MicroRNA-targeted therapeutics for lung cancer treatment

Introduction: Lung cancer is one of the leading causes of cancer-related mortality worldwide. MicroRNAs (miRNAs) are endogenous non-coding small RNAs that repress the expression of a broad array of target genes. Many efforts have been made to therapeutically target miRNAs in cancer treatments using miRNA mimics and miRNA antagonists.

Areas covered: This article summarizes the recent findings with the role of miRNAs in lung cancer, and discusses the potential and challenges of developing miRNA-targeted therapeutics in this dreadful disease.

Expert opinion: The development of miRNA-targeted therapeutics has become an important anti-cancer strategy. Results from both preclinical and clinical trials of microRNA replacement therapy have shown some promise in cancer treatment. However, some obstacles, including drug delivery, specificity, off-target effect, toxicity mediation, immunological activation and dosage determination should be addressed. Several delivery strategies have been employed, including naked oligonucleotides, liposomes, aptamer-conjugates, nanoparticles and viral vectors. However, delivery remains a main challenge in miRNA-targeting therapeutics. Furthermore, immune-related serious adverse events are also a concern, which indicates the complexity of miRNA-based therapy in clinical settings.     

MiR-199a-5p and miR-375 affect colon cancer cell sensitivity to cetuximab by targeting PHLPP1

Objectives: We aimed to analyze the differentially-expressed miRNAs in colon cancer cells in order to identify novel potential biomarkers involved in cancer cell resistance.

Design and methods: We investigated the miRNA expression profile of GEO human colon carcinoma cells, sensitive to the EGFR inhibitor Cetuximab (CTX) and their CTX-resistant counterpart (GEO CR) by using a miRNA chip.

Results: We found 27 upregulated and 10 downregulated miRNAs in GEO CR compared with GEO cells with a fold change ≥ 2. Among the upregulated miRNAs, we focused on miR-199a-5p and miR-375. We report that their enforced expression promotes CTX resistance, whereas their silencing sensitizes to the same drug. The ability of miR-199a-5p and miR-375 to target PHLPP1 (PH domain and leucine-rich repeat protein phosphatase 1), a tumor suppressor that negatively regulates the AKT pathway, accounts, at least in part, for their drug-resistance activity. Indeed, restoration of PHLPP1 increases sensitivity of the GEO cells to CTX and reverts the resistance-promoting effect of miR-199a-5p and miR-375.

Conclusion: This study proposes miR-199a-5p and miR-375 as contributors to CTX resistance in colon cancer and suggests a novel approach based on miRNAs as tools for the therapy of this tumor.     

Serum microRNA profiles among dioxin exposed veterans with monoclonal gammopathy of undetermined significance

ABSTRACT

Previously an increased risk for monoclonal gammopathy of undetermined significance (MGUS), a precursor of multiple myeloma (MM), was reported among Vietnam veterans exposed to Agent Orange and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Dysregulated expression of certain microRNAs (miRNAs) was demonstrated in MGUS and MM. Given the important role of miRNAs in cellular homeostasis, the aim of this study was to determine if there was an association between serum levels of selected miRNAs and TCDD in 47 MGUS cases identified in our previous investigation using serum specimens and exposure data archived by the Air Force Health Study (AFHS). A total of 13 miRNA levels (let-7a, let-7i, miR-16, miR-20a, miR-21, miR-34a, miR-106b, miR-146a, miR-181a, miR-192, miR-205, miR-335, and miR-361) was measured in serum stored during the 2002 AFHS follow-up and the relationship to lipid-adjusted serum TCDD levels in 1987 was determined. miR-34a showed the strongest relationship with TCDD; after age-adjustment, this positive association was more pronounced. In contrast, the other 12 miRNAs displayed absolute values of age adjusted coefficient estimates below 1.16 and non-significant p-values. The observed strong positive association between high body burdens of TCDD and miR-34a, a tumor suppressor regulated by p53, in this MGUS population warrants clarification of the TCDD-miR-34a relationship and its role in the pathogenesis of MGUS and risk for MM.     

Targeting miRNAs in osteoblast differentiation and bone formation

Importance of the field: Bone tissue arises from mesenchymal stromal cells (MSCs) differentiated into the osteoblast lineage by genetic and epigenetic mechanisms. Emerging evidence indicates that the class of small non-coding single-stranded RNAs known as “microRNAs (miRNAs)” also plays a critical role in this process.

Areas covered in this review: In this short review, we summarize the biology and functional mechanisms of miRNAs. Importantly, we discuss miRNA expression, miRNA function, miRNA target prediction, miRNA overexpression and inhibition methods applied in osteoblastogenesis.

What the reader will gain: We discuss the potential therapeutic opportunities and challenges for improving the treatment of bone-related diseases by using miRNAs as a therapeutic target.

Take home message: Although various microRNAs regulate cell proliferation and differentiation, only a few miRNAs has been reported so far to play a key role in the regulation of osteoblast differentiation and bone formation.     

The changes of miRNA expression in rat hippocampus following chronic lead exposure

miRNAs have been found to contribute to normal brain functions, nervous system diseases, as well as neurotoxicities induced by external agents. However, whether they are involved in lead-induced neurotoxicities is still not clear. To identify that, a lead-induced chronic neurotoxicity model of rats was built. Both miRNA microarray analysis and qRT-PCR were performed to determine the change of miRNA expression in hippocampus. Then 3 bioinformatics databases were used to analyze the relative target genes of these miRNA, which were further confirmed by qRT-PCR and Western blot. In the present study, lead exposure resulted in the changed expression of 7 miRNAs: miR-204, miR-211, miR-448, miR-449a, miR-34b, and miR-34c were greatly up-regulated while miR-494 was greatly down-regulated. Bioinformatics analysis results showed that the target genes of 6 up-regulated miRNAs were related to neural injury and neurodegeration, axon and synapse function, neural development and regeneration. Correspondingly, the expression levels of mature mRNAs and proteins of three target genes (Bcl-2, Itpr1, and Map2k1) were greatly repressed, verifying the results of bioinformatics analysis. Taken together, our results showed that the expression of several miRNAs reported to be associated with neurophysiological pathways and neurodegenerative diseases changed in rat hippocampus following chronic lead exposure. These miRNAs may play important roles in lead-induced neurotoxicity.     

Let-7 microRNA as a potential therapeutic target with implications for immunotherapy

ABSTRACT

Introduction: MicroRNAs (miRNA) are a class of small non-coding RNA that play a major role in various cellular processes by negatively regulating gene expression. In the past decade, miRNA dysregulation has been reported to be closely linked to inflammatory diseases. The immune response modulates cancer initiation and progression; miRNAs including let-7 family members have been shown to act as key regulators of the immune responses in various diseases and cancers. Notably, the let-7 miRNA has been reported to be closely associated with immunity, specifically with Toll-like receptors that mediate cytokine expression during pathogen infection and with the regulation of various other immune effectors.

Areas covered: In this review, the authors describe the discovery of let-7 as the starting point of the RNA revolution and highlight let-7 as an efficient tool for cancer and immune therapy.

Expert opinion: let-7 miRNA has emerged as a key player in cancer therapy and immune responses and it has potential role as a new immunotherapeutic target. However, while there are challenges regarding miRNA delivery, the exciting emergence of personalized medicine for cancer and immunotherapy could be beneficial for the development of let-7 therapeutics.     

MicroRNA-210 and its theranostic potential

Introduction: MicroRNAs (miRNAs) are a set of small single-stranded noncoding RNAs with diverse biological functions. As a prototypical hypoxamir, human microRNA-210 (hsa-miR-210) is one of the most widely studied miRNAs thus far. In addition to its involvement in sophisticated regulation of numerous biological processes, miR-210 has also been shown to be associated with the development of different human diseases including various types of cancers, cardiovascular and cerebrovascular diseases, and immunological diseases. Given its multi-faceted functions, miR-210 may serve as a novel and promising theranostic target for prevention and treatment of diseases.

Areas covered: This review aims to provide a comprehensive overview of miR-210, the regulation of its expression, biological functions and molecular mechanisms, with particular emphasis on its diagnostic and therapeutic potential.

Expert opinion: Although the exact roles of miR-210 in various diseases have not been fully clarified, targeting miR-210 may be a promising therapeutic strategy. Further investigations are also needed to facilitate therapeutic-clinical applications of miR-210 in human diseases.     

Targeting miR-375 in gastric cancer

Introduction: Gastric cancer remains a major cancer burden in the world, with a poor 5-year survival rate. It is necessary to develop new effective therapeutic strategies to improve the long-term clinical outcome. MicroRNA (miRNA), a class of small non-coding RNA, has been identified as a key regulator of gene expression, and is implicated in the pathogenesis of gastric cancer.

Areas covered: This review summarizes the role of miRNAs in gastric carcinogenesis, with an emphasis on the expression and function of miR-375 in gastric cancer and beyond. It also discusses the opportunities and challenges of miR-375 as a potential therapeutic target for gastric cancer. The genes targeted by miR-375, including JAK2 and 3′-phosphoinositide dependent protein kinase-1 (PDK1), are also candidates for gastric cancer therapy.

Expert opinion: Although radical surgery and rational chemotherapy are still the main treatment for gastric cancer, targeting miRNAs, in combination with other conventional therapies, may serve as a promising therapy strategy to improve the clinical outcome.     

Decreased expression of miR-20a and miR-92a in the serum from sulfur mustard-exposed patients during the chronic phase of resulting illness

Abstract

Context: Sulfur mustard (SM), with extensive nucleophilic and alkylating properties, was employed during the Iran–Iraq war by Iraqi forces. The most critical complications attributed to SM are related to dangerous pulmonary disorders collectively known as “mustard lung”. The symptoms gradually emerge over a long period, becoming chronic, and are dependent on time and the amount of exposed SM. Because of the unknown and complex nature of the disease, no differential diagnostic method or absolute treatment strategy has been formally developed.

Objective: The aim of our study was to determine the expression pattern of the microRNAs (miRNAs) miR-92a and miR-20a in the serum of patients with mustard lung along with that of normal individuals. miRNAs have been shown to possess stable persistence in biofluids like plasma and serum and are considered non-aggressive biomarkers helpful for diagnosis and treatment of many diseases.

Materials and methods: A highly sensitive approach called stem-loop real-time quantitative polymerase chain reaction was employed to study the expression of miRNAs. Results: The expression of miR-92a and miR-20a was significantly down-regulated in the serum of patients with mustard lung compared to the control group.

Discussion: Down-regulation of miR-92a and miR-20a may be due to chronic epigenetic alterations after SM exposure, which finally leads to changes in vital cellular processes such as differentiation, proliferation and so forth.

Conclusion: Our findings may provide a differential diagnostic method that is effective for diagnosing lung diseases caused by SM exposure. Additionally, these miRNAs may be regarded as probable targets for treatment of lung injuries.     

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.     

Therapeutic targeting of miRNAs in neuroblastoma

Importance of the field: Neuroblastomas arise from precursor cells of the sympathetic nervous system and are noted for highly heterogeneous clinical behavior. These tumors currently account for ～ 15% of all childhood cancer related deaths in spite of intensive multimodal chemotherapy and are a major problem in pediatric oncology. The identification of novel therapeutic targets is urgently required to reduce patient morbidity.

Areas covered in this review: The purpose of this article is to review and synthesize all of the rapidly expanding evidence for the contribution of microRNAs (miRNAs) in neuroblastoma aggressive disease pathogenesis, along with the prospect of using small RNAs as therapeutics.

What the reader will gain: The reader will obtain insight on the miRNAs that are dysregulated in neuroblastoma along with potential therapeutic strategies and the most promising targets.

Take home message: A number of miRNAs which are associated with aggressive disease pathogenesis in neuroblastoma patients have been demonstrated to contribute in major ways to cell proliferation rates, apoptosis, differentiation, invasiveness and tumor growth in vitro and in vivo. Directly or indirectly interfering with the function of these miRNAs may prove to be an important and novel form of therapy.     

MicroRNA expression in BRAF-mutated and wild-type metastatic melanoma and its correlation with response duration to BRAF inhibitors

Objective: Currently, the treatment of BRAF V600-mutated metastatic melanoma with BRAF inhibitors gives a response rate of ～ 50% with a progression-free survival of ～ 6 – 7 months. In order to identify predictive biomarkers capable of stratifying BRAF-mutated patients at high risk of shorter response duration to anti-BRAF therapy, the authors analyzed the expression of 15 microRNAs (miRNAs) targeting crucial genes involved in melanoma biology and drug response.

Research design and methods: A total of 15 miRNAs and target gene expression were investigated in 43 patients (30 BRAF-mutated, and 13 BRAF wild-type). Moreover, 20 BRAF-mutated patients treated with vemurafenib were analyzed for miRNA expression in respect to time-to-progression.

Results: All miRNAs except miR-192 showed low expression in BRAF-mutated as compared with BRAF wild-type patients. In particular, miR-101, miR-221, miR-21, miR-338-3p and miR-191 resulted in significant downregulation in BRAF-mutated patients. Moreover, high expression of miR-192 and miR-193b* and low expression of miR-132 resulted in significant association with shorter progression.

Conclusion: Three miRNAs were significantly associated with clinical outcome in metastatic melanoma patients. An increased understanding of the molecular assessment of BRAF-mutated melanomas could allow development of specific molecular tests able to predict response duration.     

Nanoparticle-mediated delivery of therapeutic genes: focus on miRNA therapeutics

Introduction: Micro RNAs (miRNA) are 21 – 23 nucleotides long and regulate the expression of coding genes by binding imperfectly with their 3′ UTR region. The miRNA profile is altered in pathological processes, making miRNAs good targets for drug therapy. Restoration of down-regulated miRNA or inhibition of overexpressed miRNA to return miRNA to its normal state is the basis of miRNA-based therapy. This review focuses on nanocarriers used for the delivery of miRNA that confer physical stability to the unstable RNA structure, protect the RNA from nuclease degradation and aid in effective silencing of target genes.

Areas covered: The necessity of the nanocarrier for the delivery of the miRNA is emphasized and the recent research on liposome-, metal- and polymer-mediated miRNA delivery for the inhibition or replacement of the disease-related miRNA is summarized.

Expert opinion: The size, charge and surface properties of nanocarriers have to be tuned to ensure effective and safe delivery of the miRNA in clinical practice. The immune responses related to the nanocarriers and the double-stranded nucleotide delivery remain to be addressed. Also, the binding of miRNAs to non-specific targets has to be studied in more detail because miRNAs have multiple targets due to partial binding unlike siRNA.     

MicroRNAs: small but potent oncogenes or tumor suppressors

MicroRNAs (miRNAs) are small, non-coding RNAs that modulate the expression of target mRNA. Many miRNAs are known to be up- or downregulated in a variety of cancers, suggesting a role for miRNAs in tumorigenesis. The correlation between the expression of miRNAs and their effects on target oncogenes, on tumorigenesis and on the proliferation of cancer cells is beginning to gain experimental evidence. For example, the miRNA (miR)-17-92 cluster has been characterized as an oncogene, while let-7 represses Ras and miR-15a/-16-1 represses Bcl-2, thereby acting as tumor suppressors. Thus, an oncogenic or tumor suppressive miRNA may have potential as a therapeutic target to control cancers. This review will discuss the relationship between miRNAs and tumorigenesis, and the potential for modulating miRNAs for the treatment of cancer.     

miR-27a在妇科肿瘤中的研究进展 #br#

微小 RNA（miRNA）是一类内源性的非编码小 RNA,通常可通过特异性降解 mRNA或抑制蛋白质的翻译, 在转录后水平调控靶基因的表达,参与机体的多个生理或病理过程。miRNA可通过调节癌基因和抑癌基因的表达 来参与肿瘤的发生发展,在不同类型的肿瘤中及肿瘤的不同发展阶段,miRNA分子的表达谱呈现不同的特征。其 中,miR-27a定位于人类 19号染色体,在子宫内膜癌、宫颈癌、卵巢癌等多种妇科肿瘤中异常表达。本文对 miR-27a 在子宫内膜癌、宫颈癌和卵巢癌中的作用及其临床应用进展进行综述,为开发新型的肿瘤分子标志物或靶向药物提 供理论依据。     

Evaluation of microRNA responses in ARPE-19 cells against the oxidative stress

Purpose: This study aimed to determine microRNA (miRNA) expression profile of human retinal pigment epithelium cell (ARPE-19) against the oxidative stress induced by hydrogen peroxide (H₂O₂).

Methods: ARPE-19 cells were incubated with different concentrations of H₂O₂ (200, 600 and 800?μM) for 18?h, and then cell viability, vascular endothelial growth factor levels and total oxidant status were evaluated. Expressions of 1152 miRNA were determined by quantitative real-time PCR in each group.

Results: Expressions of 90 miRNA were significantly changed in the ARPE-19 cells incubated with H₂O₂ compared to control group. However, miR-143-3p was only found to be expressed in groups incubated with H₂O₂. While 24 miRNA (hsa-miR-200c-3p, miR-192-5p, miR-194-5p, miR-141-3p, miR-658, miR-18?b-5p, miR-486-5p, miR-525-3p, miR-493-3p, miR-518d-3p, miR-29?b-1-5p, miR-675-3p, miR-1238-3p, miR-195-3p, miR-1539, miR-490-5p, miR-3200-5p, miR-1273d, miR-130a-5p, miR-30?b-5p, miR-1247-5p, miR-1910-5p, miR27a-5p and miR-200?b-3p) upregulated due to the increased dose of H₂O₂, nine miRNA (hsa-miR-96-5p, miR-33a-5p, miR-345-5p, miR-106?b-3p, miR-1285-3p, miR-23?b-5p, miR-27?b-5p, miR-103a-3p and miR-4289) were also found to be downregulated.

Conclusion: This study suggests that oxidative stress may be an important factor on expression of miRNAs in ARPE-19 cells. These miRNAs may have a role in the pathogenesis of age-related macular degeneration related to oxidative stress. However, this relationship needs to be examined in new studies by evaluation of pathways and target genes.