基于趋化因子受体5靶点的HIV-1治疗研究进展

随着人类免疫缺陷病毒(HIV-1)感染在全球的蔓延及耐药株的出现,寻求有效的治疗方法成为当务之急。趋化因子受体5(Chemokine receptor 5,CCR5)是HIV-1侵入靶细胞的主要辅助受体之一。目前已发现许多CCR5拮抗剂,其中一些化合物已进入临床试验或应用;以CCR5为靶点的基因治疗亦取得了一定的进展。本综述以CCR5为靶点的药物和基因治疗两方面的研究进展进行总结。     

DLX6-AS1通过竞争性结合miR-15上调Caspase-1诱导巨噬细胞焦亡

为探讨长链非编码RNA (long noncoding RNA, lncRNA) DLX6-AS1在巨噬细胞焦亡中的作用及相关机制,采用生物信息学分析、实时荧光定量PCR和双荧光素酶报告基因实验等,在THP-1巨噬细胞中分析并验证lncRNA DLX6-AS1下游微RNA (microRNA, mi RNA)及mi RNA的下游靶基因;通过免疫荧光染色等实验检测DLX6-AS1/miR-15/caspase-1轴对巨噬细胞焦亡的影响。结果显示, DLX6-AS1在焦亡巨噬细胞中表达上调,敲降DLX6-AS1可抑制巨噬细胞焦亡,但这种抑制作用被mi R-15抑制剂逆转; mi R-15通过调控其靶基因caspase-1表达,抑制巨噬细胞焦亡。本研究表明, DLX6-AS1通过竞争性结合mi R-15,解除mi R-15对其靶基因caspase-1的抑制作用,从而诱导巨噬细胞焦亡,这将丰富lncRNA调控巨噬细胞焦亡的理论基础。     

长链非编码RNA-重编码调控因子与肿瘤的研究进展

长链非编码RNA(LncRNA)是一类长度超过200核苷酸且不编码蛋白质的RNA分子。肿瘤基因组学的快速发展使LncRNA在人类肿瘤研究方面的功能更加显著。基因间LncRNA(LincRNA)-重编码调控因子(ROR)作为一种新型LncRNA,其作用机制在结直肠癌、胰腺癌、乳腺癌的发生发展过程中有报道。我们就LincRNA-ROR在肿瘤中的相关调控机制以及在不同肿瘤中的研究现状做简要综述,以便对其有进一步了解。     

lncRNA与miRNA相互调控作用及其与肿瘤的关系研究

长链非编码RNA (long non-coding RNA,lncRNA)是一类转录本长度大于200 bp的非编码RNA,可作为人类基因组中一类重要的调控分子通过多种方式发挥其生物学功能.近年来的研究表明,lncRNA也可以作为一种竞争性内源性RNA (competing endogenous RNA, ceRNA) 与miRNA相互作用,参与靶基因的表达调控,并在肿瘤的发生发展中发挥重要的作用.本综述在简要介绍lncRNA功能研究现状和主要研究方法的基础上,进一步分析了lncRNA与miRNA之间的互相调控关系及其在肿瘤发生发展中的作用,以便为后续的研究提供新的思路.     

长链非编码RNA在神经退行性疾病中作用机制的研究进展

长链非编码RNA (long non-coding RNA, lncRNA)是指一组在真核细胞中转录长度超过200个核苷酸的非编码RNA (non-coding RNA, ncRNA),是细胞基因调控网络的基本组成部分,具有组织特异性和条件表达特异性。以往研究证明, lncRNA在中枢神经系统(central nervous system, CNS)大量富集,显示出复杂的时空表达谱,并以多种方式参与大脑发育的调控。近年来,越来越多的研究提示, lncRNA基因位点的失调或突变与多种CNS相关的神经退行性疾病(neurodegenerative diseases, NDDs)密切相关,如阿尔茨海默病(Alzheimer’s disease, AD)、帕金森病(Parkinson’s disease, PD)、多发性硬化(multiple sclerosis, MS)、亨廷顿病(Huntington disease,HD)及肌萎缩侧索硬化(amyotrophic lateral sclerosis, ALS)等。本文将介绍lncRNA在NDDs中的研究进展,为理解这一类疾病的病因、病理机制...     

长链非编码RNA调节缺血性脑卒中损伤和修复的研究进展

长链非编码RNA(long noncoding RNA,lnc RNA)是一组在转录、转录后和表观遗传水平发挥作用的调控序列,其在中枢神经系统中特异性高表达,对中枢神经系统发育和疾病发展具有重要调控作用。缺血性脑卒中诱导脑内大量lnc RNA表达改变,提示lnc RNA与缺血性脑卒中复杂的病理过程有关,这将有利于全面认识缺血性脑卒中的病理机制及脑缺血损伤后的分子调控网络,并提供新的治疗方向。尽管有少数研究报道lnc RNA在缺血性心脏病中的作用,但目前对于其在缺血性脑卒中病理发展中的作用知之甚少。综述目前已知的lnc RNA在脑缺血再灌注损伤、细胞凋亡与抗凋亡及损伤后神经再生与修复中的作用,并提出了未来可能的lnc RNA在缺血性脑卒中损伤与修复中的研究方向。     

长链非编码RNA SNHG17通过抑制p57表达促进肺癌进展

目的:分析肺癌中长链非编码RNA(lncRNA)小核仁RNA宿主基因17(SNHG17)与p57的表达相关性及功能联系。方法:通过starBase数据库分析SNHG17和p57在肺癌组织和正常组织中的表达差异;采用人正常肺上皮细胞BEAS-2B和人肺癌细胞系A549、H1975进一步分析SNHG17和p57在肺癌细胞和正常肺细胞中的表达差异;采用qRT-PCR和Western印迹检测si-SNHG17在mRNA和蛋白表达方面对SNHG17和p57的影响;采用CCK-8法检测siSNHG17对A549细胞增殖的影响;采用Transwell法检测si-SNHG17对A549细胞迁移和侵袭能力的影响。结果:通过数据分析发现SNHG17在肺腺癌和肺鳞癌组织中显著高表达,而p57在肺腺癌和肺鳞癌组织中却显著低表达;与正常肺细胞相比,SNHG17和p57在肺癌细胞中的表达趋势与在肺癌组织中一致;SNHG17和p57的表达呈负相关;沉默SNHG17使p57的表达一定程度上调,A549细胞的增殖、迁移和侵袭能力受到抑制。结论:SNHG17在肺癌中高表达,促进肺癌细胞增殖,并通过调节p57的表达来抑制肺癌细胞的增殖和迁移。SNHG17和p57在肺癌中的具体作用机制仍有待进一步研究。     

竞争性内源RNA的研究进展及研究策略

竞争性内源RNA(competing endogenous RNA,ce RNA)通过结合同一种mi RNA参与其靶基因的表达调控。研究发现,假基因转录物、长链非编码RNA(long non-coding RNA,lnc RNA)、编码蛋白质的m RNA、环形RNA(circular RNA,circ RNA)等都可以作为ce RNA参与基因表达的调控,并与肿瘤的发生发展有着重要的联系。本文在近年来ce RNA研究进展的基础上,从ce RNA研究的常用技术、研究策略、生物信息学分析、ce RNA表达一致性等方面进行综述,开展ce RNA研究需要采取的研究策略。     

基于lncRNA测序探讨瑞舒伐他汀对糖尿病大鼠心肌损伤的治疗途径和潜在靶点

他汀类药物能为糖尿病心肌病(diabetic cardiomyopathy, DCM)的治疗带来一定的收益,但是其发挥作用的具体分子途径尚不明确。近期研究表明,长非编码lncRNA(long noncoding RNA, lncRNA)的异常表达与DCM的病理发展过程密切相关。为比较经瑞舒伐他汀(rosuvastatin)干预的糖尿病大鼠与常规治疗大鼠的心肌损伤程度差异,探讨瑞舒伐他汀对DCM的治疗途径和潜在靶点,本文提取DCM大鼠心肌组织总RNA,制备lncRNA芯片,筛选出差异表达的lncRNA并进行生物信息学分析。结果显示,与模型组相比,治疗组中表达呈显著差异的靶点基因有770个被上调,884个表达下调,主要与改善代谢紊乱、调节心肌细胞与胶原纤维的比例、减轻心肌损伤与运动负担、预防自主神经及微循环病变、改变生物进食习惯等功能相关;所参与的信号通路则主要富集在感官途径、信号传导、脂质代谢等方面。提示瑞舒伐他汀可通过调节这些lncRNA,参与糖脂能量代谢与离子平衡、抑制心肌纤维化进程、改善高糖毒性对自主神经功能的影响等治疗途径,发挥治疗DCM的作用。     

Long noncoding RNA growth arrest-specific 5 facilitates glioma cell sensitivity to cisplatin by suppressing excessive autophagy in an mTOR-dependent manner

Malignant glioma is a severe type of brain tumor with a grim prognosis. The occurrence of resistance compromises the efficacy of chemotherapy for glioma. Long noncoding RNA growth arrest-specific 5 (GAS5) has recently become an attractive target for cancer therapy by regulating cell growth, invasion, and migration. Nevertheless, its role in glioma chemoresistance remains elusive. In the current study, the expression of GAS5 was decreased in glioma cell lines, and lower levels of GAS5 were observed in U138 and LN18 glioma cells that had low sensitivity to cisplatin. Functional assay confirmed that knockdown of GAS5 enhanced cell resistance to cisplatin in U87 cells, which had a relatively high expression of GAS5. Conversely, elevation of GAS5 increased cell sensitivity to cisplatin in U138 cells that had a relatively low expression of GAS5. Mechanistically, cisplatin exposure evoked excessive autophagy concomitant with an increase in autophagy-related LC3II expression and a decrease in autophagy substrate p62 expression, which was reversely muted after GAS5 overexpression. In addition, GAS5 restored cisplatin-inhibited mammalian target of rapamycin (mTOR) activation. Preconditioning with mTOR antagonist rapamycin engendered not only mTOR inhibition but also abrogated GAS5-mediated depression in cisplatin-evoked autophagy. Notably, blocking the mTOR pathway also attenuated GAS5-increased sensitivity to cisplatin in U138 cells. Cumulatively, these findings indicate that GAS5 may blunt the resistance of glioma cells to cisplatin by suppressing excessive autophagy through the activation of mTOR signaling, implying a promising therapeutic strategy against chemoresistance in glioma.     

LncRNA-UCA1 modulates progression of colon cancer through regulating the miR-28-5p/HOXB3 axis

Emerging evidence has shown that the long noncoding RNA urothelial carcinoma–associated 1 (UCA1) plays a tumor-promoting role in colorectal cancer, while miR-28-5p shows tumor-inhibitory activity in several tumor types. However, the mechanisms both of these in colon cancer progression are still unknown. In this work, the detailed roles and mechanisms of UCA1 and its target genes in colon cancer were studied. The results showed that UCA1 was upregulated in colon cancer tissues when compared with the adjacent nonhumorous tissues, as well as in the various colon cancer cell lines, but the expression of miR-28-5p showed an opposite trend. Furthermore, a high UCA1 level in colon cancer tissues is positively associated with the tumor size and advanced tumor stages. Functional assays revealed that both UCA1 knockdown and miR-28-5p overexpression could inhibit colon cancer cell growth and migration. Further mechanistic studies indicated that UCA1 knockdown played tumor suppressive roles in SW480 and HT116 cells through binding with miR-28-5p. We also, for the first time, identified HOXB3 as the target gene of miR-28-5p and that HOXB3 overexpression could mediate the functions of UCA1 in cell proliferation and migration of colon cancer cells. In conclusion, our data provided evidence for the regulatory network of UCA1/miR-28-5p/HOXB3 in colon cancer, suggesting that UCA1, miR-28-5p, and HOXB3 are the potential targets for colon cancer therapy.     

HIF1A-AS2 predicts poor prognosis and regulates cell migration and invasion in triple-negative breast cancer

The aberrant expression of hypoxia-inducible factor 1 alpha (HIF1A)-antisense RNA 2 (HIF1A-AS2) was found in various human cancers including breast cancer. The aim of this study was to present more evidence about the role HIF1A-AS2 on triple-negative breast cancer (TNBC). In our results, HIF1A-AS2 was also found to be upregulated in TNBC tissues compared with non-TNBC tissues or adjacent normal tissues. Besides, HIF1A-AS2 expression was also elevated in TNBC cell lines compared with the normal breast epithelial cell line. Moreover, high expression of HIF1A-AS2 was associated with lymph node metastasis, distant metastasis and unfavorable histological grade in TNBC patients. Survival analysis showed a TNBC patient with high HIF1A-AS2 expression had shorter overall survival than patients with low HIF1A-AS2 expression, and HIF1A-AS2 high expression acted as an independent poor prognostic factor for overall survival in TNBC patients. The cell migration and invasion assays suggested inhibition of HIF1A-AS2 obviously depressed TNBC cell migration and invasion. In conclusion, HIF1A-AS2 serves as a novel biomarker for predicting clinical progression and prognosis in TNBC.     

基于生物信息学分析KCNQ1OT1在胃癌中的作用

长非编码RNA KCNQ1OT1在多种肿瘤中高表达,但是在胃癌中的研究较少并且研究结果不一致,其在胃癌中具体的作用机制也缺乏相关研究。通过癌症基因组图谱(The Cancer Genome Atlas, TCGA)公共数据库分析发现:KCNQ1OT1在胃癌中普遍高表达,且高表达KCNQ1OT1的胃癌病人预后不良,它与胃癌多种临床因素密切相关,尤其是与TP53的突变有明显的相关性,而且其表达与免疫细胞浸润明显相关;KCNQ1OT1在胃癌肿瘤细胞系中普遍高表达,敲低后可抑制胃癌肿瘤细胞的增殖能力,共表达网络分析发现,其表达与肿瘤代谢有密切的相关性;谷氨酰胺酶1(glutaminase 1, GLS1)在胃癌中普遍高表达,与预后不良密切相关,KCNQ1OT1与GLS1的表达具有明显的相关性,敲低KCNQ1OT1的表达可抑制GLS1 mRNA的表达,而过表达GLS1可以部分逆转敲低KCNQ1OT1造成的胃癌细胞增殖能力的下降,因此推测KCNQ1OT1可能通过GLS1调控胃癌肿瘤细胞的生长。本研究通过大数据及实验验证了KCNQ1OT1在胃癌中的表达及功能,提示KCNQ1OT1有可能通过调控谷氨酰胺代谢来促进了胃癌的发生发展,这为分子靶向治疗胃癌的临床研究提供了新的靶点和思路。