长链非编码RNA HULC 与肿瘤的研究进展

随着全基因组测序和转录测序技术的发展,长链非编码RNA(long noncoding RNA,lncRNA)逐渐成为研究的热点,越来越多的 lncRNA 分子被发现。HULC（highly up-regulated in liver cancer）RNA 是一种在肝癌中发现的特异性高表达的 lncRNA,在转录后水平调节基因表达。 lncRNA HULC 调节异常与人类许多疾病尤其是恶性肿瘤相关,有望成为新型肿瘤诊断标志物和肿瘤治疗的靶点。本文就近年来 lncRNA HULC 与肿瘤的研究进展进行综述。     

长链非编码RNA在脑胶质瘤中的研究进展

胶质瘤是颅内最常见的恶性肿瘤,具有细胞快速增殖和新生血管生成等特征。长链非编码RNA(lncRNA)是一类不具备蛋白质编码能力的RNA,其转录本长度超过200 nt,主要通过调控编码蛋白基因的表达、染色体重构、组蛋白修饰以及作为小分子RNA的前体分子在人类肿瘤中发挥作用。研究发现,lncRNA水平可以影响胶质瘤细胞增殖、迁移、耐药和新生血管生成等。本文对lncRNA在胶质瘤发生发展过程中的研究进展进行综述,以期为胶质瘤的治疗提供新的科学依据。     

长链非编码RNA HOTAIR,H19,HULC联合检测对HBV相关肝癌的诊断价值

目的探讨长链非编码RNA HOTAIR,H19,HULC联合检测对HBV相关肝癌的诊断价值。方法将早期HBV相关肝癌患者120例作为肿瘤组、健康体检者120例作为对照组。通过实时荧光定量PCR检测长链非编码RNA HOTAIR,H19,HULC的表达量。用受试者工作特征曲线(receiver operating characteristic curve,ROC)的AUC分析长链非编码RNA HOTAIR,H19,HULC表达量在早期HBV相关肝癌中的诊断意义。结果HBV相关肝癌患者血清中长链非编码RNA HOTAIR,H19,HULC的表达量均高于健康体检者(P<0.05)。长链非编码RNA HOTAIR,H19,HULC鉴别早期HBV相关肝癌患者与健康人群的灵敏度分别为86%,89%,91%,特异度分别为85%,90%,93%;长链非编码RNA HOTAIR,H19,HULC联合鉴别诊断早期HBV相关肝癌的灵敏度为91.67%,特异度为93.33%,准确度为92.50%。结论长链非编码RNA HOTAIR,H19,HULC的表达量可作为诊断早期HBV相关肝癌的潜在标志。     

长链非编码RNA在胶质母细胞瘤中异常表达研究

背景与目的：近来研究表明,长链非编码RNA在胶质瘤的发生与发展中发挥重要作用。本研究旨在通过基因芯片分析lncRNAs在胶质母细胞瘤（GBM）和正常脑组织中的表达概况,比较lncRNA差异表达与组织之间的表达谱差异。方法：应用基因芯片技术检测lncRNAs在GBM和正常脑组织的表达谱差异．并筛选出差异表达lncRNA进行分析。结果：lncRNA芯片的数据：原发性胶质母细胞瘤与正常脑组织中LncRNA表达上调3倍基因2032个,LncRNA表达下调3倍基因2036个（P〈0．01）。其中21个lncRNAs上调30倍以上．7个lncRNAs下调超过30倍（P〈0．01）。结论：利用lncRNA基因芯片较大规模地对胶质瘤中的lncRNAs差异表达进行探讨．对lncRNA在其中的功能及潜在的基因治疗功能具有十分重要的意义：差异表达的lncRNAs包括一些抑癌及促癌lncRNA,其在胶质母细胞瘤的发展中扮演重要的角色．通过它们的目标基因在GBM的复发和恶性进展中发挥作用．     

长链非编码RNA在肿瘤耐药中的研究进展

化疗药物耐药性仍然是目前肿瘤有效化疗的主要障碍。尽管肿瘤耐药机制受到了广泛的探索,但至今尚未被完全阐明。长链非编码RNA是近年来的研究热点,参与了基因组功能的许多方面包括基因转录、剪接、表观遗传学以及细胞周期、细胞分化、发育和多能性等过程。在肿瘤耐药中lncRNA可能通过促进DNA修复、改变药物代谢和细胞膜流出、调节细胞凋亡率和影响上皮细胞-间充质转化等过程,调节化疗敏感性。同时,lncRNA表达谱与肿瘤耐药的演变有密切关系。因此,发现新的lncRNA在肿瘤耐药中的机制对于制定新的治疗策略以克服耐药性具有积极意义。     

长链非编码RNA与肺癌

长链非编码RNA（lncRNA）是一类转录本长度超过200个核苷酸的小分子RNA,不具有蛋白编码功能,起初被认为是基因组转录的“噪音”,近年来却被证实在生物体内对基因的表达具有调控作用,与肿瘤的发生发展密切相关。肺癌是一种严重危害人们健康的恶性肿瘤性疾病,研究发现lncRNA在肺肿瘤中表达失调,异常表达的lncRNA能作为关键的调控因子,参与多种生物学过程,影响肿瘤转移与侵袭、肺癌细胞的增殖和凋亡、肿瘤血管生成及调节肿瘤耐药,为肺癌临床治疗提供新思路。此外,lncRNA还可作为潜在的生物标志物用于肺癌早期诊断及评估肺癌预后。本文就lncRNA在肺癌研究中的进展进行综述。     

长链非编码RNA与肿瘤

长链非编码RNA （IncRNA）是重要的基因表达调控因子,它广泛参与多种生理及病理过程.近年来研究证实IncRNA与肿瘤密切相关,并显露出作为肿瘤诊断和治疗新靶点的潜能.     

长链非编码RNA与肿瘤研究进展

在基因组中大量转录的长链非编码RNA, 因其在致癌与肿瘤抑制途径中显露出的潜在作用而成为肿瘤研究的新热点。虽然这些新基因在各种人类肿瘤中普遍异常表达, 但其中大部分的生物学功能仍未可知。近年来, 许多研究显示长链非编码RNA, (Long non-coding RNAs, LncRNAs)与肿瘤的发生、发展密切相关。本文结合国内外最新报道, 对LncRNAs在各种肿瘤中的研究进展作一综述。      

特异长链非编码RNA在鼻咽癌中的表达及其意义

目的 分析长链非编码RNA（long non-coding RNA, lncRNA）在鼻咽癌与慢性鼻咽炎组织中表达水平的变化,寻找可能与鼻咽癌发生发展相关的特异lncRNA。方法 采用lncRNA芯片技术分析lncRNA和mRNA在鼻咽癌与慢性鼻咽炎组织的表达谱,筛选差异表达的lncRNA和mRNA,进一步研究使用了聚类分析、GO分析、pathway分析等生物信息学技术。结果 差异表达的lncRNA（2倍以上变化且P＜0.05）共856条,其中上调的共 425条,下调的共431条;差异表达的mRNA共767条,其中上调的共426条,下调的共341条。利用聚类分析方法将差异表达的lncRNA分成3类：增强子型lncRNA、HOX 基因簇、基因间lncRNA。GO分析将mRNA分成3类：生物学过程类、细胞组分类、分子功能类。Pathway分析显示mRNA共参与28条信号通路,其中参与细胞因子-细胞因子受体相互作用信号通路的上调差异表达的mRNA的富集度最高。结论 与慢性鼻咽炎相比,lncRNA在鼻咽癌组织的表达水平明显改变,提示差异表达的lncRNA可能与鼻咽癌的发生发展有关。     

长链非编码RNA与宫颈癌的相关性

长链非编码RNA（lncRNA）是一类不编码蛋白,转录本长度超过200nt 的非编码RNA 分子。是以RNA的形式在多层面上调控基因的表达水平。多年的国内外研究显示,不同的lncRNA 种类在宫颈癌的发生发展、诊断、治疗及预后中起着不同的重要作用。还可为特异性靶点治疗提供新的研究方向。本文概述近几年的几种 lncRNA在宫颈癌中的作用。     

长链非编码RNA HOTAIR抑制膀胱尿路上皮癌对阿霉素的敏感性

目的:研究长链非编码RNA HOTAIR在膀胱尿路上皮癌中的表达,明确其对膀胱尿路上皮癌对阿霉素敏感性的调控作用.方法:HOTAIR基因在膀胱尿路上皮癌及癌旁组织中的表达由实时定量PCR法检测.将HOTAIR基因的表达载体和沉默载体分别转染膀胱尿路上皮癌J82细胞,实时定量PCR验证转染效果.应用MTT法检测HOTAIR基因表达改变对于J82细胞的增殖能力及对阿霉素敏感性的调控作用.结果:HO-TAIR基因在膀胱尿路上皮癌表达显著上调.HOTAIR基因的表达载体和沉默载体能够显著上调或沉默HO-TAIR基因的表达.HOTAIR高表达能够促进J82细胞增殖,抑制J82细胞对阿霉素的敏感性;而HOTAIR表达沉默的J82细胞增殖能力下调明显,对阿霉素的敏感性明显增加.结论:长链非编码RNA HOTAIR在膀胱尿路上皮癌中高表达,HOTAIR能够作为癌基因促进膀胱尿路上皮癌的细胞增殖能力并抑制膀胱尿路上皮癌对阿霉素敏感性.     

长链非编码RNA在膀胱尿路上皮癌中的研究进展

长链非编码RNA（long noncoding RNA,lncRNA）是一组长度>200bp,缺少特异性开放阅读框,几乎不具备蛋白编码功能的内源性RNA分子。lncRNA可在转录、转录后及表观遗传学水平等方面调控基因表达,从而影响多种生物学进程。膀胱尿路上皮癌中多种lncRNA发挥癌基因或抑癌基因的作用,并与膀胱癌的诊断、治疗、预后及肿瘤细胞的增殖、迁移、侵袭密切相关。本文就膀胱癌中lncRNA的研究进展进行综述,并探讨lncRNA与膀胱癌的发生、发展之间的关系,为寻找膀胱癌分子标志物、药物靶点提供新的方向。      

Quality of life in low-grade glioma patients receiving temozolomide

The purpose of this study was to describe the quality of life (QOL) of low-grade glioma (LGG) patients at baseline prior to chemotherapy and through 12 cycles of temozolomide (TMZ) chemotherapy. Patients with histologically confirmed LGG with only prior surgery were given TMZ for 12 cycles. QOL assessments by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) were obtained at baseline prior to chemotherapy and at 2-month intervals while receiving TMZ. Patients with LGG at baseline prior to chemotherapy had higher reported social well-being scores (mean difference = 5.0; p < 0.01) but had lower reported emotional well-being scores (mean difference = 2.2; p < 0.01) compared to a normal population. Compared to patients with left hemisphere tumors, patients with right hemisphere tumors reported higher physical well-being scores (p = 0.01): 44% could not drive, 26% did not feel independent, and 26% were afraid of having a seizure. Difficulty with work was noted in 24%. Mean change scores at each chemotherapy cycle compared to baseline for all QOL subscales showed either no significant change or were significantly positive (p < 0.01). Patients with LGG on TMZ at baseline prior to chemotherapy reported QOL comparable to a normal population with the exception of social and emotional well-being, and those with right hemisphere tumors reported higher physical well-being scores compared to those with left hemisphere tumors. While remaining on therapy, LGG patients were able to maintain their QOL in all realms. LGG patients' QOL may be further improved by addressing their emotional well-being and their loss of independence in terms of driving or working.     

Cilengitide modulates attachment and viability of human glioma cells,but not sensitivity to irradiation or temozolomide in vitro

Cilengitide is a cyclic peptide antagonist of integrins αvβ3 and αvβ5 that is currently being evaluated as a novel therapeutic agent for recurrent and newly diagnosed glioblastoma. Its mode of action is thought to be mainly antiangiogenic but may include direct effects on tumor cells, notably on attachment, migration, invasion, and viability. In this study we found that, at clinically relevant concentrations, cilengitide (1–100 μM) induces detachment in some but not all glioma cell lines, while the effect on cell viability is modest. Detachment induced by cilengitide could not be predicted by the level of expression of the cilengitide target molecules, αvβ3 and αvβ5, at the cell surface. Glioma cell death induced by cilengitide was associated with the generation of caspase activity, but caspase activity was not required for cell death since ectopic expression of cytokine response modifier (crm)-A or coexposure to the broad-spectrum caspase inhibitor zVAD-fmk was not protective. Moreover, forced expression of the antiapoptotic protein marker Bcl-X_L or altering the p53 status did not modulate cilengitide-induced cell death. No consistent effects of cilengitide on glioma cell migration or invasiveness were observed in vitro. Preliminary clinical results indicate a preferential benefit from cilengitide added to temozolomide-based radiochemotherapy in patients with O⁶-methylguanine DNA methyltransferase (MGMT) gene promoter methylation. Accordingly, we also examined whether the MGMT status determines glioma cell responses to cilengitide alone or in combination with temozolomide. Neither ectopic expression of MGMT in MGMT-negative cells nor silencing the MGMT gene in MGMT-positive cells altered glioma cell responses to cilengitide alone or to cilengitide in combination with temozolomide. These data suggest that the beneficial clinical effects derived from cilengitide in vivo may arise from altered perfusion, which promotes temozolomide delivery to glioma cells.     

尼妥珠单抗联合放疗加同期替莫唑胺治疗高分级胶质瘤的初步研究

背景与目的：尼妥珠单抗（nimotuzumab）是抗人表皮生长因子受体（epithelial growth factor receptor,EGFR）人源化单克隆抗体,能够抑制肿瘤细胞增殖并增加放化疗敏感性。本研究运用前瞻性方法对尼妥珠单抗联合放疗加同期替莫唑胺（temozolomide,TMZ）治疗高分级的脑胶质瘤（high-grade glioma,HGG）患者的不良反应和近期疗效进行初步观察。方法：2008年7月—2009年6月期间共17例HGG患者入组,均采用TMZ同期放化疗加TMZ辅助化疗,其中12例新诊断为HGG的患者放疗总剂量为60Gy/30次,3例复发HGG患者为50Gy/25次,2例脑干复发HGG患者为40Gy/20次;放疗期间每天口服TMZ50mg/m2,放疗结束后4周循环口服TMZ;放疗期间每周静脉滴注尼妥珠单抗注射液。记录治疗反应,计算6个月无疾病进展生存率和总生存率。结果：本组病例急性不良反应多为Ⅰ～Ⅱ级,没有Ⅲ级以上不良反应,有1例因发生Ⅱ级湿疹性皮炎,从而中断尼妥珠单抗治疗。16例作近期疗效评价,其中PR4例,SD10例,PD2例。6个月无进展生存率和总生存率分别为72.1%和86.3%。其中3例发生肿瘤假性进展。结论：本研究初步显示尼妥珠单抗联合放疗加同期替莫唑胺治疗HGG不良反应较小,患者可以耐受,近期疗效较好,远期疗效尚需进一步观察。     

Phase II trial of continuous low-dose temozolomide for patients with recurrent malignant glioma

Background

In this phase II trial, we investigated the efficacy of a metronomic temozolomide schedule in the treatment of recurrent malignant gliomas (MGs).

Methods

Eligible patients received daily temozolomide (50 mg/m²) continuously until progression. The primary endpoint was progression-free survival rate at 6 months in the glioblastoma cohort (N = 37). In an exploratory analysis, 10 additional recurrent grade III MG patients were enrolled. Correlative studies included evaluation of 76 frequent mutations in glioblastoma (iPLEX assay, Sequenom) aiming at establishing the frequency of potentially “drugable” mutations in patients entering recurrent MG clinical trials.

Results

Among glioblastoma patients, median age was 56 y; median Karnofsky Performance Score (KPS) was 80; 62% of patients had been treated for ≥2 recurrences, including 49% of patients having failed bevacizumab. Treatment was well tolerated; clinical benefit (complete response + partial response + stable disease) was seen in 10 (36%) patients. Progression-free survival rate at 6 months was 19% and median overall survival was 7 months. Patients with previous bevacizumab exposure survived significantly less than bevacizumab-naive patients (median overall survival: 4.3 mo vs 13 mo; hazard ratio = 3.2; P = .001), but those patients had lower KPS (P = .04) and higher number of recurrences (P < .0001). Mutations were found in 13 of the 38 MGs tested, including mutations of EGFR (N = 10), IDH1 (N = 5), and ERBB2 (N = 1).

Conclusions

In spite of a heavily pretreated population, including nearly half of patients having failed bevacizumab, the primary endpoint was met, suggesting that this regimen deserves further investigation. Results in bevacizumab-naive patients seemed particularly favorable, while results in bevacizumab-failing patients highlight the need to develop further treatment strategies for advanced MG.

Clinical trials.gov identifier

{"type":"clinical-trial","attrs":{"text":"NCT00498927","term_id":"NCT00498927"}}NCT00498927 (available at http://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT00498927","term_id":"NCT00498927"}}NCT00498927)     

A pilot study using carboplatin,vincristine, and temozolomide in children with progressive/symptomatic low-grade glioma: a Children's Oncology Group study

Background

This study was initiated to test the feasibility and toxicity of a regimen that alternates the administration of weekly carboplatin and vincristine with temozolomide in the management of children with progressive and/or symptomatic low-grade glioma.

Methods

Eligible children received a 10-week induction regimen followed by six 10-week cycles of maintenance chemotherapy. Feasibility was evaluated with short-term and long-term endpoints. Short-term feasibility was evaluated by the ability to complete induction and 1 maintenance cycle in 24 weeks without >25% reduction in either carboplatin or temozolomide. Long-term feasibility was evaluated by the ability to administer induction and 4 maintenance cycles within 60 weeks without >25% reduction in either carboplatin or temozolomide. Efficacy was assessed by response to initial chemotherapy and 5-year event-free survival. Initial pathology was reviewed centrally.

Results

Sixty-six patients were enrolled on the study. It was feasible to deliver the regimen, and toxicity was acceptable. The only significant toxicities were hematologic. Both the short-term and long-term feasibility endpoints were met. The short-term feasibility success rate was 87% (95% CI: 77%–96%) and the long-term feasibility success rate was 79% (95% CI: 68%–90%). The 5-year event-free survival was 46% (95% CI: 33%–58%) and the 5-year survival was 87% (95% CI: 75%–93%).

Conclusion

It was feasible to deliver the combination of weekly carboplatin and vincristine alternating with temozolomide to children with progressive/symptomatic low-grade glioma with acceptable toxicities. This combination appears to be effective in delaying progression. Further trials are needed to establish the relative efficacy of this regimen compared with other regimens in use.     

长链非编码RNA MEG3抑制人胃癌SGC-7901细胞增殖的研究

目的:探讨长链非编码RNA MEG3在临床胃癌组织及细胞中的表达情况,以及过表达MEG3对人胃癌细胞增殖能力的影响。方法:采用实时定量PCR检测人胃癌组织及细胞系中MEG3的表达,并结合病理资料分析胃癌组织MEG3表达与临床病理特征之间的关系。采用四甲基偶氮唑蓝（MTT）法和克隆形成实验检测过表达MEG3前后胃癌细胞增殖的变化。结果:相对于正常胃组织及细胞,在胃癌组织和细胞中MEG3的表达水平明显下调。胃癌组织中MEG3表达与组织学分级、肿瘤浸润深度和TNM分期相关,但与年龄、性别及区域淋巴结转移无关。在SGC-7901细胞中转染MEG3过表达质粒后能显著上调MEG3的表达水平。过表达MEG3能明显抑制胃癌细胞的增殖能力。结论:MEG3对胃癌细胞增殖的调控至关重要,过表达MEG3能明显抑制胃癌细胞的增殖能力。提示MEG3的表达下调可能在胃癌的发生、发展中起重要作用。     

Synergistic inhibition of angiogenesis and glioma cell-induced angiogenesis by the combination of temozolomide and enediyne antibiotic lidamycin

Present work mainly evaluated the inhibitory effects of lidamycin (LDM), an enediyne antibiotic, on angiogenesis or glioma-induced angiogenesis in vitro and in vivo, especially its synergistic anti-angiogenesis with temozolomide (TMZ). LDM alone efficiently inhibited proliferations and induced apoptosis of rat brain microvessel endothelial cells (rBMEC). LDM also interrupted the tube formation of rat brain microvessel endothelial cells (rBMEC) and rat aortic ring spreading. The blockade of rBMEC invasion and C6 cell-induced rBMEC migration by LDM was associated with decrease of VEGF secretion in a co-culture system. TMZ dramatically potentiated the effects of LDM on anti-proliferation, apoptosis induction, and synergistically inhibited angiogenesis events. As determined by western blot and ELISA, the interaction of tumor cells and the rBMEC was markedly interrupted by LDM plus TMZ with synergistic regulations of VEGF induced angiogenesis signal pathway, tumor cell invasion/migration, and apoptosis signal pathway. Immunofluorohistochemistry of CD31 and VEGF showed that LDM plus TMZ resulted in synergistic decrease of microvessel density (MVD) and VEGF expression in human glioma U87 cell subcutaneous xenograft. This study indicates that the high efficacy of LDM and the synergistic effects of LDM plus TMZ against glioma are mediated, at least in part, by the potentiated anti-angiogenesis.