The involvement of microRNAs in malignant transformation

In the multiple steps in cancer progression, microRNAs (miRNAs) play significant roles in each stage. Reports of considerable differences in expression levels of miRNAs between normal and malignant tissues are understandable considering miRNAs are key regulators of gene expression. Dysregulation of miRNA expression levels in neoplasia occurs because many miRNAs are located in "fragile sites", which are frequently deleted in cancer. miRNAs are often down regulated in cancerous tissues and target oncogenic proteins are classified as tumour suppressor miRNAs, such as let-7. While, miRNAs that are frequently over-expression in neoplastic tissues compared to normal tissues and regulate tumour suppressor proteins are categorized as "oncomiRs". In this review, we summarize information about microRNAs involved in the emerging field of cancer stem cells, and microRNAs involved in breast cancer, an area of our expertise. The application of miRNAs to cancer therapeutics and diagnostics is emerging as an important field of gene therapy. The diverse nature of miRNAs in cancer is continually being elucidated to lead to the enigmatic treatment options for neoplastic disease.     

Individual and combined effects of DNA methylation and copy number alterations on miRNA expression in breast tumors

Background

The global effect of copy number and epigenetic alterations on miRNA expression in cancer is poorly understood. In the present study, we integrate genome-wide DNA methylation, copy number and miRNA expression and identify genetic mechanisms underlying miRNA dysregulation in breast cancer.

Results

We identify 70 miRNAs whose expression was associated with alterations in copy number or methylation, or both. Among these, five miRNA families are represented. Interestingly, the members of these families are encoded on different chromosomes and are complementarily altered by gain or hypomethylation across the patients. In an independent breast cancer cohort of 123 patients, 41 of the 70 miRNAs were confirmed with respect to aberration pattern and association to expression. In vitro functional experiments were performed in breast cancer cell lines with miRNA mimics to evaluate the phenotype of the replicated miRNAs. let-7e-3p, which in tumors is found associated with hypermethylation, is shown to induce apoptosis and reduce cell viability, and low let-7e-3p expression is associated with poorer prognosis. The overexpression of three other miRNAs associated with copy number gain, miR-21-3p, miR-148b-3p and miR-151a-5p, increases proliferation of breast cancer cell lines. In addition, miR-151a-5p enhances the levels of phosphorylated AKT protein.

Conclusions

Our data provide novel evidence of the mechanisms behind miRNA dysregulation in breast cancer. The study contributes to the understanding of how methylation and copy number alterations influence miRNA expression, emphasizing miRNA functionality through redundant encoding, and suggests novel miRNAs important in breast cancer.     

Identification of canine circulating miRNAs as tumor biospecific markers using Next-Generation Sequencing and Q-RT-PCR

Delay in cancer diagnosis often results in metastasis and an inability to successfully treat the tumor. The use of broadly cancer-specific biomarkers at an early stage may improve cancer treatment and staging. This study has explored circulatory exosomal miRNAs as potential diagnostic biomarkers to identify cancer patients. Secretory exosomal miRNAs were isolated from 13 canine cancer cell lines (lymphoma, mast cell tumor, histiocytic cell line, osteosarcoma, melanoma, and breast tumor) and were sequenced by Next-Generation sequencing (NGS). We have identified 6 miRNAs (cfa-miR-9, -1841, ?1306, ?345, ?132, and ?26b) by NGS that were elevated in all cancer cell types. The miRNAs identified by NGS were then examined by Q-RT-PCR. The PCR data demonstrated similar expression patterns to those seen with NGS but provided fold differences that were much lower than those seen for NGS. Cfa-miR-9 was found to be the most consistently elevated miRNA in NGS and PCR, making it the most likely miRNA to prove diagnostic. In this study, we have demonstrated that it is possible to identify exosomal miRNAs with elevated secretion across multiple tumor types that could be used as circulatory diagnostic biomarkers for liquid biopsy in the future.     

miR221/222 in cancer: their role in tumor progression and response to therapy

miRNAs are small non-coding RNAs of ~24 nt that can block mRNA translation and/or negatively regulate its stability. There is a large body of evidence that dysregulation of miRNAs is a hallmark of cancer. miRNAs are often aberrantly expressed and their function is linked to the regulation of oncogenes and/or tumor suppressor genes involved in cell signaling pathway. miR-221 and miR-222 are two highly homologous microRNAs, whose upregulation has been recently described in several types of human tumors. miR-221/222 have been considered to act as oncogenes or tumor suppressors, depending on tumor system. Silencing oncomiRs or gene therapy approaches, based on re-expression of miRNAs that are down-regulated in cancer cells, could represent a novel anti-tumor approach for integrated cancer therapy. Here we will review the role of miR-221/222 in cancer progression and their use as prognostic and therapeutic tools in cancer.     

The diverse functions of microRNAs in animal development and disease

MicroRNAs (miRNAs) control gene expression by translational inhibition and destabilization of mRNAs. While hundreds of miRNAs have been found, only a few have been studied in detail. miRNAs have been implicated in tissue morphogenesis, cellular processes like apoptosis, and major signaling pathways. Emerging evidence suggests a direct link between miRNAs and disease, and miRNA expression signatures are associated with various types of cancer. In addition, the gain and loss of miRNA target sites appears to be causal to some genetic disorders. Here, we discuss the current literature on the role of miRNAs in animal development and disease.     

Cancer microRNAs: from subtype profiling to predictors of response to therapy

MicroRNAs (miRNAs) are key regulators of gene expression that regulate important oncogenes and tumor suppressors. Many miRNAs can also act as oncogenes or tumor suppressors, and thus the altered expression of miRNAs is a hallmark of many cancer types. Dysregulated miRNAs provide a potentially powerful new tool that could be used to enable the characterization of tumor environments and identify novel and important oncogenic pathways. More recently, there has been growing interest in the field of miRNAs as biomarkers of cancer risk, diagnosis and response to therapy. Understanding the associations between miRNA expression and cancer phenotypes, and the potential of miRNA profiling in clinical applications, promises to be highly rewarding in the field of cancer research.     

miR-451与人类肿瘤关系的研究进展

Micro RNAs(miRNA)是一类在转录后水平调控基因表达的小分子非编码RNAs,通过调节细胞的增殖、分化、凋亡使机体维一个动态平衡。近年来,大量研究表明许多miRNA可作为原癌基因或者抑癌基因参与肿瘤的发生、发展,进一步研究发现,通过检测和调控这些miRNA,可用于肿瘤的早期诊断和治疗。最近一系列研究发现miRNA-451(miR-451)在许多肿瘤中存在差异性表达,与这些肿瘤的发生、发展、治疗有着密切的联系。本文对人类肿瘤中miR-451表达、调控的相关研究做一综述,为miR-451在肿瘤的诊断、治疗及预后中的应用提供重要资料。     

MicroRNAs and intestinal pathophysiology

MicroRNAs (miRNAs) represent an abundant class of endogenously expressed small RNAs, which is believed to control the expression of proteins through specific interaction with their mRNAs. MiRNAs are non-coding RNAs of 18 to 24 nucleotides that negatively regulate target mRNAs by binding to their 3'-untranslated regions (UTR). Most eukaryotic cells utilize miRNA to regulate vital functions such as cell differentiation, proliferation or apopotosis. The diversity of miRNAs and of their mRNA targets strongly indicate that they play a key role in the regulation of protein expression. To date, more than 500 different miRNAs have been identified in animals and plants. There are at least 326 miRNAs in the human genome, comprising 1-4% of all expressed human genes, which makes miRNAs one of the largest classes of gene regulators. A single miRNA can bind to and regulate many different mRNA targets and, conversely, several different miRNAs can bind to and cooperatively control a single mRNA target. The correlation between the expression of miRNAs and their effects on tumorigenesis and on the proliferation of cancer cells is beginning to gain experimental evidences. Recent studies showed that abnormal expression of miRNAs represents a common feature of cancer cells and that they can function as tumor suppressor genes or as oncogenes. Therefore, this diversity of action for miRNAs on several target genes could be one of the common mechanisms involved in the deregulation of protein expression observed during intestinal disorders. In this review, the emergent functions of miRNAs in colorectal cancer and their potential role in the intestinal inflammatory process are discussed.     

miR-125b Acts as a Tumor Suppressor in Breast Tumorigenesis via Its Novel Direct Targets ENPEP,CK2-α, CCNJ,and MEGF9

MicroRNAs (miRNAs) play important roles in diverse biological processes and are emerging as key regulators of tumorigenesis and tumor progression. To explore the dysregulation of miRNAs in breast cancer, a genome-wide expression profiling of 939 miRNAs was performed in 50 breast cancer patients. A total of 35 miRNAs were aberrantly expressed between breast cancer tissue and adjacent normal breast tissue and several novel miRNAs were identified as potential oncogenes or tumor suppressor miRNAs in breast tumorigenesis. miR-125b exhibited the largest decrease in expression. Enforced miR-125b expression in mammary cells decreased cell proliferation by inducing G2/M cell cycle arrest and reduced anchorage-independent cell growth of cells of mammary origin. miR-125b was found to perform its tumor suppressor function via the direct targeting of the 3’-UTRs of ENPEP, CK2-α, CCNJ, and MEGF9 mRNAs. Silencing these miR-125b targets mimicked the biological effects of miR-125b overexpression, confirming that they are modulated by miR-125b. Analysis of ENPEP, CK2-α, CCNJ, and MEGF9 protein expression in breast cancer patients revealed that they were overexpressed in 56%, 40–56%, 20%, and 32% of the tumors, respectively. The expression of ENPEP and CK2-α was inversely correlated with miR-125b expression in breast tumors, indicating the relevance of these potential oncogenic proteins in breast cancer patients. Our results support a prognostic role for CK2-α, whose expression may help clinicians predict breast tumor aggressiveness. In particular, our results show that restoration of miR-125b expression or knockdown of ENPEP, CK2-α, CCNJ, or MEGF9 may provide novel approaches for the treatment of breast cancer.