 17 studies for miR-222 which assessed OS were included in the meta-analysis. High expression of miR-221 and miR-222 significantly predicted poor OS (HR: 1.48, 95% CI: 1.14-1.93, p = 0.003 and HR: 1.90, 95% CI: 1.43-2.54, p < 0.001, respectively). Subgroup analysis revealed that the finding on miR-221 was not as robust as the one on miR-222. Furthermore, high miR-222 expression was also associated with worse progression-free survival and disease-free survival pooled with recurrence-free survival. Conclusions: The meta-analysis demonstrated that high expression of miR-222 is associated with poor prognosis in cancer patients, whereas the significance of miR-221 remains unclear. More work is required to fully elucidate the role of miR-221 and miR-222 in cancer prognosis, particularly in view of the limitations of existing results, including the significant heterogeneity and limited number of studies for some cancers.
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Project description:BackgroundExtracellular microRNAs (miRNAs) embedded in circulating exosomes may serves as prognostic biomarkers in cancer.ObjectiveTo identify and evaluate plasma exosomal miRNAs for prognosis in castration-resistant prostate cancer (CRPC).Design, setting, and participantsRNA sequencing was performed to identify candidate exosomal miRNAs associated with overall survival in a screening cohort of 23 CRPC patients. Candidate miRNAs were further evaluated for prognosis using quantitative real-time polymerase chain reaction in a follow-up cohort of 100 CRPC patients.Outcome measurements and statistical analysisCox regression and Kaplan-Meier survival analyses were used to evaluate survival association using candidate miRNAs along with clinical prognostic factors.Results and limitationsRNA sequencing in screening cohort generated approximately 6.80 million mappable reads per patient. Of those with normalized read counts ≥ 5, 43% were mapped to miRNAs for a total of 375 known and 57 novel miRNAs. Cox regression analysis identified an association of miR-1290, -1246, and -375 with overall survival (false discover rate < 0.05). Of those, higher levels of miR-1290 and -375 were significantly associated with poor overall survival (p < 0.004) in the follow-up cohort. Incorporation of miR-1290/-375 into putative clinical prognostic factors-based models in CRPC stage significantly improved predictive performance with a time-dependent area under the curve increase from 0.66 to 0.73 (p = 6.57 × 10(-6)).ConclusionsPlasma exosomal miR-1290 and miR-375 are promising prognostic biomarkers for CRPC patients. Prospective validation is needed for further evaluation of these candidate miRNAs.Patient summaryIn this study, we evaluated whether small RNAs circulating in blood could be used to predict clinical outcomes in late-stage prostate cancer patients. We identified two blood-based small RNAs whose levels showed significant association with survival. Our results warrant further investigation because the noninvasive blood-based test has great potential in the management of late-stage prostate cancer.
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Project description:Dicer is crucial for the maturation of microRNAs (miRNAs) and its dysregulation may contribute to tumor initiation and progression. The study explored the clinical implications of Dicer and its post-transcriptional regulation by microRNAs in cervical cancer. qRT-PCR and immunohistochemistry investigated Dicer mRNA and protein levels in cervical cancer tissues. The relationship between Dicer expression and survival was analyzed. MiRNA target prediction identified miRNAs that might target Dicer. Luciferase reporter and gain- or loss-of-function assays were performed. The results showed that 36.7% of cervical cancer cases showed low expression of Dicer mRNA and 63.3% cases showed high expression. At the protein level, 51% cases showed negative expression and 49% cases showed positive expression. Dicer mRNA and protein expressions were significantly associated with distant metastasis and recurrence in cervical cancer (P=0.002 and P=0.012, respectively). Multivariate Cox analysis indicated that low Dicer expression (P=0.016) and tumor stage (P=0.047) were independent predictors. Among the miRNAs predicted to target Dicer, 10 were detected by RT-PCR; their expressions were significantly higher in cervical cancers with lower Dicer expression than in those with higher Dicer expression and were negatively correlated with Dicer expression level (P<0.05). In vitro experiments demonstrated that miR-130a directly targeted Dicer mRNA to enhance migration and invasion in SiHa cells. Finally, survival analysis indicated that higher expression of miR-130a was significantly associated with poor disease-free survival. Taken together, Dicer expression regulated by miR-130a is an important potential prognostic factor in cervical cancer.
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Project description:MicroRNA (miRNAs) are negative regulators of gene expression and can function as tumor suppressors or oncogenes. Expression patterns of miRNAs and their role in the pathogenesis of hepatocellular carcinoma (HCC) are still poorly understood. We profiled miRNA expression in tissue samples (104 HCC, 90 adjacent cirrhotic livers, 21 normal livers) as well as in 35 HCC cell lines. A set of 12 miRNAs (including miR-21, miR-221/222, miR-34a, miR-519a, miR-93, miR-96, and let-7c) was linked to disease progression from normal liver through cirrhosis to full-blown HCC. miR-221/222, the most up-regulated miRNAs in tumor samples, are shown to target the CDK inhibitor p27 and to enhance cell growth in vitro. Conversely, these activities can be efficiently inhibited by an antagomiR specific for miR-221. In addition, we show, using a mouse model of liver cancer, that miR-221 overexpression stimulates growth of tumorigenic murine hepatic progenitor cells. Finally, we identified DNA damage-inducible transcript 4 (DDIT4), a modulator of mTOR pathway, as a bona fide target of miR-221. Taken together, these data reveal an important contribution for miR-221 in hepatocarcinogenesis and suggest a role for DDIT4 dysregulation in this process. Thus, the use of synthetic inhibitors of miR-221 may prove to be a promising approach to liver cancer treatment.
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Project description:Hepatocellular carcinoma (HCC) is a common digestive system disease with no curative treatment. Zinc finger protein 385D antisense RNA 2 (ZNF385D‑AS2) is a long non‑coding RNA (lncRNA) that has been predicted to function in human diseases, including several types of cancer. Yet, it has not been investigated in relation to liver cancer. Thus, the present study was designed with an aim to elucidate the prognostic significance of lncRNA ZNF385D‑AS2 in HCC. The Cancer Genome Atlas‑Liver Hepatocellular Carcinoma (TCGA‑LIHC) collection of data was utilized to analyze the expression of lncRNA ZNF385D‑AS2 in liver cancer. Then Chi‑square tests were used to evaluate the correlation between clinical characteristics and lncRNA ZNF385D‑AS2 expression. The significance of lncRNA ZNF385D‑AS2 in patient prognosis was evaluated using Kaplan‑Meier curves and Cox analysis. Concomitantly, Gene Set Enrichment Analysis (GSEA) was performed to analyze the most closely related cytological behavior. Finally, we used the Database for Annotation, Visualization and Integrated Discovery (DAVID) and KOBAS software and data from the Gene Expression Omnibus (GEO) database to analyze the possible competing endogenous RNA (ceRNA) network pattern as well as the co‑expression network in liver cancer. Based on the results, analysis of RNA‑Seq gene expression data for 303 patients with primary tumors revealed low expression of ZNF385D‑AS2 in liver cancer. Low expression of ZNF385D‑AS2 was found to be significantly associated with sex (P=0.050), T stage (P=0.049), M stage (P=0.040), N stage (P<0.001) and clinical stage (P=0.037). Patients with ZNF385D‑AS2 low‑expression liver cancers had a shorter median overall survival compared with the patients with ZNF385D‑AS2 high‑expression liver cancers (P=0.0079). Cox analysis identified ZNF385D‑AS2 low‑expression as an independent prognostic variable (AUC=0.594) for overall survival in liver cancer patients. Co‑expression and ceRNA predictive analysis data suggested that there may be a regulatory signaling axis between ZNF385D‑AS2 and miR‑96 and miR‑182. In conclusion, our results suggests that low expression of ZNF385D‑AS2 is predictive of a poor prognosis of liver cancer patients.
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Project description:Hepatocellular carcinoma (HCC) is a common disease of the digestive system with no curative treatments. Long noncoding RNA tyrosine protein kinase transmembrane receptor 1 antisense RNA 1 (lncRNA ROR1‑AS1) is an lncRNA whose functions have been predicted in human diseases; however, its important role in cancer has been probed only in mantle cell lymphoma, not in HCC. Therefore, the present study aimed to elucidate the prognostic significance of lncRNA ROR1‑AS1 in HCC. The Cancer Genome Atlas Liver Hepatocellular Carcinoma was used to analyze the expression of ROR1‑AS1 in liver cancer. χ2 tests were performed to evaluate associations between clinical characteristics and ROR1‑AS1 expression. The role of ROR1‑AS1 in HCC prognosis was assessed using Kaplan‑Meier curves and proportional hazards model (Cox) analysis. Gene set enrichment analysis was performed by using a Gene Expression Omnibus dataset. At the same time, Multi Experiment Matrix was used to predict genes that may be co‑expressed with ROR1‑AS1. The Database for Annotation, Visualization and Integrated Discovery and KO‑Based Annotation System were used to analyze the most closely associated cytological behaviors and pathways in HCC. Then, the genes in the three databases were integrated to screen mRNAs, microRNAs and lncRNAs that had co‑expression relationships with ROR1‑AS1. Cytoscape, Search Tool for the Retrieval of Interacting Genes/Proteins and Molecular Evolutionary Genetics Analysis were used to map potential regulatory networks and developmental relationships associated with ROR1‑AS1. Finally, 12 genes most closely associated with ROR1‑AS1 were identified, and their relationship was described using a Circos plot. The results showed that ROR1‑AS1 was upregulated in HCC, and its expression was related to clinical stage, T stage and N stage. Furthermore, Kaplan‑Meier curves and Cox analysis indicated that high expression of ROR1‑AS1 was associated with poor prognosis, and that ROR1‑AS1 was an independent risk factor for HCC. Co‑expression data suggested that there may be a large regulatory network of 45 genes with indirect associations with ROR1‑AS1, a small regulatory network of 15 genes with direct or indirect regulatory relationships, and a special regulatory network containing 12 genes directly associated with ROR1‑AS1. The present findings indicated that high expression of ROR1‑AS1 suggests poor prognosis in patients with HCC.
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Project description:Liver cancer stem cells (CSCs) are functionally defined by their ability to undergo self‑renewal, and may contribute to metastasis, recurrence and drug resistance in liver cancer. The long non‑coding RNA metastasis‑associated lung adenocarcinoma transcript 1 (MALAT1) has been implicated in tumor formation and metastasis of liver cancer. However, the exact mechanism by which MALAT1 modulates liver CSC features remains largely unknown. In the present study, the expression level of MALAT1 was elevated in cancer spheroids compared with the corresponding levels noted in parental liver cancer cells, whereas the suppression of MALAT1 resulted in markedly reduced sphere formation and decreased expression of stemness factors in liver cancer cells. Dual‑luciferase assay and RNA pull‑down assays further indicated an interaction between MALAT1 and microRNA (miR)‑375, and identified Yes‑associated protein 1 (YAP1) as a direct target of miR‑375 in liver cancer cells. In addition, YAP1 expression was correlated with MALAT1 in liver cancer. The reduced expression of YAP1 caused by knockdown of MALAT1 with MALAT1 small interfering RNA (si‑MALAT1) could be partially abolished by miR‑375 inhibition, suggesting that MALAT1 may regulate YAP1 expression by sponging miR‑375. Furthermore, YAP1 overexpression rescued the decrease in CSC features of liver cancer cells caused by si‑MALAT1, further supporting that MALAT1‑mediated YAP1 signaling was required for the stem‑like characteristics of liver CSCs. The present study revealed that MALAT1 may promote CSC properties of liver cancer cells by upregulating YAP1 expression via sponging miR‑375. The MALAT1/miR‑375/YAP1 axis may serve as a novel target for liver cancer therapy, particularly for the eradication of liver CSCs.
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Project description:Extracellular microRNAs (miRNAs) embedded in circulating exosomes may serves as prognostic biomarkers in cancer. This study was performed to identify and evaluate plasma exosomal miRNAs for prognostication in castration resistant prostate cancer (CRPC). RNA sequencing was performed to identify candidate exosomal miRNAs associated with overall survival in a screening cohort of 23 CRPC patients. Candidate miRNAs were further evaluated for prognosis using qRT-PCR in a follow-up cohort of 100 patients. Cox regression and Kaplan–Meier survival curve analysis were used to evaluate prognostic value of miRNA candidates with and without incorporation of clinical prognostic factors (age, Gleason score and time from androgen deprivation therapy to clinical progression). In the screening cohort, we obtained ~6.80 million mappable RNA reads per patient. Of those with normalized read counts ? 5, 43% were mapped to miRNAs for a total of 375 known and 57 novel miRNAs. Cox regression analysis identified an association of miR-1290, -1246, and -375 with overall survival (FDR<0.1). Of those, higher levels of miR-1290 and -375 were verified to be significantly associated with poor overall survival (p<0.004) in the follow-up cohort. The miR-1290/-375-based prediction model showed better performance with time-dependent area under the curve (AUC) =72% compared to clinical variable-based model with AUC=65%. Plasma exosomal miR-1290 and miR-375 are promising prognostic biomarkers for CRPC patients. Prospective validation is needed for further development of these candidate miRNAs.
2014-12-30 | GSE58410 | GEO
Project description:PurposemicroRNAs have emerged as key regulators of gene expression, and their altered expression has been associated with tumorigenesis and tumor progression. Thus, microRNAs have potential as both cancer biomarkers and/or potential novel therapeutic targets. Although accumulating evidence suggests the role of aberrant microRNA expression in endometrial carcinogenesis, there are still limited data available about the prognostic significance of microRNAs in endometrial cancer. The goal of this study is to investigate the prognostic value of selected key microRNAs in endometrial cancer by the analysis of archival formalin-fixed paraffin-embedded tissues.Experimental designTotal RNAs were extracted from 48 paired normal and endometrial tumor specimens using Trizol based approach. The expression of miR-26a, let-7g, miR-21, miR-181b, miR-200c, miR-192, miR-215, miR-200c, and miR-205 were quantified by real time qRT-PCR expression analysis. Targets of the differentially expressed miRNAs were quantified using immunohistochemistry. Statistical analysis was performed by GraphPad Prism 5.0.ResultsThe expression levels of miR-200c (P<0.0001) and miR-205 (P<0.0001) were significantly increased in endometrial tumors compared to normal tissues. Kaplan-Meier survival analysis revealed that high levels of miR-205 expression were associated with poor patient overall survival (hazard ratio, 0.377; Logrank test, P = 0.028). Furthermore, decreased expression of a miR-205 target PTEN was detected in endometrial cancer tissues compared to normal tissues.ConclusionmiR-205 holds a unique potential as a prognostic biomarker in endometrial cancer.
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