microRNAs and lung cancer: tumors and 22-mers

Work over the last decade has revealed novel regulatory mechanisms in pathological disease states that are mediated by microRNAs and has inspired researchers to begin elucidating the specific roles of miRNAs in the regulation of genes involved in cancer development and progression. Recently, miRNAs have been explored as therapeutic targets and diagnostic markers of cancer. In this paper, we review recent advances in the study of miRNAs involved in tumorigenesis, focusing on miRNA regulation of genes that have been demonstrated to play critical roles in lung cancer development. We discuss miRNA regulation of genes that play critical roles in the process of malignant transformation, angiogenesis and tumor metastasis, the dysregulation of miRNA expression in cancer development, and the development of miRNA-based diagnostics and therapeutics.     

特异性微小RNA在恶性黑色素瘤中的研究进展

微小RNA（miRNA）是一类小分子非编码调控性RNA,以细胞及组织特异性方式表达,在维持细胞自身稳态及癌变过程中具有关键性作用.近年来,研究表明许多特异性miRNA与恶性黑色素瘤的发生发展有关.黑色素瘤相关性miRNA通常定位于肿瘤易发生基因扩增及缺失的基因组区域.文章旨在探讨特异性miRNA通过各种途径对不同靶基因的调控从而参与恶性黑色素瘤的生物学进程,并描述了黑色素瘤的治疗现状.     

Micro-RNAs associated with metastasis in uveal melanoma identified by multiplexed microarray profiling

Uveal (ocular) melanoma is a highly aggressive cancer that leads to metastatic death in up to half of patients despite successful local therapy. Biomarkers of metastatic risk are critically needed to institute new adjuvant treatment strategies in high-risk patients. Previously, we showed that two prognostically significant molecular subtypes of uveal melanoma could be identified based on gene expression profiling of the primary tumor. In this study, we investigated the value of micro-RNA (miRNA) expression patterns in predicting metastatic risk. A genome-wide, microarray-based approach was used to screen for differentially expressed miRNAs using the Agilent miRNA microarray (Agilent Technologies, Foster City, California, USA) platform containing probes for 470 human miRNAs. Unsupervised analysis was performed using principal component analysis, and supervised analysis was performed using significance analysis of microarrays. Tumors readily clustered based on miRNA expression into two groups that corresponded to the gene expression-based subtypes: class 1 (low metastatic risk) and class 2 (high metastatic risk). The most significant discriminators were let-7b and miR-199a, and the expression of these miRNAs was validated by quantitative PCR. A classifier that included the top six miRNA discriminators accurately distinguished class 1 from class 2 tumors with 100% sensitivity and specificity. miRNA expression may represent a highly accurate biomarker for metastatic risk in uveal melanoma. In addition, these results may provide new insights into the role of miRNAs in tumor progression and the metastatic phenotype.     

MicroRNA in colorectal cancer: from benchtop to bedside

Colon carcinogenesis represents a stepwise progression from benign polyps to invasive adenocarcinomas and distant metastasis. It is believed that these pathologic changes are contributed by aberrant activation or inactivation of protein-coding proto-oncogenes and tumor suppressor genes. However, recent discoveries in microRNA (miRNA) research have reshaped our understanding of the role of non-protein-coding genes in carcinogenesis. In this regard, a remarkable number of miRNAs exhibit differential expression in colon cancer tissues. These miRNAs alter cell proliferation, apoptosis and metastasis through their interactions with intracellular signaling networks. From a clinical perspective, polymorphisms within miRNA-binding sites are associated with the risk for colon cancer, whereas miRNAs isolated from feces or blood may serve as biomarkers for early diagnosis. Altered expression of miRNA or polymorphisms in miRNA-related genes have also been shown to correlate with patient survival or treatment outcome. With further insights into miRNA dysregulation in colon cancer and the advancement of RNA delivery technology, it is anticipated that novel miRNA-based therapeutics will emerge.     

miRNA在原发性肝癌中的研究进展

原发性肝癌是世界范围内最常见和最具侵袭性的恶性肿瘤之一。miRNA是一系列调控基因转录后表达的非编码小RNA。研究发现,miRNA具有癌基因和抑癌基因的作用,在肿瘤的发生和发展中起着重要的作用。已有证据表明,原发性肝癌中存在一些异常表达的miRNA,它们多靶向于肝癌发生、发展相关的基因和信号通路,从而广泛调节肝癌细胞的增殖、分化、凋亡、侵袭和转移等重要的涉及癌细胞发生演变的病理过程。异常表达的miRNA及其功能靶标的发现不仅丰富了肝癌的发病机制,也为探索新的基因靶向治疗提供了可能; miRNA表达谱还与肝癌病理类型、恶性程度、分期、分级等临床病理过程密切相关,提示miRNA不仅可能用于肝癌诊断及个体化治疗,也可能作为判断预后的工具。本文就肝癌发生、发展、诊断、靶向治疗和预后中发挥重要作用的miRNA及其作用靶点作一综述。     

DNA methylation of microRNA genes in multiple myeloma

DNA methylation is one of the heritable epigenetic modifications, leading to repressed gene expressions and consequent phenotypic alterations without changing the DNA sequence. MicroRNA (miRNA) is a novel class of short non-coding RNA molecules regulating a wide range of cellular functions through translational repression of their target genes. Recently, epigenetic dysregulation of tumor-suppressor miRNA genes by promoter DNA methylation has been implicated in human cancers, including multiple myeloma (MM). This article presents a brief overview of the pathogenesis of MM, the role of DNA methylation in cancer biology, methods of DNA methylation analysis, miRNA biology and dysregulation of miRNAs in MM and summaries the current data on the role of DNA methylation of tumor-suppressive miRNAsin MM.     

Metastamirs: a stepping stone towards improved cancer management

MicroRNAs (miRNAs) are non-coding RNAs that regulate protein expression. Aberrant miRNA expression in cancer has been well documented; miRNAs can act as oncogenes or tumor-suppressor genes, depending on the cellular context and target genes that they regulate, and are involved in tumor progression and metastasis. The potential mechanisms by which miRNAs are involved in tumor aggressiveness include migration, invasion, cell proliferation, epithelial-to-mesenchymal transition, angiogenesis and apoptosis. MiRNAs are involved in various cellular pathways and an miRNA can elicit more than one biological effect in a given cell. Existing data show the potential clinical utility of miRNAs as prognostic and predictive markers for aggressive and metastatic cancers. The stability of miRNAs in formalin-fixed, paraffin-embedded tissues and body fluids is advantageous for biomarker discovery and validation. In addition, miRNAs can be extracted from small biopsy specimens, which is a further advantage. Finally, miRNAs are potential therapeutic agents for personalized cancer management.     

The role of microRNAs in human breast cancer progression

Over the past decade, microRNAs (miRNAs) have become a new paradigm of gene regulation. miRNAs are involved in a wide array of carcinogenic processes. Indeed, increasing evidence has shown the importance of miRNAs in cancer, suggesting their possible use as diagnostic, predictive and prognostic biomarkers, leading to miRNA-based anti-cancer therapies, either alone or in combination with current targeted therapies, with the goal of improving cancer treatment responses and increasing cure rates. The advantage of using a miRNA approach is based on the ability to concurrently target multiple effectors of pathways involved in cell proliferation, migration and survival. This review sheds new light on miRNA regulation of genes that play critical roles in the process of malignant transformation and tumour metastasis, the dysregulation of miRNA expression in cancer development and the development of miRNA-based diagnostics and therapeutics.     

Exploring the role of miRNAs in renal cell carcinoma progression and metastasis through bioinformatic and experimental analyses

Metastasis results in most of the cancer deaths in clear cell renal cell carcinoma (ccRCC). MicroRNAs (miRNAs) regulate many important cell functions and play important roles in tumor development, metastasis and progression. In our previous study, we identified a miRNA signature for metastatic RCC. In this study, we validated the top differentially expressed miRNAs on matched primary and metastatic ccRCC pairs by quantitative polymerase chain reaction. We performed bioinformatics analyses including target prediction and combinatorial analysis of previously reported miRNAs involved in tumour progression and metastasis. We also examined the co-expression of the miRNAs clusters and compared expression of intronic miRNAs and their host genes. We observed significant dysregulation between primary and metastatic tumours from the same patient. This indicates that, at least in part, the metastatic signature develops gradually during tumour progression. We identified metastasis-dysregulated miRNAs that can target a number of genes previously found to be involved in metastasis of kidney cancer as well as other malignancies. In addition, we found a negative correlation of expression of miR-126 and its target vascular endothelial growth factor (VEGF)-A. Cluster analysis showed that members of the same miRNA cluster follow the same expression pattern, suggesting the presence of a locus control regulation. We also observed a positive correlation of expression between intronic miRNAs and their host genes, thus revealing another potential control mechanism for miRNAs. Many of the significantly dysregulated miRNAs in metastatic ccRCC are highly conserved among species. Our analysis suggests that miRNAs are involved in ccRCC metastasis and may represent potential biomarkers.     

Emerging links between epigenetic alterations and dysregulation of noncoding RNAs in cancer

Epigenetic changes, including DNA methylation and histone modification, play key roles in the dysregulation of tumor-related genes, thereby affecting numerous cellular processes, including cell proliferation, cell adhesion, apoptosis, and metastasis. In recent years, numerous studies have shown that noncoding RNAs (ncRNAs) are key players in the initiation and progression of cancer and epigenetic mechanisms are deeply involved in their dysregulation. Indeed, the growing list of microRNA (miRNA) genes aberrantly methylated in cancer suggests that a large number of miRNAs exert tumor-suppressive or oncogenic effects. In addition, it now appears that long ncRNAs may be causally related to epigenetic dysregulation of critical genes in cancer. Dissection of the relationships between ncRNAs and epigenetic alterations may lead to the development of novel approaches to the diagnosis and treatment of cancer.     

Targeted therapy for uveal melanoma

Uveal melanoma is the most common primary intra-ocular malignancy in adults. Overall mortality rate remains high because of the development of metastatic disease, which is highly resistant to systemic therapy. Improved understanding of the molecular pathogenesis of cancers has led to a new generation of therapeutic agents that interfere with a specific pathway critical in tumor development or progression. Although no specific genes have been linked to the pathogenesis of uveal melanoma, which differs from that of cutaneous melanoma, progress has been made in identifying potential targets involved in uveal melanoma apoptosis, proliferation, invasion, metastasis, and angiogenesis. This review focuses on the prospects for improving the systemic therapy of uveal melanoma using molecularly targeted agents that are currently in clinical use as well as agents being tested in clinical trials. Preclinical studies suggest potential benefit of inhibitors of Bcl-2, ubiquitin-proteasome, histone deactylase, mitogen-activated protein kinase and phosphatidylinositol-3-kinase-AKT pathways, and receptor tyrosine kinases. Modifiers of adhesion molecules, matrix metalloproteinase, and angiogenic factors also have demonstrated potential benefit. Clinical trials of some of these approaches have been initiated in patients with metastatic uveal melanoma as well as in the adjuvant setting after primary therapy.     

miRNA在骨肉瘤中的研究进展

骨肉瘤是一种恶性程度很高的原发性骨肿瘤,其发生率约为0．04～0．05／万,多数起源于骨间叶细胞,好发部位为长骨,一般为股骨远端或胫骨近端,其次为肱骨近端。好发于10～20岁的青少年,占骨恶性肿瘤的20％左右,肺转移是其主要死亡原因,随着新辅助化疗、保肢手术等的开展,5年生存率提高到近60％～70％。但由于化疗耐药性等问题的存在,患者仍面临着复发及肺转移的困扰。基因治疗、免疫治疗和分子靶向治疗等生物治疗技术的发展也为骨肉瘤的治疗开辟了新的道路,为骨肉瘤患者带来希望。     

miRNAs in the pathogenesis of oncogenic human viruses

Tumor viruses are a class of pathogens with well established roles in the development of malignant diseases. Numerous bodies of work have highlighted miRNAs (microRNAs) as critical regulators of tumor pathways and it is clear that the dysregulation of cellular miRNA expression can promote tumor formation. Tumor viruses encode their own miRNAs and/or manipulate the expression of cellular miRNAs to modulate their host cell environment, thereby facilitating their respective infection cycles. The modulation of these miRNA responsive pathways, however, often influences certain signal transduction cascades in ways that favor tumorigenesis. In this review, we discuss the roles of virally-encoded and virally-regulated cellular miRNAs in the respective viral life cycles and in virus associated pathogenesis.     

A novel oncogenic role for the miRNA-506-514 cluster in initiating melanocyte transformation and promoting melanoma growth

Malignant melanoma is the most aggressive form of skin cancer and its incidence has doubled in the last two decades. It represents only 4% of skin cancer cases per year, but causes as many as 74% of skin cancer deaths. Early detection of malignant melanoma is associated with survival rates of up to 90%, but later detection (stage III to stage IV) is associated with survival rates of only 10%. Dysregulation of microRNA (miRNA) expression has been linked to tumor development and progression by functioning either as a tumor suppressor, an oncogene or a metastasis regulator in multiple cancer types. To understand the role of miRNA in the pathogenesis of malignant melanoma and identify biomarkers of metastasis, miRNA expression profiles in skin punches from 33 metastatic melanoma patients and 14 normal healthy donors were compared. We identified a cluster of 14 miRNAs on the X chromosome, termed the miR-506-514 cluster, which was consistently overexpressed in nearly all melanomas tested (30-60 fold, P<0.001), regardless of mutations in N-ras or B-raf. Inhibition of the expression of this cluster as a whole, or one of its sub-clusters (Sub-cluster A) consisting of six mature miRNAs, led to significant inhibition of cell growth, induction of apoptosis, decreased invasiveness and decreased colony formation in soft agar across multiple melanoma cell lines. Sub-cluster A of the miR-506-514 cluster was critical for maintaining the cancer phenotype, but the overexpression of the full cluster was necessary for melanocyte transformation. Our results provide new insights into the functional role of this miRNA cluster in melanoma, and suggest new approaches to treat or diagnose this disease.     

MiRNA in melanoma-derived exosomes

Proteins, RNAs and viruses can be spread through exosomes, therefore transport utilizing these nanovesicles is of the great interest. MiRNAs are common exosomal constituents capable of influencing expression of a variety of target genes. MiRNA signatures of exosomes are unique in cancer patients and differ from those in normal controls. The knowledge about miRNA profiles of tumor-derived exosomes may contribute to better diagnosis, determination of tumor progression and response to treatment, as well as to the development of targeted therapies. We summarize the current knowledge with regard to miRNAs that are found in exosomes derived from tumors, particularly from melanoma.