Role of exosomal microRNAs in lung cancer biology and clinical applications

Exosomes, small extracellular vesicles ranging from 30 to 150 nm, are secreted by various cell types, including tumour cells. Recently, microRNAs (miRNAs) were identified to be encapsulated and hence protected from degradation within exosomes. These exosomal miRNAs can be horizontally transferred to target cells, in which they subsequently modulate biological processes. Increasing evidence indicates that exosomal miRNAs play a critical role in modifying the microenvironment of lung cancers, possibly facilitating progression, invasion, angiogenesis, metastasis and drug resistance. In this review, we summarize the novel findings on exosomal miRNA functions during lung cancer initiation and progression. In addition, we highlight their potential role and challenges as biomarkers in lung cancer diagnosis, prognosis and drug resistance and as therapeutic agents.     

Role of microRNAs in ovarian cancer pathogenesis and potential clinical implications

Despite important improvements over the past two decades, the overall cure rate of epithelial ovarian cancer (EOC) remains only ～30%. Although much has been learned about the proteins and pathways involved in early events of malignant transformation and drug resistance, a major challenge still remaining is the identification of markers for early diagnosis and prediction of response to chemotherapy.Recently, it has become clear that alterations in the expression of microRNAs (miRNAs) contribute to the pathogenesis and progression of several human malignancies. In this review we discuss current data concerning the accumulating evidence of the role of miRNAs in EOC pathogenesis and tumor characterization; their dysregulated expression in EOC; and their still undefined role in diagnosis, prognosis and prediction of response to therapy. The most frequently deregulated miRNAs are members of the let-7 and miR-200 families, the latter involved in epithelial-to-mesenchymal transition (EMT). EMT is part of normal ovarian surface epithelium physiology, being the key regulator of the post-ovulatory repair process, and failure to undergo EMT may be one of the events leading to transformation. A general down-modulation of miRNA expression is observed in EOC compared to normal tissue. However, a clear consensus on the miRNA signatures associated with prognosis or prediction of response to therapy has not yet been reached.     

Role and regulation of autophagy in cancer

Autophagy is an intracellular self-degradative mechanism which responds to cellular conditions like stress or starvation and plays a key role in regulating cell metabolism, energy homeostasis, starvation adaptation, development and cell death. Numerous studies have stipulated the participation of autophagy in cancer, but the role of autophagy either as tumor suppressor or tumor promoter is not clearly understood. However, mechanisms by which autophagy promotes cancer involves a diverse range of modifications of autophagy associated proteins such as ATGs, Beclin-1, mTOR, p53, KRAS etc. and autophagy pathways like mTOR, PI3K, MAPK, EGFR, HIF and NFκB. Furthermore, several researches have highlighted a context-dependent, cell type and stage-dependent regulation of autophagy in cancer. Alongside this, the interaction between tumor cells and their microenvironment including hypoxia has a great potential in modulating autophagy response in favour to substantiate cancer cell metabolism, self-proliferation and metastasis. In this review article, we highlight the mechanism of autophagy and their contribution to cancer cell proliferation and development. In addition, we discuss about tumor microenvironment interaction and their consequence on selective autophagy pathways and the involvement of autophagy in various tumor types and their therapeutic interventions concentrated on exploiting autophagy as a potential target to improve cancer therapy.     

Epigenetic regulation of microRNAs in cancer: an integrated review of literature

MicroRNAs (miRNAs) belong to the heterogeneous class of non-coding RNAs (ncRNAs) that regulate the translation and degradation of target mRNAs, and control approximately 30% of human genes. MiRNA genes might be silenced in human tumors (oncomiRs) by aberrant hypermethylation of CpG islands that encompass or lie adjacent to miRNA genes and/or by histone modifications. We performed literature search for research articles describing epigenetically regulated miRNAs in cancer and identified 45 studies that were published between 2006 and 7/2010. The data from those papers are fragmented and methodologically heterogeneous and our work represents first systematic review towards to integration of diverse sets of information. We reviewed the methods used for detection of miRNA epigenetic regulation, which comprise bisulfite genomic sequencing PCR (BSP), bisulfite pyrosequencing, methylation specific PCR (MSP), combined bisulfite restriction analysis (COBRA), methylation sensitive single nucleotide primer extension (Ms-SNuPE), MassARRAY technique and some modifications of those methods. This integrative study revealed 122 miRNAs that were reported to be epigenetically regulated in 23 cancer types. Compared to protein coding genes, human oncomiRs showed an order of magnitude higher methylation frequency (11.6%; 122/1048 known miRNAs). Nearly half, (45%; 55/122) epigenetically regulated miRNAs were associated with different cancer types, but other 55% (67/122) miRNAs were present in only one cancer type and therefore representing cancer-specific biomarker potential. The data integration revealed miRNA epigenomic hot spots on the chromosomes 1q, 7q, 11q, 14q and 19q. CpG island analysis of corresponding miRNA precursors (pre-miRNAs) revealed that 20% (26/133) of epigenetically regulated miRNAs had a CpG island within the range of 5kb upstream, among them 14% (19/133) of miRNAs resided within the CpG island. Our integrative survey and analyses revealed candidate cancer-specific miRNA epigenetic signatures which provide the basis for new therapeutic strategies in cancer by targeting the epigenetic regulation of miRNAs.     

Role of microRNAs in diabetes

Diabetes is one of the most common chronic diseases in the world. Multiple and complex factors including various genetic and physiological changes can lead to type 1 and type 2 diabetes. However, the major mechanisms underlying the pathogenesis of diabetes remain obscure. With the recent discovery of microRNAs (miRNAs), these small ribonucleotides have been implicated as new players in the pathogenesis of diabetes and diabetes-associated complications. MiRNAs have been shown to regulate insulin production, insulin secretion, and insulin action. This review summarizes the recent progress in the cutting-edge research of miRNAs involved in diabetes and diabetes related complications.     

microRNAs in the regulation of adipogenesis and obesity

Worldwide obesity is a growing health problem, associated with increased risk of chronic disease. Understanding the molecular basis of adipogenesis and fat cell development in obesity is essential to identify new biomarkers and therapeutic targets for the development of anti-obesity drugs. microRNAs (miRNAs) appear to play regulatory roles in many biological processes associated with obesity, including adipocyte differentiation, insulin action and fat metabolism. Recent studies show miRNAs are dysregulated in obese adipose tissue. During adipogenesis miRNAs can accelerate or inhibit adipocyte differentiation and hence regulate fat cell development. In addition miRNAs may regulate adipogenic lineage commitment in multipotent stem cells and hence govern fat cell numbers. Recent findings suggest miR-519d may be associated with human obesity, but larger case-control studies are needed. Few miRNA targets have been experimentally validated in adipocytes but interestingly both miR-27 and miR-519d target PPAR family members, which are well established regulators of fat cell development. In this review recent advances in our understanding of the role of miRNAs in fat cell development and obesity are discussed. The potential of miRNA based therapeutics targeting obesity is highlighted as well as recommendations for future research which could lead to a breakthrough in the treatment of obesity.     

Emerging Role of microRNAs in Dementia

MicroRNAs are small non-coding RNAs regulating mRNA translation. They play a crucial role in regulating homeostasis in neurons, especially in regulating local and stimulation dependent protein synthesis. Since activity-mediated protein synthesis in neurons is critical for memory and cognition, microRNAs have become key players in modulating these processes. Dementia is a broad term used for symptoms involving decline of memory and cognition. Several studies have implicated the dysregulation of microRNAs in many brain diseases like neurodegenerative diseases, neurodevelopmental disorders, brain injuries and dementia. In this review, we give an overview of microRNA-mediated regulation of proteins and cellular processes affected in dementia pathology, hence illustrating the importance of microRNAs in normal functioning. We also focus on a relatively less explored area in dementia pathology—the importance of activity-mediated protein synthesis at the synapse and the role of microRNAs in modulating this. Overall, this review will be helpful in looking at the significance of microRNAs in dementia from the perspective of defective regulation of protein synthesis and synaptic dysfunction.     

微核糖核酸在肿瘤血管生成中的调节作用

微核糖核酸（microRNAs,miRNAs）是广泛存在于真核生物中的一类短小的、不编码蛋白质的RNA家族,由18-25个核苷酸组成的单链RNA。研究表明microRNAs对肿瘤的发生发展具有重要的调节作用。肿瘤血管生成是实体瘤侵袭转移的关键步骤,抗肿瘤血管生成的治疗已成为当前研究的焦点,已有研究表明,microRNAs参与肿瘤血管生成的调节作用,通过对肿瘤血管生成相关因子的调控,影响肿瘤生成。     

微核糖核酸在肿瘤血管生成中的调节作用

微核糖核酸(microRNAs,miRNAs)是广泛存在于真核生物中的一类短小的、不编码蛋白质的RNA家族,由18-25个核苷酸组成的单链RNA。研究表明microRNAs对肿瘤的发生发展具有重要的调节作用。肿瘤血管生成是实体瘤侵袭转移的关键步骤,抗肿瘤血管生成的治疗已成为当前研究的焦点,已有研究表明,microRNAs参与肿瘤血管生成的调节作用,通过对肿瘤血管生成相关因子的调控,影响肿瘤生成。