Clinicopathological and prognostic significance of microRNA-107 and its relationship to DICER1 mRNA expression in gastric cancer

Article · March 2012with18 Reads
DOI: 10.3892/or.2012.1709 · Source: PubMed
Abstract
microRNAs (miRNAs) are small non-coding RNAs that regulate target gene expression. It is known that miRNA-107 (miR-107) promotes cancer invasion and metastasis. However, the relationship between clinicopathological factors and the prognostic significance of miR-107 for gastric cancer patients remains elusive. In this study, we evaluated the prognostic value of miR-107 using tissue samples from gastric cancer patients. Furthermore, the relationship between miR-107 and the mRNA levels of its target gene DICER1 was examined. The expression levels of miR-107 and DICER1 mRNA in tumor tissues and adjacent normal tissues of 161 gastric cancer patients were examined (TNM stage I, 29 patients; stage II, 31 patients; stage III, 51 patients and stage IV, 50 patients). miR-107 levels were measured by Taqman microRNA assays, and DICER1 mRNA levels were measured by the Taqman real-time RT-PCR method. In the analysis by real-time PCR-based miRNA arrays using pooled RNA samples from five gastric cancer patients, expression of miR-107, miR-21, miR-196a, miR-26b, miR-9, miR-142-3p, miR-30b, miR-150, miR-191 and miR-17 was found to be upregulation. The mean expression level of miR-107 was significantly higher in the tumor tissues compared to that of normal tissues. In the comparison of clinicopathological factors, miR-107 expression showed significant association with depth of tumor invasion, lymph node metastasis and stage. In Kaplan-Meier survival curve analysis, overall survival rates (OS) and disease-free survival rates (DFS) of patients with high miR-107 expression were significantly worse than those of patients with low miR-107 expression. In the Cox multivariate analysis, it was shown that miR-107 expression in gastric cancer tissues was an independent prognostic factor for OS and DFS. Significant inverse correlations were demonstrated between miR-107 and DICER1 mRNA. Our results indicate that miR-107 may be useful as an effective biomarker for prediction of a poor prognosis in gastric cancer patients.
    • MiR-217 was also found to regulate and be regulated by miR-30a-3p, which suppresses p53[30]. Previously, introduction of synthetic miR-107 suppressed growth of human non-small cell lung cancer cell lines[31]and high levels of miR-107 were associated with a better survival outcome in gastric cancer[32]. MiR-107 was found to target DICER1 and thereby regulate tumor invasion and metastasis (Fig. 3)[33].
    [Show abstract] [Hide abstract] ABSTRACT: Background One of the fundamental challenges in cancer is to detect the regulators of gene expression changes during cancer progression. Through transcriptional silencing of critical cancer-related genes, epigenetic change such as DNA methylation plays a crucial role in cancer. In addition, miRNA, another major component of epigenome, is also a regulator at the post-transcriptional levels that modulate transcriptome changes. However, a mechanistic role of synergistic interactions between DNA methylation and miRNA as epigenetic regulators on transcriptomic changes and its association with clinical outcomes such as survival have remained largely unexplored in cancer. Methods In this study, we propose an integrative framework to identify epigenetic interactions between methylation and miRNA associated with transcriptomic changes. To test the utility of the proposed framework, the bladder cancer data set, including DNA methylation, miRNA expression, and gene expression data, from The Cancer Genome Atlas (TCGA) was analyzed for this study. Results First, we found 120 genes associated with interactions between the two epigenomic components. Then, 11 significant epigenetic interactions between miRNA and methylation, which target E2F3, CCND1, UTP6, CDADC1, SLC35E3, METRNL, TPCN2, NACC2, VGLL4, and PTEN, were found to be associated with survival. To this end, exploration of TCGA bladder cancer data identified epigenetic interactions that are associated with survival as potential prognostic markers in bladder cancer. Conclusions Given the importance and prevalence of these interactions of epigenetic events in bladder cancer it is timely to understand further how different epigenetic components interact and influence each other. Electronic supplementary material The online version of this article (doi:10.1186/s12920-017-0269-y) contains supplementary material, which is available to authorized users.
    Full-text · Article · May 2017
    • Finally, a circRNA-microRNA-gene regulatory network was constructed consisting of 22 circRNAs, 17 microRNAs and 130 PCGs (Fig 5, S3Table). Among these microRNAs, several microRNAs were found related to cancers, such as has-miR-34a-5p has been reported related to several types of cancers, for example, colorectal cancer[36]; has-miR-107 exhibit aberrant expression in a variety of cancers, including hepatocellular[37], gastric cancer[38], and Glioma[39]etc. The GO analysis suggested that these PCGs mainly involved in metabolic and regulation-related process (Fig 6A).
    [Show abstract] [Hide abstract] ABSTRACT: Hepatocellular carcinoma (HCC) is currently still a major factor leading to death, lacking of reliable biomarkers. Therefore, deep understanding the pathogenesis for HCC is of great importance. The emergence of circular RNA (circRNA) provides a new way to study the pathogenesis of human disease. Here, we employed the prediction tool to identify circRNAs based on RNA-seq data. Then, to investigate the biological function of the circRNA, the candidate circRNAs were associated with the protein-coding genes (PCGs) by GREAT. We found significant candidate circRNAs expression alterations between normal and tumor samples. Additionally, the PCGs associated with these candidate circRNAs were also found have discriminative expression patterns between normal and tumor samples. The enrichment analysis illustrated that these PCGs were predominantly enriched for liver/cardiovascular-related diseases such as atherosclerosis, myocardial ischemia and coronary heart disease, and participated in various metabolic processes. Together, a further network analysis indicated that these PCGs play important roles in the regulatory and the PPI network. Finally, we built a classification model to distinguish normal and tumor samples by using candidate circRNAs and their associated genes, respectively. Both of them obtained satisfactory results (~ 0.99 of AUC for circRNA and PCG). Our findings suggested that the circRNA could be a critical factor in HCC, providing a useful resource to explore the pathogenesis of HCC.
    Full-text · Article · Mar 2017
    • Besides, studies by Takamizawa et al.[12]and Yanaihara et al.[13]have presented evidence that transcripts of certain let-7 homologs are significantly downregulated in human lung cancer. Based on real-time polymerase chain reaction (PCR), the analysis of miRNA arrays using pooled RNA samples from five gastric cancer patients indicates that the expression of miRNA-107, miRNA-21, miRNA-196a, miRNA-26b, miRNA-9, miRNA-142-3p, miRNA-30b, miRNA-150, miRNA-191, and miRNA-17 was found to be upregulated[14]. However, it is expensive and timeconsuming to identify the associations between miRNAs and diseases using experimental methods.
    [Show abstract] [Hide abstract] ABSTRACT: Nowadays, researchers have realized that microRNAs (miRNAs) are playing a significant role in many important biological processes and they are closely connected with various complex human diseases. However, since there are too many possible miRNA-disease associations to analyze, it remains difficult to predict the potential miRNAs related to human diseases without a systematic and effective method. In this study, we developed a Matrix Completion for MiRNA-Disease Association prediction model (MCMDA) based on the known miRNA-disease associations in HMDD database. MCMDA model utilized the matrix completion algorithm to update the adjacency matrix of known miRNA-disease associations and furthermore predict the potential associations. To evaluate the performance of MCMDA, we performed leave-one-out cross validation (LOOCV) and 5-fold cross validation to compare MCMDA with three previous classical computational models (RLSMDA, HDMP, and WBSMDA). As a result, MCMDA achieved AUCs of 0.8749 in global LOOCV, 0.7718 in local LOOCV and average AUC of 0.8767+/-0.0011 in 5-fold cross validation. Moreover, the prediction results associated with colon neoplasms, kidney neoplasms, lymphoma and prostate neoplasms were verified. As a consequence, 84%, 86%, 78% and 90% of the top 50 potential miRNAs for these four diseases were respectively confirmed by recent experimental discoveries. Therefore, MCMDA model is superior to the previous models in that it improves the prediction performance although it only depends on the known miRNA-disease associations.
    Full-text · Article · Jan 2017
    • Moreover, GC patients with over-expression of miR-107[28][29][30], miR-143[40], miR-145[41,42], miR-181b/c[17,47,48,55,56], miR-196a/b[59], miR-20b[23,66], miR-23a/b[77][78][79], miR-34[17,47,48,55,56]and miR-630[100]and decreased expression of miR-1[111], miR-1207-5p[121], miR-125a-3p/-5p[24,[125][126][127], miR-185[140], miR-193b[60], miR-20a[111], miR-206[150,151], miR-215[142], miR-217[153], miR-27a[111], miR-29c[169], miR-34a[172,173], miR-423-5p[111], and miR-520d-3p[99]indicate advanced tumor stage or TNM stage. High levels of miR-107[28][29][30], miR-181b/c[17,47,48,55,56], miR-192[57], miR-196a/b[59], miR-20b[23,66], miR-21[68][69][70][71][72], miR-214[24,74], miR-23a/b[77][78][79], miR-25[26,27,80], miR-27a[23,81], miR-630[100], and miR-650[101]and decreased levels of Let-7g[24,109,110], miR-1207-5p[121], miR-125a-3p/-5p[24,[125][126][127]and miR-126[128][129][130], miR-146a[24,134], miR-148a[46,[135][136][137], miR-153[139], miR-218[154][155][156][157][158][159][160], miR-22[151,161], miR-27a[111], miR-29c[169], miR-335[171], miR-34a[172,173], miR-429[177], miR-433[24,86,109,110,174]and miR-520d-3p[99]are associated with invasion or LNM, as well as metastasis. Conversely, the tumor suppressors miR-125a and miR146a are significantly correlated with lymph node metastasis, indicating that they could be prognostic factors of overall survival[126,134].
    [Show abstract] [Hide abstract] ABSTRACT: Human gastric cancer (GC) is characterized by a high incidence and mortality rate, largely because it is normally not identified until a relatively advanced stage owing to a lack of early diagnostic biomarkers. Gastroscopy with biopsy is the routine method for screening, and gastrectomy is the major therapeutic strategy for GC. However, in more than 30% of GC surgical patients, cancer has progressed too far for effective medical resection. Thus, useful biomarkers for early screening or detection of GC are essential for improving patients' survival rate. MicroRNAs (miRNAs) play an important role in tumorigenesis. They contribute to gastric carcinogenesis by altering the expression of oncogenes and tumor suppressors. Because of their stability in tissues, serum/plasma and other body fluids, miRNAs have been suggested as novel tumor biomarkers with suitable clinical potential. Recently, aberrantly expressed miRNAs have been identified and tested for clinical application in the management of GC. Aberrant miRNA expression profiles determined with miRNA microarrays, quantitative reverse transcription-polymerase chain reaction and next-generation sequencing approaches could be used to establish sample specificity and to identify tumor type. Here, we provide an up-to-date summary of tissue-based GC-associated miRNAs, describing their involvement and that of their downstream targets in tumorigenic and biological processes. We examine correlations among significant clinical parameters and prognostic indicators, and discuss recurrence monitoring and therapeutic options in GC. We also review plasma/serum-based, GC-associated, circulating miRNAs and their clinical applications, focusing especially on early diagnosis. By providing insights into the mechanisms of miRNA-related tumor progression, this review will hopefully aid in the identification of novel potential therapeutic targets.
    Full-text · Article · Jun 2016
    • A U T H O R C O P Y Nonetheless, two discordances could be found in our list of up-regulated miRNAs as it has been previously reported that miR-503 [63] and miR-107 [64] are down-regulated in lung cancer, acting as tumor suppressors. Although, oncogenic role for miR-107 has been previously reported in other kind of can- cers [65,66], no such contradictory observations does exist for miR-503 and instead all of preceding studies unanimously represent tumor suppressive role of miR-503 in different malignancies [67,68] .
    [Show abstract] [Hide abstract] ABSTRACT: Non-small cell lung cancer (NSCLCs) is a prevalent and heterogeneous subtype of lung cancer accounting for 85 percent of patients. MicroRNAs (miRNAs), a class of small endogenous non-coding RNAs, incorporate into regulation of gene expression post-transcriptionally. Therefore, deregulation of miRNAs' expression has provided further layers of complexity to the molecular etiology and pathogenesis of different diseases and malignancies. Although, until now considerable number of studies has been carried out to illuminate this complexity in NSCLC, they have remained less effective in their goal due to lack of a holistic and integrative systems biology approach which considers all natural elaborations of miRNAs' function. It is able to reliably nominate most affected signaling pathways and therapeutic target genes by deregulated miRNAs during a particular pathological condition. Herein, we utilized a holistic systems biology approach, based on appropriate re-analyses of microarray datasets followed by reliable data filtering, to analyze integrative and combinatorial deregulated miRNA-mRNA interaction network in NSCLC, aiming to ascertain miRNA-dysregulated signaling pathway and potential therapeutic miRNAs and mRNAs which represent a lion' share during various aspects of NSCLC's pathogenesis. Our systems biology approach introduced and nominated 1) important deregulated miRNAs in NSCLCs compared with normal tissue 2) significant and confident deregulated mRNAs which were anti-correlatively targeted by deregulated miRNA in NSCLCs and 3) dysregulated signaling pathways in association with deregulated miRNA-mRNAs interactions in NSCLCs. These results introduce possible mechanism of function of deregulated miRNAs and mRNAs in NSCLC that could be used as potential therapeutic targets.
    Article · Jan 2016
    • Moreover, the specific mechanisms behind Dicer downregulation in cancers were not entirely clear. Several mechanisms have been described as potential regulators of Dicer such as Dicer monoallelic loss [56, 57], downregulated by the transcription factors MITF and TAp63 and miR-103/107 [58, 59]. Furthermore, the latest data illustrated that Dicer expression could also be inhibited by hypoxia through an epigenetic regulation [60].
    [Show abstract] [Hide abstract] ABSTRACT: Objective: The role of Dicer in the prognosis of cancer patients remains controversial. This systematic review is attempted to assess the influence of Dicer as a prognostic predictor for survival in diverse types of cancers. Methods: Studies were selected as candidates if they published an independent evaluation of Dicer expression level together with the correlation with prognosis in cancers. Random-effect model was applied in this meta-analysis. Heterogeneity between studies was assessed by Q-statistic with P < 0.10 to be statistically significant. Publication bias was investigated using funnel plot and test with Begg's and Egger's test. P < 0.05 was regarded as statistically significant. Results: 24 of 44 articles revealed low Dicer status as a predictor of poor prognosis. The aggregate result of overall survival (OS) indicated that low Dicer expression level resulted in poor clinical outcomes, and subgroup of IHC and RT-PCR method both revealed the same result. Overall analysis of progression-free survival (PFS) showed the same result as OS, and both the two subgroups divided by laboratory method revealed positive results. Subgroup analysis by tumor types showed low dicer levels were associated with poor prognosis in ovarian cancer (HR = 1.93, 95% CI: 1.19-3.15), otorhinolaryngological tumors (HR = 2.39, 95% CI: 1.70-3.36), hematological malignancies (HR = 2.45, 95% CI: 1.69-3.56) and neuroblastoma (HR = 4.03, 95% CI: 1.91-8.50). Conclusion: Low Dicer status was associated with poor prognosis in ovarian cancer, otorhinolaryngological tumors and ematological malignancies. More homogeneous studies with high quality are needed to further confirm our conclusion and make Dicer a useful parameter in clinical application.
    Full-text · Article · Nov 2015
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