肿瘤干细胞中异常miRNA的研究进展

微核糖核酸( microRNA,miRNA)是一类内源性非编码单链小RNA,可在转录后调节靶标mRNA的剪切或抑制mRNA翻译.研究发现,miRNA在多种病理生理过程中发挥重要作用,如细胞增殖、干细胞分化、肿瘤形成等.肿瘤干细胞常含有异常的miRNA,其中某些miRNA的异常结构或表达可影响肿瘤发展.根据miRNA表达异常对肿瘤发生、发展的不同影响,可把miRNA分为癌基因性miRNA与抑癌基因miRNA两类.随着对miRNA了解的深入,发现部分miRNA的表达还具有促进和抑制肿瘤的双向性作用.因此,通过区别miRNA对肿瘤干细胞的不同作用,可利用miRNA靶点治疗肿瘤,即利用抗miRNA疗法阻滞癌基因性miRNA;利用miRNA mimics或慢病毒恢复抑癌基因性miRNA的功能,从而抑制肿瘤发展.相信随着miRNA与肿瘤干细胞的特异性及其作用机制等方面研究的深入,miRNA将会作为一种新的肿瘤调控因子,加快肿瘤治疗的研究进展.     

肝癌相关微小RNA的研究进展

微小RNA(miRNA)是一类具有转录后调节功能的非编码单链的小分子RNA,其在肿瘤形成过程中的作用已成为目前研究的热点.大量研究提示多种miRNA的异常表达参与了肝癌的发生发展,并可用于肝癌的诊断、治疗和预后评估.深入探讨miRNA与肝癌的关系及其分子机制将为肝癌的防治提供新的思路和方法.     

MicroRNA与DNA甲基化相互调节机制在肝细胞癌中的研究进展

肝细胞癌是原发性肝癌的主要类型,也是人类恶性程度较高的肿瘤之一,其发病机制至今尚未完全阐明.表观遗传学机制在肿瘤的发生、发展中起重要作用,DNA甲基化和微小RNA (microRNA,miRNA)的调控机制属于表观遗传学的研究范畴.研究表明,DNA甲基化及miRNA在肝细胞癌的形成中分别或协同发挥着重要作用,miRNA是一类在转录后水平调节基因表达的非编码短链RNA.研究表明,DNA甲基化和组蛋白修饰不仅可以调节蛋白编码基因的表达,而且可以调节miRNA的表达.在肝细胞癌中,一些异常表达的miRNAs(如miR-125b、miR-1-1、miR-124、miR-203和miR-191)是通过表观遗传学机制调控的.另外,在肝细胞癌中还发现了一类miRNAs通过调控表观遗传学通路中关键分子来改变整个基因组的表观遗传学状态.本文就DNA甲基化和miRNA之间复杂的相互调节机制在肝细胞癌发生和发展中的研究进展进行综述.     

受DNA甲基化调控的microRNA在妇科肿瘤中的研究进展

microRNA(miRNA)是一类长约22个核苷酸的非编码小RNA,转录后水平调节基因的表达,在个体发育,细胞的增殖、凋亡、分化中发挥重要的作用.近年来研究发现,DNA甲基化可能是妇科肿瘤中miRNA表达异常的调控机制,包括癌基因miRNA低甲基化活化和抑癌基因miRNA高甲基化失活,从而导致下游靶向基因表达异常,参与妇科肿瘤的发生发展.文章主要就miRNA的DNA甲基化在妇科肿瘤中的研究进展作一综述.     

miRNA-31生物学功能及其与肿瘤关系的研究进展

微小RNA(miRNA)是一类长20～25个核苷酸的单链RNA分子,能调节靶基因的表达及相关信号通路,发挥抑癌基因或原癌基因的功能,从而影响肿瘤的发生发展.miRNA-31在多种肿瘤中异常表达,在不同类型的肿瘤中发挥不同甚至完全相反的作用,其异常表达与肿瘤的发生发展密切相关.此外,miRNA可能成为肿瘤早期诊断的标志物,对肿瘤的诊断和预后具有潜在的应用价值.目前一些研究提供了与miRNA-31失调相关的上游和下游事件的信息,有助于揭示恶性肿瘤发生的分子机制.本文对miRNA-31在恶性肿瘤发生发展、转移及治疗等方面的研究进展进行综述.     

乳腺癌相关microRNA的研究进展

微小核糖核酸(microRNA,miRNA)是近年来发现的长度约为22个核苷酸(nucleotide,nt)的内源性短链RNA,不编码蛋白质,可通过与编码蛋白质的mRNA互补结合,参与细胞增殖、分化、凋亡等多种重要细胞活动的调控.近年来发现miRNA与肿瘤的发生密切相关,研究表明miRNA可以同时调节多种癌基因或抑癌基因的表达,参与多种恶性肿瘤的演进,是肿瘤发生、发展过程中重要分子.miRNA的发现及其和肿瘤关系的揭示为寻找肿瘤新的生物治疗靶点提供了一个极有希望的研究方向.本文就miRNA在乳腺癌中的相关作用及研究进展作一综述.     

肿瘤与microRNA的DNA甲基化相关性研究进展

目的:总结国内外关于microRNA (miRNA)的DNA甲基化在各肿瘤中的研究进展.方法:应用PubMed及CNKI全文数据库检索系统,以“miRNA、DNA甲基化和肿瘤”为检索词,检索2004-04-2012-05的相关文献,共检索到英文文献401篇,中文文献40篇.文献纳入标准:1)miRNA的生物学特性;2)DNA甲基化的作用机制及与肿瘤的关系;3)miRNA的DNA甲基化与肿瘤发生发展的关系.根据纳入标准符合分析的文献27篇.结果:miRNA在肿瘤发生发展中可发挥癌基因和抑癌基因的作用,DNA甲基化是肿瘤发生的一个重要因素.20％受甲基化调控的miRNA在上游5 kb范围内有CpG岛,miRNA的DNA甲基化与CpG岛有密切关系.miR-34、miR-124、miR-9和miR-127的DNA甲基化在各种肿瘤中频繁发生,多数通过靶向调节癌基因或抑癌基因而在肿瘤发生发展中发挥作用.结论:miRNA的DNA甲基化在人类肿瘤中广泛存在,甲基化miRNA可能作为肿瘤早期诊断、治疗、转移和预后的分子标志.     

微小RNA与肿瘤浸润转移

微小RNA(miRNA)在多数肿瘤中存在异常表达,能在转录后水平调控靶基因的表达,发挥促进或抑制肿瘤浸润转移的作用,其自身的表达也受表观遗传学静息等多种机制的调节.miRNA作为一种理想的标记物,有望成为临床肿瘤治疗的新靶点.     

MicroRNA与膀胱癌的研究进展

微小RNA(MicroRNA,miRNA)是一类小分子RNA,在转录后水平对基因的表达进行调控.目前研究证明,miRNA可通过不同信号通路直接参与人类多种肿瘤的形成与发展.本文就miRNA的形成、作用机制及其与肿瘤的关系等方面予以综述,并着重介绍了miRNA在膀胱癌中的研究进展.     

miRNA调节免疫检查点在肿瘤治疗中的研究进展

肿瘤发生和发展的主要机制之一是免疫反应对癌症特异性抗原的沉默,癌症免疫监视的缺陷可能发生在肿瘤进展的任何阶段。肿瘤微环境中,对T淋巴细胞有活化或抑制作用的免疫检查点分子的异常表达可引起肿瘤细胞的免疫耐受或逃逸。靶向免疫检查点分子(如PD-1及其配体PD-L1等)已被证实是治疗多种类型癌症的新方向。微小RNA(miRNAs)在肿瘤微环境中有重要作用,研究表明一些肿瘤中miRNA的表达特异性高,其对免疫应答特别是早期调节有非常重要的作用。因此,miRNA可能成为癌症治疗中调节免疫检查点的理想分子。多种miRNA在癌细胞中异常表达,为癌症治疗提供了新的机遇,但这些miRNA的确切功能及其与免疫检查点分子间的相互作用还在探索阶段。本综述总结了近来关于miRNA作为免疫检查点分子调节剂的研究结果及其在临床实践中治疗癌症的潜在应用。     

巨噬细胞游走抑制因子在肿瘤中的作用

巨噬细胞游走抑制因子(MIF)是一种独特的促进肿瘤发生的细胞因子,可直接参与癌基因诱导的恶性转化并调节细胞的分裂,也可间接通过抑制肿瘤细胞凋亡、促进肿瘤侵袭及血管生成等多方面作用影响肿瘤的发生发展.针对MIF的肿瘤生物靶向治疗可能成为肿瘤治疗的新途径.     

Fascin:恶性肿瘤及不良预后标志

Fascin蛋白是一种F-actin的结合蛋白,能将细胞中弥散状态的actin骨架捆绑成束,这一特性使得fascin可以帮助肿瘤细胞形成侵袭伪足进而获得转移和侵袭的能力。在大部分类型的癌症患者中fascin1均存在高表达,且其高表达与患者的不良预后和生存状况存在明显相关性。近年来,越来越多的研究人员倾向于将其作为肿瘤临床预后的生物标志以及肿瘤治疗的潜在靶点。本文将对fascin1在肿瘤发生和转移中的作用及机理进行综述,探讨将其作为在肿瘤的临床治疗中的关键靶点的重要性。     

Benzophenone-3 promotion of mammary tumorigenesis is diet-dependent

Benzophenone-3 is a putative endocrine disrupting chemical and common ingredient in sunscreens. The potential of endocrine disrupting chemicals to act as agonists or antagonists in critical hormonally regulated processes, such as mammary gland development and mammary tumorigenesis, demands evaluation of its potential in promoting breast cancer. This study identifies the effects of BP-3 on mammary tumorigenesis with high-fat diet during puberty versus adulthood in Trp53-null transplant BALB/c mice. Benzophenone-3 exposure yielded levels in urine similar to humans subjected to heavy topical sunscreen exposure. Benzophenone-3 was protective for epithelial tumorigenesis in mice fed lifelong low-fat diet, while promotional for epithelial tumorigenesis in mice fed adult high-fat diet. Benzophenone-3 increased tumor cell proliferation, decreased tumor cell apoptosis, and increased tumor vascularity dependent on specific dietary regimen and tumor histopathology. Even in instances of an ostensibly protective effect, other parameters suggest greater risk. Although benzophenone-3 seemed protective on low-fat diet, spindle cell tumors arising in these mice showed increased proliferation and decreased apoptosis. This points to a need for further studies of benzophenone-3 in both animal models and humans as a potential breast cancer risk factor, as well as a more general need to evaluate endocrine disrupting chemicals in varying dietary contexts.     

细菌致癌促癌机制的研究进展

通常认为肿瘤发生来源于癌基因与抑癌基因的突变,肿瘤的发展与机体炎症反应、免疫状态、肿瘤微环境等密不可分。然而近年来,随着宏基因组学和生物信息学的不断发展进步,越来越多研究证实,细菌对肿瘤的发生发展具有重要作用。细菌可以通过自身及其产物直接作用促进肿瘤发生,也可通过影响宿主代谢、诱发炎症反应、抑制肿瘤免疫等间接方式参与肿瘤发展。本文将对细菌致癌促癌机制做简要综述。     

An imprinted locus epistatically influences Nstr1 and Nstr2 to control resistance to nerve sheath tumors in a neurofibromatosis type 1 mouse model

Cancer is a complex disease in which cells acquire many genetic and epigenetic alterations. We have examined how three types of alterations, mutations in tumor suppressor genes, changes in an imprinted locus, and polymorphic loci, interact to affect tumor susceptibility in a mouse model of neurofibromatosis type 1 (NF1). Mutations in tumor suppressor genes such as TP53 and in oncogenes such as KRAS have major effects on tumorigenesis due to the central roles of these genes in cell proliferation and cell survival. Imprinted genes expressed from only one parental chromosome affect tumorigenesis if their monoallelic expression is lost or duplicated. Because imprinted loci are within regions deleted or amplified in cancer, the parental origin of genomic rearrangements could affect tumorigenesis. Gene polymorphisms can vary tumor incidence by affecting rate-limiting steps in tumorigenesis within tumor cells or surrounding stroma. In our mouse model of NF1, the incidence of tumors mutant for the tumor suppressor genes Nf1 and Trp53 is strongly modified by a linked imprinted locus acting epistatically on two unlinked polymorphic loci, Nstr1 and Nstr2. This interaction of an imprinted locus and polymorphic susceptibility loci has profound implications for human mapping studies where the parental contribution of alleles is often unknown.     

Dietary retinoids are essential for skin papilloma formation induced by either the two-stage or the complete tumorigenesis model in female SENCAR mice.

Our previous work has shown that dietary retinoic acid (RA) is necessary for skin tumor formation induced by the two-stage protocol with the initiator 7,12-dimethylbenz[a]anthracene (DMBA) and the promoter 12-O-tetradecanoyl phorbol-13-acetate (TPA) (De Luca et al., Cancer Res., 36 (1976) 2334-2339). Here we report that retinoids are required for tumorigenesis by the two-stage as well as by the complete tumorigenesis protocol. Mice were treated with a single dose of DMBA (20 micrograms), followed by 20 applications of TPA (2 micrograms), or by 20 applications of DMBA (25 micrograms for 2 weeks and 51 micrograms thereafter). Regardless of the tumor induction protocol, tumor formation was inhibited by vitamin A-deficiency, while RA (3 micrograms/g of diet) or retinyl palmitate (RP, 6 micrograms/g) supplementation permitted the appearance of tumors. In addition, in comparison to the purified diets and regardless of their RA levels, the non-purified Purina chow diet enhanced tumor yield especially in the two-stage tumorigenesis protocol. This effect was less striking in mice with tumors induced by the complete tumorigenesis protocol. In summary, dietary retinoids are essential for skin tumor formation induced either by the two-stage or the complete tumorigenesis protocol.     

Metastasis suppressor function of tumor necrosis factor-related apoptosis-inducing ligand-R in mice: implications for TRAIL-based therapy in humans?

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer therapy, as it can induce apoptosis specifically in tumor cells but not in normal cells. Although earlier mouse tumor studies revealed a strong tissue dependency of TRAIL and its death receptor in suppressing primary tumorigenesis or experimental metastases, we recently found that TRAIL-R inhibits lymph node metastases without affecting primary tumor formation in a mouse model of multistage skin tumorigenesis. This finding uncouples the role of TRAIL in primary tumorigenesis from metastasis formation, likely by sensitization of previously TRAIL-resistant tumor cells upon detachment, an early step required for metastasis formation. Therefore, TRAIL-R is a novel metastasis suppressor, suggesting that TRAIL-related tumor therapy might be most effective in primary tumors and early metastatic cancers, before selection for TRAIL resistance occurs.     

Effects of the prostaglandin synthetase inhibitor indomethacin on tumorigenesis, tumor proliferation, cell kinetics, and receptor contents of 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in Sprague-Dawley rats fed a high- or low-fat diet

The effects of indomethacin on tumorigenesis, tumor proliferation, cell kinetics, and receptor content of 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma have been examined in female Sprague-Dawley rats. The rats were fed either a high-fat (20% corn oil) or low-fat (0.5% corn oil) diet with or without 0.005% indomethacin starting 7 days after intragastric administration of a single dose of 5 mg 7,12-dimethylbenz(a)anthracene. The results demonstrated that indomethacin completely blocked the stimulatory effect of fat on tumorigenesis, as demonstrated by a decreased tumor incidence, a decreased number of tumors per group, and an increased latency. Contrary to what had been expected, however, indomethacin promoted tumor proliferation in both the high- and low-fat diet groups, as evidenced by an increased tumor size, an increased bromodeoxyuridine-labeling index, and a decreased potential tumor-doubling time. No significant difference in either the estrogen receptor or progesterone receptor content of the tumor was noted. It can be concluded, therefore, that indomethacin significantly reduced tumorigenesis in the high-fat diet group but significantly promoted tumor proliferation in both the high- and low-fat diet groups.     

Mice deficient for the gap junction protein Connexin32 exhibit increased radiation-induced tumorigenesis associated with elevated mitogen-activated protein kinase (p44/Erk1, p42/Erk2) activation

Loss of connexin expression/gap junction intercellular communication (GJIC) has been correlated with decreased growth control and increased tumorigenesis. Studies utilizing Connexin32 (Cx32)-deficient knockout mice have demonstrated that loss of Cx32 increases susceptibility to chemically induced liver tumorigenesis. Here, in addition to dramatically increased liver tumorigenesis, we show that tumor induction utilizing X-ray radiation resulted in a statistically significant increase in overall tumor burden in Cx32-deficient mice compared with wild-type mice due to tumorigenesis in several other tissues (lung, adrenal, lymph and small intestine) even when excluding prevalent liver tumors. Irradiated Cx32-deficient mice were particularly sensitive to liver tumorigenesis (46% incidence compared with 18% in wild-type mice, P = 0.007) demonstrating that Cx32 functions as a hepatic tumor suppressor in response to radiation-associated mutation events. Cx32-deficient mice also exhibited increased lung tumorigenesis (bronchioloalveolar) with an increased progression to carcinoma when compared with wild-type mice. Two Cx32-deficient mice developed an uncommon, invasive medullary adrenal tumor type (pheochromocytoma) not observed in irradiated wild-type mice. Immunohistochemical analysis revealed increased levels of activated mitogen-activated protein kinase (MAPK) (p44/Erk1, p42/Erk2) in Cx32-deficient mouse liver tumors (P = 0.006), lung tumors (P = 0.056) and adrenal tumors (primary and metastases) compared with wild-type counterparts implicating elevated activation of MAPK-interacting pathways in Cx32-deficient tumorigenesis. Interestingly, lung tumors from Cx32-deficient mice also demonstrated decreased p27Kip1 levels compared with wild-type lung tumors (P = 0.05). This study demonstrates that loss of Cx32/GJIC plays a significant role in radiation-induced tumorigenesis of the liver and importantly that Cx32 may also play a role in tumor suppression and/or tumor progression in other tissue types such as lung and adrenal gland. Additionally, this mouse model suggests that MAPK-related pathways may be preferentially activated or conversely that tumors harboring activated MAPK pathways may selectively progress towards more advanced tumor states in the absence of Cx32-mediated GJIC.     

Reduction in the requirement of oncogenic Ras signaling to activation of PI3K/AKT pathway during tumor maintenance

While tumors become addicted to oncogenes like Ras, the microenvironment in which tumor cells reside changes during tumorigenesis; the cells are surrounded initially by normal tissue and later by tumor tissue. Hence, we asked if Ras exerts its oncogenic effects through the same set of effectors during different stages of tumorigenesis. We now show in human cells that the Ras effector pathways MAPK, RalGEF, and PI3K are required to initiate tumor growth. Conversely, activation of the PI3K/AKT pathway replaced Ras once tumors formed, although other effectors were still activated independently of Ras, presumably by factors provided upon the establishment of a tumor microenvironment. Thus, as tumorigenesis progresses the addiction of cancers to their initiating oncogene is reduced to, at least in the case of Ras, the PI3K/AKT pathway.