Emerging roles for modulation of microRNA signatures in cancer chemoprevention

miRNAs are small endogenous non-coding RNAs, approximately 21-nucleotides in length, which are shown to regulate an array of cellular processes such as differentiation, cell cycle, cell proliferation, apoptosis, and angiogenesis which are important in cancer. miRNAs can function as both tumor promoters (oncomiRs) or tumor suppressors by their ability to target numerous biomolecules that are important in carcinogenesis. Aberrant expression of miRNAs is correlated with the development and progression of tumors, and the reversal of their expression has been shown to modulate the cancer phenotype suggesting the potential of miRNAs as targets for anti-cancer drugs. Several chemopreventive phytochemicals like epigallocatechin-3-gallate, curcumin, isoflavones, indole-3-carbinol, resveratrol, and isothiocyanate have been shown to modulate the expression of numerous miRNAs in cancer cells that lead to either abrogation of tumor growth or sensitization of cancer cells to chemotherapeutic agents. This review focuses on the putative role(s) of miRNAs in different aspects of tumorigenesis and at various stages of early drug discovery that makes them a promising class of drug targets for chemopreventive intervention in cancer. We summarize the current progress in the development of strategies for miRNA-based anti-cancer therapies. We also explore the modulation of miRNAs by various cancer chemopreventive agents and the role of miRNAs in drug metabolism. We will discuss the role of miRNAs in cancer stem cells and epithelial-to-mesenchymal transition; and talk about how modulation of miRNA expression relates to altered glycosylation patterns in cancer cells. In addition, we consider the role of altered miRNA expression in carcinogenesis induced by various agents including genotoxic and epigenetic carcinogens. Finally, we will end with a discussion on the potential involvement of miRNAs in the development of cancer chemoresistance. Taken together, a better understanding of the complex role(s) of miRNAs in cancer may help in designing better strategies for biomarker discovery or drug targeting of miRNAs and/or their putative protein targets.     

MicroRNAs as therapeutic targets and their potential applications in cancer therapy

INTRODUCTION: The results of cancer-associated miRNA research have yielded surprising insights into the pathogenesis of a range of different cancers. Many of the dysregulated miRNAs are involved in the regulation of genes that are essential for carcinogenesis. AREAS COVERED: This review discusses the latest discovery of miRNAs acting as oncogenes and tumor suppressor genes, as well as the potential applications of miRNA regulations in cancer therapy. Several translational studies have demonstrated the feasibility of targeting oncogenic miRNAs and restoring tumor-suppressive miRNAs for cancer therapy using in vivo model systems. EXPERT OPINION: miRNAs are extensive regulators of cancer progression. With increasing understanding of the miRNA target genes and the cellular behaviors influenced by them, modulating the miRNA activities may provide exciting opportunities for cancer therapy. Despite the hurdles incurred in acquiring effective systemic drug delivery systems, in vivo delivery of miRNAs for therapeutic purposes in preclinical animal models is rapidly developing. Accumulating evidences indicate that using miRNA expression alterations to influence molecular pathways has the potential of being translated into clinical applications.     

The role of microRNAs in cancer: diagnostic and prognostic biomarkers and targets of therapies

INTRODUCTION: miRNAs are noncoding RNAs that target specific mRNA with subsequent regulation of particular genes, implicated in various biological processes. In cancer, miRNAs could show a different expression from normal tissues. miRNAs have a role as oncogenes when they target tumor suppressor genes and similarly they are tumor suppressors when they target oncogenes. AREAS COVERED: In this review, areas covered include the role of miRNAs in cancer diagnosis, prognosis and research for achievement of therapeutic strategies implicating miRNAs in oncology. As biogenesis of miRNAs is fundamental to understand their usefulness, this has also been discussed. Both miRNA expression profiles in cancer tissues and miRNA levels in peripheral blood were studied for improvement in the management of cancer patients. EXPERT OPINION: miRNAs have the potential for better understanding of tumor biology, but could also provide clinical advancement in management and therapy of various malignancies. The possibility of miRNA detection in peripheral blood would allow an eager expansion of their application in various clinical settings for cancer. The applicability of miRNA expression profiles still needs to be defined.     

MicroRNAs and Cancer Therapeutics

MicroRNAs (miRNAs) are small physiological non-coding RNAs that regulate gene expression through an RNA interference (RNAi) mechanism. The expression of miRNAs is tightly controlled both spatially and temporally. Aberrant miRNA expression has been correlated with various cancers. Recent findings suggest that some miRNAs can function as tumor suppressors or oncogenes. In model experiments, the cancer phenotype of some cells can be reverted to normal when the cells are treated with miRNA mimics or inhibitors. Here, we discuss in brief the potential utility of miRNA-based cancer therapy as well as the current limitations thwarting their useful clinical application.     

Role of microRNAs in gynecological pathology

microRNAs (miRNAs) are 21-22 nucleotide non-coding RNAs that regulate gene expression and play fundamental roles in biological processes. These small molecules bind to target mRNAs, leading to translational repression and/or mRNA degradation. Aberrant miRNA expression is associated with several human diseases such as cancer, cardiovascular disorders, inflammatory diseases and gynecological pathology. The present article reviews the role of miRNAs in four gynecological disorders that affect the ovary or the uterus, one benign and frequent disease (endometriosis) that is classified as a tumor-like lesion and three malignant gynecological diseases (endometrial, cervical and ovarian cancers). Endometriosis, defined as the presence of endometrium outside the uterus, is one of the most frequent benign gynecological diseases. Similarly to tumor metastasis, endometriotic implants require neovascularization to proliferate, invade the extracellular matrix and establish an endometriotic lesion. Despite its high prevalence and incapacitating symptoms, the exact pathogenic mechanism of endometriosis remains unsolved. A relationship between endometriosis and gynecological cancer, especially ovarian cancer, has been reported. Endometriosis is a multifactorial and polygenic disease, and emerging data provide evidence that a dysregulation of miRNA expression may be involved. miRNAs appear to be potent regulators of gene expression in endometriosis, raising the prospect of using miRNAs as biomarkers and therapeutic tools in this disease. In cancer, miRNAs have an important role as regulatory molecules, acting as oncogenes (oncomiRs) or tumor suppressors. Endometrial cancer is one of the most frequent gynecological malignancies in the developed countries. Cervical cancer, also one of the most common cancers in women, is associated with high-risk human papillomaviruses although this infection alone may not be enough to induce the malignant transformation. Ovarian cancer is the fifth leading cause of all cancer-related deaths among women. Over 80% of cases are diagnosed at an advanced stage, with a reduced five-year survival rate. Recent studies have shown that miRNAs are aberrantly expressed in different human cancer types, including endometrial, cervical and ovarian cancer, and that specific dysregulated miRNAs may act as biomarkers of patients' outcome. Recently, miRNAs have been detected in serum and plasma, and circulating miRNA expression profiles have now been associated with a range of different tumor types. Their accessibility in peripheral blood and stability given the fact that miRNAs circulate confined within exosomes, make researchers foster hope in their role as emerging biomarkers of cancer and other disorders. The development of therapies that might block the expression or mimic the functions of miRNAs could represent new therapeutic strategies for any of the aforementioned gynecological disorders.     

Regulation of microRNAs by Natural Agents: An Emerging Field in Chemoprevention and Chemotherapy Research

In recent years, microRNAs have received greater attention in cancer research. These small, non-coding RNAs could inhibit target gene expression by binding to the 3′ untranslated region of target mRNA, resulting in either mRNA degradation or inhibition of translation. miRNAs play important roles in many normal biological processes; however, studies have also shown that aberrant miRNA expression is correlated with the development and progression of cancers. The miRNAs could have oncogenic or tumor suppressor activities. Moreover, some miRNAs could regulate formation of cancer stem cells and epithelial-mesenchymal transition phenotype of cancer cells which are typically drug resistant. Furthermore, miRNAs could be used as biomarkers for diagnosis and prognosis, and thus miRNAs are becoming emerging targets for cancer therapy. Recent studies have shown that natural agents including curcumin, isoflavone, indole-3-carbinol, 3,3′-diindolylmethane, (-)-epigallocatechin-3-gallate, resveratrol, etc. could alter miRNA expression profiles, leading to the inhibition of cancer cell growth, induction of apoptosis, reversal of epithelial-mesenchymal transition, or enhancement of efficacy of conventional cancer therapeutics. These emerging results clearly suggest that specific targeting of miRNAs by natural agents could open newer avenues for complete eradication of tumors by killing the drug-resistant cells to improve survival outcome in patients diagnosed with malignancies.     

miRNA: small molecules as potential novel biomarkers in cancer

Four different types of small RNAs functionally associated with gene silencing have been discovered in animals including small interfering RNAs (siRNAs), microRNAs (miRNAs), and Piwi-interacting RNAs (piRNAs). Experimental evidence suggests that miRNAs regulate the expression of more than 30% of protein-coding genes. These molecules can also act as oncogenes or tumor suppressors. Expression profiling has revealed characteristic miRNA signatures not only in human cancers but also in serum and blood cells of cancer patients. Numerous human miRNA genes map to chromosomal regions which are susceptible to amplification, deletion or translocation in the process of tumor development. Despite the pivotal role of miRNA in cancer precise mechanisms of action are yet to be elucidated. This review is focused on recent findings related to the emerging field of miRNA serving as novel potential biomarkers in cancer diagnosis, prognosis and possibly, therapies.     

MicroRNAs as therapeutic targets and their potential applications in cancer therapy

Introduction: The results of cancer-associated miRNA research have yielded surprising insights into the pathogenesis of a range of different cancers. Many of the dysregulated miRNAs are involved in the regulation of genes that are essential for carcinogenesis.

Areas covered: This review discusses the latest discovery of miRNAs acting as oncogenes and tumor suppressor genes, as well as the potential applications of miRNA regulations in cancer therapy. Several translational studies have demonstrated the feasibility of targeting oncogenic miRNAs and restoring tumor-suppressive miRNAs for cancer therapy using in vivo model systems.

Expert opinion: miRNAs are extensive regulators of cancer progression. With increasing understanding of the miRNA target genes and the cellular behaviors influenced by them, modulating the miRNA activities may provide exciting opportunities for cancer therapy. Despite the hurdles incurred in acquiring effective systemic drug delivery systems, in vivo delivery of miRNAs for therapeutic purposes in preclinical animal models is rapidly developing. Accumulating evidences indicate that using miRNA expression alterations to influence molecular pathways has the potential of being translated into clinical applications.     

Diet,MicroRNAs and Prostate Cancer

MicroRNAs (miRNAs) constitute an evolutionarily conserved class of small non-coding RNAs that are endogenously expressed with crucial functions in fundamental cellular processes such as cell cycle, apoptosis and differentiation. Disturbance of miRNA expression and function leads to deregulation of basic cellular processes leading to tumorigenesis. A growing body of experimental evidence suggests that human tumors have deregulated expression of microRNAs, which have been proposed as novel oncogenes or tumor suppressors. Recent studies have shown that microRNA expression patterns serve as phenotypic signatures of different cancers and could be used as diagnostic, prognostic and therapeutic tools. A few studies have analyzed global microRNA expression profiles or the functional role of microRNAs in prostate cancer. Here we have reviewed the role of microRNAs in prostate carcinogenesis by summarizing the findings from such studies. In addition, recent evidence indicates that dietary factors play an important role in the process of carcinogenesis through modulation of miRNA expression, though such studies are lacking in regards to prostate cancer. It has been proposed that dietary modulation of miRNA expression may contribute to the cancer-protective effects of dietary components. In this review, we have summarized findings from studies on the effect of dietary agents on miRNA expression and function.     

Targeting microRNAs in cancer: rationale, strategies and challenges

MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs that regulate gene expression. Early studies have shown that miRNA expression is deregulated in cancer and experimental data indicate that cancer phenotypes can be modified by targeting miRNA expression. Based on these observations, miRNA-based anticancer therapies are being developed, either alone or in combination with current targeted therapies, with the goal to improve disease response and increase cure rates. The advantage of using miRNA approaches is based on its ability to concurrently target multiple effectors of pathways involved in cell differentiation, proliferation and survival. In this Review, we describe the role of miRNAs in tumorigenesis and critically discuss the rationale, the strategies and the challenges for the therapeutic targeting of miRNAs in cancer.     

MicroRNA: Potential Targets for the Development of Novel Drugs?

MicroRNA (miRNA) is an endogenous non-protein coding small RNA molecule that negatively regulates gene expression by the degradation of messenger RNA (mRNA) or the suppression of mRNA translation. miRNA plays important roles in physiologic processes such as cellular development, differentiation, proliferation, apoptosis, and stem cell self-renewal. Studies show that deregulation of miRNA expression is closely associated with tumorigenicity, invasion, and metastasis. The functionality of aberrant miRNAs in cancer could act either as oncogenes or tumor suppressors during tumor initiation and progression. Similar to protein-coding gene regulation, dysregulation of miRNAs may be related to changes in miRNA gene copy numbers, epigenetic modulation, polymorphisms, or biogenesis modifications. Elucidation of the miRNA expression profiles (miRNomes) of many types of cancers is starting to decode the regulatory network of miRNA-mRNA interactions from a systems biology perspective. Experimental evidence demonstrates that modulation of specific miRNA alterations in cancer cells using miRNA replacement or anti-miRNA technologies can restore miRNA activities and repair gene regulatory networks affecting apoptotic signaling pathways or drug sensitivity, and improve the outcome of treatment. Numerous animal studies for miRNA-based therapy offer the hope of targeting miRNAs as an alternative cancer treatment. Developing the small molecules to interfere with miRNAs could be of great pharmaceutical interest in the future.     

microRNA与消化系肿瘤的研究进展

microRNA是一类长约19～25nt,能在转录后水平负性调节mRNA表达的小分子非编码单链RNA。它们广泛存在于真核生物体内,参与调节各种细胞过程．包括细胞凋亡、造血细胞分化、新陈代谢、皮肤生发及神经系统发育。miRNA作为调控基因表达的重要分子在肿瘤发生和发展中的作用越来越受到重视,阐明miRNA在肿瘤发生和发展中的作用机制具有重要的理论意义。miRNA在肿瘤发生和发展过程中的重要调控功能预示其将成为人类癌症诊断和治疗方面的新星。文章综述jmiRNA在胃癌、结肠癌、肝癌和胰腺癌中作用机制的研究进展。     

Crosstalk between TGF-β signaling and the microRNA machinery

The activin/transforming growth factor-β (TGF-β) pathway plays an important role in tumorigenesis either by its tumor suppressor or tumor promoting effect. Loss of members of the TGF-β signaling by somatic mutations or epigenetic events, such as DNA methylation or regulation by microRNA (miRNA), may affect the signaling process. Most members of the TGF-β pathway are known to be targeted by one or more miRNAs. In addition, the biogenesis of miRNAs is also regulated by TGF-β both directly and through SMADs. Based on these interactions, it appears that autoregulatory feedback loops between TGF-β and miRNAs influence the fate of tumor cells. Our aim is to review the crosstalk between TGF-β signaling and the miRNA machinery to highlight potential novel therapeutic targets.     

Implication of microRNAs in drug resistance for designing novel cancer therapy

Recently, microRNAs (miRNAs) have received increasing attention in the field of cancer research. miRNAs play important roles in many normal biological processes; however, the aberrant miRNA expression and its correlation with the development and progression of cancers is an emerging field. Therefore, miRNAs could be used as biomarkers for diagnosis of cancer and prediction of prognosis. Importantly, some miRNAs could regulate the formation of cancer stem cells and the acquisition of epithelial–mesenchymal transition, which are critically associated with drug resistance. Moreover, some miRNAs could target genes related to drug sensitivity, resulting in the altered sensitivity of cancer cells to anti-cancer drugs. Emerging evidences have also shown that knock-down or re-expression of specific miRNAs by synthetic anti-sense oligonucleotides or pre-miRNAs could induce drug sensitivity, leading to increased inhibition of cancer cell growth, invasion, and metastasis. More importantly, recent studies have shown that natural agents including isoflavone, 3,3′-diindolylmethane, and (?)-epigallocatechin-3-gallate altered miRNA expression profiles, leading to an increased sensitivity of cancer cells to conventional therapeutics. These emerging results suggest that specific targeting of miRNAs by different approaches could open new avenues for cancer treatment through overcoming drug resistance and thereby improve the outcome of cancer therapy.