MicroRNA在肿瘤干细胞中的调控作用研究进展

肿瘤干细胞（CSCs）是导致肿瘤复发、转移和耐药的根源之一。microRNA（miRNAs）是一类小分子非编码RNA,可与靶mRNA的3＇UTR区域结合而导致该mRNA分子的翻译受到抑制,参与多种生物功能的调节。最近的研究发现,miRNAs参与CSCs的分化、自我更新等生物学特性的调控。miRNAs可以作为CSCs研究的一个新的切入点。本文就近年来该方面的研究进展做简要综述。     

靶向miRNA的肿瘤干细胞治疗策略

肿瘤干细胞学说认为,肿瘤组织中存在一小部分具有无限增殖、自我更新、放化疗耐受以及高致瘤能力等干细胞特性的肿瘤干细胞(cancer stem cells,CSCs),它们是肿瘤无法治愈并不断进展的重要原因。微小RNA(microRNAs,miRNAs)是一类短链非编码RNA,通过降解mRNA或抑制mRNA翻译的方式调控着众多基因的表达。研究显示,miRNA在多种肿瘤的CSCs中异常表达,CSCs的恶性表型维持需要众多miRNA的参与。近年来,靶向miRNA的CSCs治疗实验研究已经初步展现出良好的安全性和疗效。针对miRNA的治疗策略将成为CSCs治疗的一个新的研究方向,最大限度地清除CSCs将使治愈肿瘤逐渐成为可能。     

MicroRNA与乳腺癌干细胞

乳腺癌干细胞是导致乳腺癌复发、转移和耐药的根源之一。microRNA(miRNAs)是一类小分子非编码RNA,可与靶mRNA的3’UTR区域结合而导致该mRNA分子的翻译受到抑制,参与多种生物功能的调节。最近研究发现,miRNAs参与乳腺癌干细胞的分化、自我更新等生物学特性的调控。MiRNAs可以作为乳腺癌干细胞研究的一个新的切入点。本文就近年来该方面的研究进展做简要综述。     

肿瘤侵袭转移相关microRNAs的研究进展

近年来大量研究表明microRNAs(miRNAs)与人类多种肿瘤的发生发展及侵袭转移存在着密切关系,miRNAs可能成为一类新的致癌基因或抑癌基因,它们通过抑制靶mRNA翻译或诱导靶mRNA降解在转录后水平调控基因表达,具有癌基因或抑癌基因的功能,参与肿瘤的发生、发展及侵袭转移。     

微小RNAs在良恶性胸腔积液中的研究进展

microRNAs(miRNAs）是长度为19~24 nt的非编码小RNA,可通过与其靶mRNA特异性结合导致mRNA降解或翻译抑制,从而负向调控基因表达。miRNAs参与包括细胞分化、增殖、凋亡等一系列重要细胞活动的调控。miRNAs的异常表达与人类肿瘤密切相关。miRNAs具有较强的稳定性,广泛存在人体组织、体液中。本文就miRNAs在胸腔积液中的研究进展作一综述,以期为良恶性胸腔积液的鉴别等提供新的概念及思路。     

长链非编码RNA在肿瘤干细胞放射耐受性中的作用

肿瘤干细胞(CSCs)指肿瘤内部一类具有自我更新能力和多向分化潜能的细胞,虽然仅占整个肿瘤细胞的小部分,却是导致肿瘤发生、扩散和复发的“起源细胞”,这也正是肿瘤放疗失败的根源所在。CSCs对放疗具有耐受性,并以直接或间接方式促进肿瘤转移,因而被认为是肿瘤转移的基础。此外,CSCs的异质性可能是造成器官特异性转移的原因之一。长链非编码RNA (lncRNA)是一类长度>200个核苷酸,且无蛋白质编码能力的RNA分子,参与肿瘤发生和发展,并与肿瘤放射耐受性的形成密切相关。近年来肿瘤放射耐受性相关的lncRNA及其与CSCs关系的研究日益成为热点。本文就放疗后lncRNA介导的CSCs的调节以及lncRNA在肿瘤放射耐受中的作用进行综述。     

肿瘤干细胞与肿瘤转移的分子影像学检测及研究进展北大核心CSCD

肿瘤干细胞(cancer stem cells,CSCs)是一类具有自我更新及多向分化潜能的癌细胞亚群。一些研究表明,CSCs参与并调节了肿瘤的转移过程,为转移发生的微环境建立提供了条件。因此,对CSCs的识别和示踪在研究肿瘤转移的分子机制方面显得尤为重要。近年来发展起来的分子影像技术,以CSCs表面特有的生物标志物为靶点,应用不同的显像手段,为揭示CSCs在肿瘤进展中的生物学行为和潜在分子机制提供了可视化依据。因此,本文就转移干细胞的定义、转移相关的CSCs表面标志物、分子影像技术在CSCs检测中的应用、CSCs相关的转移微环境以及干细胞导向的肿瘤治疗等方面作一综述。     

MircoRNA-26a与肿瘤

微小RNA(microRNAs,miRNAs)是一类由20个-22个核苷酸组成的小片段非编码RNA,通过靶向结合基因mRNA的3'非翻译区(3'-UTR)调控其表达.许多研究报道miRNAs参与肿瘤的发生发展.MiR-26a在不同的肿瘤中发挥不同的作用,在肿瘤增殖、转移侵袭、血管形成、生物代谢及诊断预后中都有作用.本文就miR-26a与肿瘤关系的研究进展进行综述.     

microRNAs在胃癌发生发展中的研究进展

微小RNAs（miRNAs）是一组小的非编码RNA,在胃癌中起着至关重要的作用。miRNAs通过靶基因mRNA产生双重的、相反的作用,即致癌或抑癌作用。致癌miRNAs在胃癌中过表达,并能抑制肿瘤抑制基因。相反,肿瘤抑制miRNAs在胃癌中表达通常下调,从而导致癌症的发展。异常表达的miRNAs参与胃癌的发生发展并调控不同的表型,如增殖、凋亡、转移及耐药性等。此外,miRNAs还可用于胃癌的诊断和预后预测等。本文综述了miRNAs在胃癌发展中的作用,以及miRNAs在诊断和预后中的潜在应用价值。     

非黏附性球培养在肿瘤干细胞研究中的应用现状

肿瘤干细胞(cancer stem cells,CSCs)理论的提出为肿瘤靶向治疗研究提供了新的思路,靶向杀灭CSCs将可能有效消除肿瘤。有效、特异地分离和培养CSCs是开展CSCs研究的前提。非黏附性球培养最初应用于成体干细胞的研究,后来应用于CSCs自我更新能力的研究,近来已成为富集肿瘤干细胞的常用方法之一。本文综述非黏附性球培养CSCs的应用原理、关键问题以及相关研究进展。     

肿瘤干细胞与microRNA的研究进展

肿瘤干细胞是肿瘤的起源性细胞, 具有高度的致瘤性和耐药性。微小RNA(microRNA或miRNA)是由21~25个核苷酸组成的内源性非编码单链RNA, 是基因表达调控因子, 参与许多生物功能的调节。最近的研究发现, microRNA参与肿瘤干细胞的分化、自我更新等生物学特性的调控。肿瘤干细胞和microRNAs可以作为肿瘤研究的一个新的切入点。本文就近年来的研究进展做简要综述。      

Clinical implications of microRNAs in liver cancer stem cells

The prognosis of patients diagnosed with hepatocellular carcinoma (HCC) is often dismal, mainly due to late presentation, high recurrence rate, and frequent resistance to chemotherapy and radiotherapy. Accumulating evidence on the differential microRNA (miRNA) expression patterns between non-tumor and HCC tissues or between liver cancer stem cells (CSCs) and non-CSC subsets and the significant clinical implications of these differences suggest that miRNAs are a promising, non-invasive marker for the prognosis and diagnosis of the disease. This perspective article summarizes the current knowledge of miRNAs in liver CSCs and highlights the need for further investigations of the role of miRNAs in regulating liver CSC subsets for possible future clinical applications.     

A TARBP2-dependent miRNA expression profile underlies cancer stem cell properties and provides candidate therapeutic reagents in Ewing sarcoma

We have recently demonstrated that human pediatric mesenchymal stem cells can be reprogrammed toward a Ewing sarcoma family tumor (ESFT) cancer stem cell (CSC) phenotype by mechanisms that implicate microRNAs (miRNAs). Here, we show that the miRNA profile of ESFT CSCs is shared by embryonic stem cells and CSCs from divergent tumor types. We also provide evidence that the miRNA profile of ESFT CSCs is the result of reversible disruption of TARBP2-dependent miRNA maturation. Restoration of TARBP2 activity and systemic delivery of synthetic forms of either of two of its targets, miRNA-143 or miRNA-145, inhibited ESFT CSC clonogenicity and tumor growth in vivo. Our observations suggest that CSC self-renewal and tumor maintenance may depend on deregulation of TARBP2-dependent miRNA expression.     

MicroRNA regulation of cancer stem cells

Cancer stem cells (CSC), or cancer cells with stem cell properties, have been reported in many human tumors and are thought to be responsible for tumor initiation, therapy resistance, progression, relapse, and metastasis. Despite their potential clinical importance, how CSCs are regulated at the molecular level is not well understood. MicroRNAs (miRNA), small noncoding RNAs that play critical roles in normal stem cell functions during development, have emerged as important regulators of CSCs as well. In this review, we summarize the current major findings of miRNA regulation of various CSCs and discuss our recent findings that miR-34a suppresses prostate CSCs and metastasis by directly repressing CD44. This recent progress has important implications for understanding how CSCs are intricately regulated by networks of miRNAs and for developing novel mechanism-based miRNA therapeutics that specifically target CSCs.     

Extracellular vesicles from human liver stem cells inhibit renal cancer stem cell-derived tumor growth in vitro and in vivo

Cancer stem cells (CSCs) are considered as responsible for initiation, maintenance and recurrence of solid tumors, thus representing the key for tumor eradication. The antitumor activity of extracellular vesicles (EVs) derived from different stem cell sources has been investigated with conflicting results. In our study, we evaluated, both in vitro and in vivo, the effect of EVs derived from human bone marrow mesenchymal stromal cells (MSCs) and from a population of human liver stem cells (HLSCs) of mesenchymal origin on renal CSCs. In vitro, both EV sources displayed pro-apoptotic, anti-proliferative and anti-invasive effects on renal CSCs, but not on differentiated tumor cells. Pre-treatment of renal CSCs with EVs, before subcutaneous injection in SCID mice, delayed tumor onset. We subsequently investigated the in vivo effect of MSC- and HLSC-EVs systemic administration on progression of CSC-generated renal tumors. Tumor bio-distribution analysis identified intravenous treatment as best route of administration. HLSC-EVs, but not MSC-EVs, significantly impaired subcutaneous tumor growth by reducing tumor vascularization and inducing tumor cell apoptosis. Moreover, intravenous treatment with HLSC-EVs improved metastasis-free survival. In EV treated tumor explants, we observed both the transfer and the induction of miR-145 and of miR-200 family members. In transfected CSCs, the same miRNAs affected cell growth, invasion and survival. In conclusion, our results showed a specific antitumor effect of HLSC-EVs on CSC-derived renal tumors in vivo, possibly ascribed to the transfer and induction of specific antitumor miRNAs. Our study provides further evidence for a possible clinical application of stem cell-EVs in tumor treatment.     

miRNA profiling in pancreatic cancer and restoration of chemosensitivity

Pancreatic cancers relapse due to small but distinct population of cancer stem cells (CSCs) which are in turn regulated by miRNAs. The present study identifies a series of miRNAs which were either upregulated (e.g. miR-146) or downregulated (e.g. miRNA-205, miRNA-7) in gemcitabine resistant MIA PaCa-2 cancer cells and clinical metastatic pancreatic cancer tissues. Gemcitabine resistant MIA PaCa-2 cells possessed distinct ALDH-positive CSC fraction expressing stem cell markers OCT3/4 and CD44 and chemoresistance marker class III β-tubulin (TUBB3) which decreases on transfection with miR-205 resulting in the restoration of chemosensitivity to gemcitabine.     

MicroRNA signature in the chemoprevention of functionally-enriched stem and progenitor pools (FESPP) by Active Hexose Correlated Compound (AHCC)

Purpose: Many breast cancer patients use natural compounds in their battle against breast cancer. Active Hexose Correlated Compound (AHCC®) is a cultured mushroom mycelium extract shown to favorably modulate the immune system and alleviate cancer burden. Cancer Stem cells (CSCs) are a subset of highly tumorigenic cancer cells that are thought to be responsible for recurrence. CSCs can be epigenetically regulated by microRNAs (miRNAs). We hypothesized that AHCC may influence CSCs by modulating tumor-suppressor or oncogenic miRNAs. Methods: Functionally-enriched stem and progenitor pools (FESPP) were isolated in the form of mammospheres from MDA-MB-231, MCF-7, and 4T1 cells, exposed to AHCC in both regular and primary culture from Balb/c mice, and analyzed by visual counting and flow cytometry. Cell motility was also observed in MDA-MB-231 cells. Profiling and RT-qPCR were performed to determine AHCC influence on miRNAs in MDA-MB-231 mammospheres. Additionally, Balb/c mice were orally gavaged with AHCC, and tumor growth parameters and miR-335 expression were analyzed. MDA-MB-231 cells were transfected with miR-335 and analyzed by western blot. Results: We demonstrated that AHCC reduced mammosphere growth in three cell lines and in primary culture, prevented cell migration, and upregulated miR-335 expression in MDA-MB-231 cells and mouse tumor samples. Among the differentially regulated miRNAs in CSCs, we focused on tumor suppressor miR-335, known to target extracellular matrix protein Tenascin C (TNC). TNC is involved in CSC immune evasion pathways. In MDA-MB-231, inhibition of miR-335 increased TNC protein expression. Conclusions: These results support that AHCC limits FESPP growth, partly by targeting miRNA pathways.     

microRNAs in cancer stem cells: current status and future directions

The presence of stem-like cells in cancer, popularly known as cancer stem cells, have been known for a long time but it was the research of Bonnet and Dick in leukemia which got cancer researchers interested in them. Over the past few years, a lot of research has gone into the characterization of cancer stem cells (CSCs) from different tumors. CSCs have been elucidated in almost all solid tumors. The growth of this field has not been without controversies as many researchers considered CSCs to be a transient population of little consequence. The field has nevertheless progressed providing us not only a better understanding of cancer and its related facets like proliferation, EMT, and metastasis but also generating a hope for new generation therapeutics with CSCs as their targets. This search for drugs which target CSCs has also focused on miRNAs. miRNAs are small non-coding regulatory RNA molecules capable of fine-tuning the gene expression. The miRNA profile of CSCs is remarkably different from non-stem cancer cells and many miRNAs have also been shown to regulate self-renewal and differentiation properties of CSCs. The differential miRNA profile in CSCs make them probable biomarkers for the prognosis of cancer and their specificity in targeting the properties of CSCs make them potential targets for therapeutic intervention. This review critically analyzes the advancement of the miRNA research in CSC context and also explores the prospect of miRNA therapies against CSCs.