长链非编码RNA在肝细胞肝癌中的研究进展

肝细胞肝癌(HCC)是肝癌最常见的病理类型,患者病死率高。对HCC发生发展机制的认知局限是其不良预后的重要原因。长链非编码RNA(lncRNA)是基因调控的重要组成部分,在不同疾病患者和不同组织中的表达具有特异性。近年来,lncRNA在癌症发生发展中作用的研究逐渐深入,这为HCC早期诊断、病情控制和预后评估提供了新的方法和思路。本文就长链非编码RNA在HCC中的研究进展作一综述。     

Long noncoding RNA CCDC26 as a potential predictor biomarker contributes to tumorigenesis in pancreatic cancer

Pancreatic cancer (PC) is the fourth most common cancer worldwide and has the least patient survival rate of any cancer. Emerging studies have demonstrated that long noncoding RNAs (lncRNAs) were present in cancer patients and have shown great potential as powerful markers and therapeutic targets. However, little is known about the role of lncRNAs in PC. The present study aimed to investigate the expression pattern, clinical significance and biological function of lncRNA CCDC26 (CCDC26) in PC. With quantitative real-time PCR, we analyzed CCDC26 expression levels in 40 PC patients. We found that the CCDC26 expression was significantly higher in PC tissues than in normal tissues. CCDC26 levels were correlated with tumor size, tumor number, and reduced overall survival (OS). Univariate and multivariate analysis showed that CCDC26 expression is an independent prognostic factor of OS in patients with PC. Additionally, ROC^AUC of CCDC26 was up to 0.663, implicating that CCDC26 could be a diagnostic marker for distinguishing PC from normal. Knockdown of CCDC26 expression by small interfering RNA significantly promoted growth arrest and apoptosis. Moreover, we found that the expression of CCDC26 was positively correlated with PCNA and Bcl2. Our data suggest that CCDC26 may be identified as a novel oncogene in PC, and responsible for growth and apoptosis of cancer cell, partly by regulating the PCNA and Bcl2 expression. This work provides a novel biomarker and therapeutic target of PC for cancer clinic in future.     

Emerging role of long noncoding RNAs in recurrent hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains one of the most frequent types of liver cancer and is characterized by a high recurrence rate. Recent studies have proposed that long non-coding RNAs (lncRNAs) are potential biomarkers in several recurrent tumor types. It is now well understood that invasion, migration, and metastasis are important factors for tumor recurrence. Moreover, some of the known risk factors for HCC may affect the expression levels of several types of lncRNAs and thus affect the recurrence of liver cancer through lncRNA regulation. In this paper, we review the biological functions, molecular mechanisms, and roles of lncRNAs in HCC and summarize current knowledge about lncRNAs as potential biomarkers in recurrent HCC.     

血清lncRNA H19在非小细胞肺癌筛查及预后评估中的价值

目的分析非小细胞肺癌(NSCLC)患者血清lnc RNA H19表达水平及其筛查和预后价值。方法实时荧光定量PCR检测70例NSCLC患者和60例体检健康者血清lnc RNA H19表达水平,并分析血清H19水平与NSCLC患者临床病理参数的关系;利用ROC曲线分析H19对NSCLC的筛查效能;Kaplan-Meier法绘制不同H19水平的NSCLC患者生存曲线,Cox多因素回归模型分析NSCLC预后的独立危险因素。结果NSCLC组血清H19表达水平(1.72±0.27)明显高于健康人对照组(1.00±0.08),差异有统计学意义(t=19.911,P0.01)。ROC曲线结果表明,血清H19筛查NSCLC的AUC~(ROC)为0.864,特异性为81.7%,敏感性为74.3%。血清H19表达与TNM分期、肿瘤大小、淋巴结转移有关(P均0.05),但与年龄、性别、吸烟史、分化程度、病理分型等无关(P0.05)。H19高表达组中位生存时间为35个月,而H19低表达组中位生存时间为49个月,差异有统计学意义(Log-rankχ~2=4.874,P=0.027)。TNM分期、肿瘤大小、淋巴结转移、血清H19表达水平是影响NSCLC患者预后的独立风险因素(P均0.05)。结论NSCLC患者血清Lnc RNA H19明显升高,并且与NSCLC不良预后密切相关,有望成为NSCLC筛查和预后评估的分子标志物。     

MiR-101在乳腺癌中的表达及其意义

目的:探讨miR-101在乳腺癌组织中的表达变化。方法:收集乳腺癌组织及对应的癌旁组织,以qRT-PCR方法测定miR-101在乳腺癌组织中的表达变化。在乳腺癌细胞中转染miR-101 mimics、mimics control,以qRT-PCR方法检测上调效果,MTT方法测定细胞增殖变化,流式细胞术测定细胞凋亡变化,Transwell小室测定细胞迁移和侵袭数目变化,蛋白质印迹法测定细胞中cleaved caspase-3和MMP-2蛋白表达变化。结果:miR-101在乳腺癌组织中的表达水平明显低于癌旁组织(P<0.05)。与miR-NC比较,miR-101细胞中miR-101表达水平升高,细胞增殖能力降低,细胞凋亡率升高,细胞侵袭和迁移数目下降,细胞内的cleaved caspase-3蛋白水平表达升高,MMP-2蛋白表达水平减少(P<0.05)。结论:MiR-101在乳腺癌组织中表达下调,上调miR-101抑制乳腺癌细胞增殖、侵袭和迁移并诱导细胞凋亡。     

A novel prognostic model associated with the overall survival in patients with breast cancer based on lipid metabolism‐related long noncoding RNAs

BackgroundLipid metabolism is closely related to the occurrence and development of breast cancer. Our purpose was to establish a novel model based on lipid metabolism‐related long noncoding RNAs (lncRNAs) and evaluate the potential clinical value in predicting prognosis for patients suffering from breast cancer.MethodsRNA data and clinical information for breast cancer were obtained from the cancer genome atlas (TCGA) database. Lipid metabolism‐related lncRNAs were identified via the criteria of correlation coefficient |R ²| > 0.4 and p < 0.001, and prognostic lncRNAs were identified to establish model through Cox regression analysis. The training set and validation set were established to certify the feasibility, and all samples were separated into high‐risk group or low‐risk group. Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) were conducted to evaluate the potential biological functions, and the immune infiltration levels were explored through Cibersortx database.ResultsA total of 14 lncRNAs were identified as protective genes ({"type":"entrez-nucleotide","attrs":{"text":"AC022150.4","term_id":"7711716","term_text":"AC022150.4"}}AC022150.4, {"type":"entrez-nucleotide","attrs":{"text":"AC061992.1","term_id":"7630731","term_text":"AC061992.1"}}AC061992.1, AC090948.3, {"type":"entrez-nucleotide","attrs":{"text":"AC092794.1","term_id":"15027722","term_text":"AC092794.1"}}AC092794.1, {"type":"entrez-nucleotide","attrs":{"text":"AC107464.3","term_id":"19339290","term_text":"AC107464.3"}}AC107464.3, AL021707.8, {"type":"entrez-nucleotide","attrs":{"text":"AL451085.2","term_id":"13561296","term_text":"AL451085.2"}}AL451085.2, AL606834.2, FLJ42351, LINC00926, LINC01871, TNFRSF14−AS1, {"type":"entrez-nucleotide","attrs":{"text":"U73166.1","term_id":"1613889","term_text":"U73166.1"}}U73166.1 and USP30−AS1) with HRs < 1 while 10 lncRNAs ({"type":"entrez-nucleotide","attrs":{"text":"AC022150.2","term_id":"7021694","term_text":"AC022150.2"}}AC022150.2, {"type":"entrez-nucleotide","attrs":{"text":"AC090948.1","term_id":"13384352","term_text":"AC090948.1"}}AC090948.1, {"type":"entrez-nucleotide","attrs":{"text":"AC243960.1","term_id":"325121040","term_text":"AC243960.1"}}AC243960.1, AL021707.6, ITGB2−AS1, OTUD6B−AS1, SP2−AS1, TOLLIP−AS1, {"type":"entrez-nucleotide","attrs":{"text":"Z68871.1","term_id":"1164911","term_text":"Z68871.1"}}Z68871.1 and ZNF337−AS1) were associated with increased risk with HRs >1. A total of 24 prognostic lncRNAs were selected to construct the model. The patients in low‐risk group were associated with better prognosis in both training set (p < 0.001) and validation set (p < 0.001). The univariate and multivariate Cox regression analyses revealed that risk score was an independent prognostic factors in both training set (p < 0.001) and validation set (p < 0.001). GO and GSEA analyses revealed that these lncRNAs were related to metabolism‐related signal pathway and immune cells signal pathway. Risk score was negatively correlated with B cells (r = −0.097, p = 0.002), NK cells (r = −0.097, p = 0.002), Plasma cells (r = −0.111, p = 3.329e‐04), T‐cells CD4 (r = −0.064, p = 0.039) and T‐cells CD8 (r = −0.322, p = 2.357e‐26) and positively correlated with Dendritic cells (r = 0.077, p = 0.013) and Monocytes (r = 0.228, p = 1.107e‐13).ConclusionThe prognostic model based on lipid metabolism lncRNAs possessed an important value in survival prediction of breast cancer patients.     

Long noncoding RNA LINC01296 plays an oncogenic role in colorectal cancer by suppressing p15 expression

ObjectiveTo examine the role of the long noncoding RNA LINC01296 in colorectal carcinoma (CRC) and to explore the underlying mechanism.MethodsWe detected LINC01296 expression levels in a cohort of 51 paired CRC and normal tissues. We also assessed the effects of LINC01296 on cell proliferation and apoptosis in CRC cells in vitro, and measured its effect on tumor growth in an in vivo mouse model. We identified the potential downstream targets of LINC01296 and assessed its regulatory effects.ResultsExpression levels of LINC01296 were elevated in 37/51 CRC tissues compared with the corresponding normal tissues and were significantly associated with tumor stage, lymph node metastasis, and distant metastasis. Knockdown of LINC01296 using antisense oligonucleotides inhibited cell proliferation and promoted apoptosis of colon cancer cells in vitro and inhibited tumor growth in vivo. Knockdown of LINC01296 also significantly increased the gene expression of p15 in colon cancer cells. LINC01296-specific suppression of p15 was validated by the interaction between enhancer of zeste homolog 2 and LINC01296.ConclusionOverexpression of LINC01296 suppressed the expression of p15 leading to CRC carcinogenesis. These findings may provide the basis for novel future CRC-targeted therapies.     

基于长链非编码RNA的表达谱特征构建乳腺癌患者预后的风险模型

目的构建长链非编码RNA(long non-coding RNA,LncRNA)表达特征的乳腺癌患者预后的预测模型。方法分析癌症基因组图谱(the cancer genome atlas,TCGA)数据库1081例乳腺癌患者的转录组测序数据中LncRNA表达图谱及临床特征,对TCGA数据库中112对配对的乳腺癌及正常乳腺组织的转录组测序数据进行差异表达分析和单因素分析筛选得到差异表达且与乳腺癌患者预后显著相关的LncRNA(DELncRNA),利用DEseq2包进行差异表达分析(为减弱批次效应,测序数据已用DESeq函数标准化)。1081例乳腺癌患者被分成两组:训练集(541例)和验证集(540例)。将DELncRNA纳入Cox比例风险回归模型,在训练集中筛选和建立多LncRNA预后模型并对模型进行比例风险假定检验(proportional hazards assumption,PH假定检验),计算多基因风险评分,并基于此将患者分为高风险组和低风险组,采用Kaplan-Meier方法进行生存分析,并用验证集540例患者的数据进行验证。评价该模型在TCGA数据库肺鳞癌和肝细胞肝癌等患者中的预后评估价值。基因集富集分析(gene set enrichment analysis,GSEA)分析LncRNA影响患者生存的具体机制。结果转录组测序分析筛选得到2815个差异表达基因,其中与乳腺癌患者预后显著相关的LncRNA共91个(P<0.05)。利用541例训练集乳腺癌患者的91个DELncRNA表达数据进行Cox回归分析,构建了基于5个LncRNA的Cox比例风险回归模型(训练集AUC=0.746,验证集AUC=0.650):AC004551.1、MTOR-AS1、KCNAB1-AS2、FAM230G和LINC01283,并进行PH假定检验(P=0.388)。K-M生存分析发现,训练集中高风险组的生存明显差于低风险组(中位生存时间:7.049年与12.21年,HR 0.367,95%CI 0.228~0.597,P<0.001),在验证集中高风险组患者生存时间也明显短于低风险组(中位生存时间:7.57年与10.85年,HR 0.412,95%CI 0.214~0.793,P<0.001)。在TCGA其他癌种中也得到相似的预测结果:肺鳞癌(HR 0.604,95%CI 0.383~0.951,P=0.007)及肝细胞肝癌(HR 0.551,95%CI 0.307~0.987,P=0.011)。GSEA结果提示,上述5个LncRNA的表达模式与肿瘤细胞的细胞周期调控有关。结论基于AC004551.1、MTOR-AS1、KCNAB1-AS2、FAM230G和LINC01283表达谱构建的预后模型可用于预测乳腺癌患者的预后,有利于进一步指导临床治疗。     

长链非编码RNA Lnc00478在卵巢癌组织及细胞系中的表达及临床意义

目的 探讨长链非编码RNA(LncRNA)Lnc00478在卵巢癌中的表达及其对卵巢癌生物学行为的影响.方法 收集该院2018-2019年收治的卵巢癌患者病历资料,选择手术后病理诊断为卵巢癌的标本,且癌旁组织未检测到癌细胞的标本80例,采用实时荧光定量PCR检测卵巢癌组织及癌旁组织中Lnc00478的表达水平,分析其表...     

血浆长链非编码RNA H19对乳腺癌的潜在诊断价值

目的探讨长链非编码RNA(lncRNA)H19在乳腺癌患者血浆中的表达水平及其对乳腺癌的潜在诊断价值。方法采用定量-逆转录PCR(qRT-PCR)检测24例乳腺癌患者癌组织及其癌旁组织,以及97例乳腺癌患者、30例乳腺良性疾病患者和86例体检健康者血浆中H19的表达水平,分析血浆H19表达量与乳腺癌临床病理参数的相关性;采用电化学发光免疫分析法(ECLI)检测血浆中CA153和CEA的水平,对血浆H19、CA153和CEA进行多元Logistic回归分析,绘制受试者工作特征曲线(ROC曲线)以评估血浆H19对乳腺癌的诊断效能。结果与癌旁组织相比,H19在乳腺癌组织中表达明显增高(Z=-2.371,P=0.018);乳腺癌组血浆H19水平明显高于良性病变组(U=411,P0.01)和体检健康组(U=2 138,P0.01);乳腺癌患者血浆中H19表达水平与雌激素受体(ER)、孕激素受体(PR)、c-erb B-2以及淋巴结转移相关(P均0.05);血浆H19单独诊断乳腺癌的ROC曲线下面积(AUC~(ROC))为0.827,敏感性和特异性分别为57.7%和86.4%,其对乳腺癌诊断效能明显高于CA153(AUC~(ROC)=0.661)和CEA(AUC~(ROC)=0.524),且H19、CA153和CEA联合诊断价值(AUC~(ROC)=0.853)亦高于单独检测。结论血浆中高表达的H19可能为乳腺癌诊断的一个潜在的生物学标志物。     

长链非编码RNA-LINP1对子宫内膜癌患者预后评估的临床价值

目的:探讨子宫内膜癌患者癌组织中长链非编码RNA(long non-coding RNA,lncRNA) LINP1水平对预后的判断价值。方法:选取2015年1月至2016年12月华北理工大学附属医院收治的82例子宫内膜癌患者的癌组织标本为子宫内膜癌组,另选其癌旁正常组织为癌旁对照组,采用实时荧光定量聚合酶链式反应法测...     

长链非编码RNA在肝细胞增殖、凋亡及转移中的研究进展

长链非编码RNA(lncRNAs)是一种长度大于200个核苷酸的新型RNA分子.lncRNAs可参与基因表达的调控.肝静脉闭塞病(HVOD)是造血干细胞移植(HSCT)的常见并发症,肝细胞损伤是HSCT所致HVOD的主要特征之一.由于肝是人体功能代谢、能量转换的重要器官,严重的肝功能损害是HSCT后受者的直接致死原因之一,而lncRNAs具有促进损伤肝细胞修复的作用,可有助于减少HSCT所致HVOD的发生.笔者就lncRNAs在肝细胞的增殖、凋亡及转移中的研究进展进行综述.     

长链非编码RNA在肿瘤发生及发展中的作用机制

长链非编码RNA(lncRNA)是一类转录本长度＞200个核苷酸的非编码RNA(ncRNA),其在肿瘤的发生、发展中发挥重要作用.IncRNA具有多种生物学功能,可以通过诱饵分子、支架分子和向导分子等形式,在表观遗传学水平、转录水平及转录后水平,调控蛋白质编码基因的表达.lncRNA与肿瘤细胞生长和凋亡、侵袭和转移等生物学行为密切相关.进一步阐明IncRNA在肿瘤发生、发展过程中的作用机制,有望为研究者开发肿瘤诊断和治疗的新方法提供思路.笔者拟就lncRNA调控基因表达的作用机制,及其在肿瘤诊断及治疗中的作用进行综述.     

Long noncoding RNA CCHE1 indicates a poor prognosis of hepatocellular carcinoma and promotes carcinogenesis via activation of the ERK/MAPK pathway

Survival of patients with hepatocellular carcinoma (HCC) remains poor, which is largely attributed to active carcinogenesis. Accumulating evidence implies that long noncoding RNAs (lncRNAs) could play a pivotal role in cancer biology. However, the clinical valueand biological significance of CCHE1 in HCC carcinogenesis remains to be discovered. Expression of CCHE1was analyzed in 112 HCC tissues and cell lines by qRT–PCR. The higher expression of CCHE1 was significantly correlated with tumor number, tumor size and TNM stage. Multivariate analyses revealed that CCHE1 expression served as an independent predictor for overall survival. Moreover, the effect of CCHE1 on proliferation was evaluated by MTT assays, and cell apoptosis was detected by flow-cytometric analysis. Further experiments demonstrated that CCHE1 knockdown significantly promoted growth arrest and cell apoptosis. Importantly, we further confirmed that ERK/MAPK pathway was found to be inactivated in the HCC cells after CCHE1 knockdown. To our knowledge, this is the first report showed that the role and the mechanism of CCHE1 in the progression of HCC. Together, these results suggest that lncRNA CCHE1 may serve as a candidate prognostic biomarker and target for new therapies in human HCC.     

Long noncoding RNA HULC predicts poor clinical outcome and represents pro-oncogenic activity in diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is one of the leading causes of cancer-related mortality, and responds badly to existing treatment. Thus, it is of urgent need to identify novel prognostic markers and therapeutic targets of DLBCL. Emerging studies have implicated that long noncoding RNAs (lncRNAs) are differentially expressed in various tumors and play an important role in the development of cancer. Previously, our group has reported that the novel lncRNA HULC has important biological function and clinical potential in human pancreatic cancer. Here, we investigated the expression of HULC in a cohort of DLBCL to assess its expression pattern, clinical value and molecular mechanism. Firstly, we found that HULC was remarkably overexpressed in both DLBCL tissues and cell lines. Moreover, we illustrated that HULC was closely related to DLBCL characteristics, such as Ann Arbor stages, B symptoms, CHOP-like treatment, rituximab and IPI. Importantly, we verified that HULC was an key predictive factor for DLBCL diagnosis and prognosis from sizable samples through the long time follow-ups. Furthermore, we reveal that the HULC knockdown could significantly arrest cell proliferation and induce apoptosis by repressing cyclin D1 and Bcl-2 in DLBCL cells. Our results suggested that HULC could represent a novel indicator of poor prognosis and may be served as a potential target for the diagnosis and gene therapy of DLBCL.     

超级增强子长链非编码RNA LINC01232在大肠癌组织中的表达及其对癌细胞生物学行为的影响

目的 探讨超级增强子长链非编码RNA(SE-LncRNA)LINC01232在大肠癌组织中的表达水平及其对大肠癌细胞生物学行为的影响.方法 通过基因芯片筛选4对大肠癌患者组织(癌组织和癌旁组织)中差异表达的SE-LncRNA,发现LINC01232在癌组织中显著高表达(Fold Change=2.6569,P=0.02...     

Super‐enhancer–associated long noncoding RNA RP11‐569A11.1 inhibited cell progression and metastasis by regulating IFIT2 in colorectal cancer

BackgroundRecent studies have revealed that super‐enhancer–associated long noncoding RNAs (SE‐LncRNAs) act pivotal roles in carcinogenesis. This study aimed to report the identification of a novel SE‐LncRNA, RP11‐569A11.1, and its functional role in colorectal cancer (CRC) progression.MethodsArraystar human SE‐LncRNA microarray was performed to detect differentially expressed SE‐LncRNAs in CRC tissues. RT‐qPCR was conducted to detect the expression level of RP11‐569A11.1 in CRC tissues and cells. The ROC curve was used to analyze the sensitivity and specificity of RP11‐569A11.1 in CRC diagnosis. CCK‐8 assay, colony formation assay, flow cytometry assay, and transwell assay were used to study the function of RP11‐569A11.1. RNA‐seq array was performed to analyze the potential downstream target gene of RP11‐569A11.1. Western blot assay was conducted to measure the protein level of interferon‐induced protein with tetratricopeptide repeat 2 (IFIT2).ResultsA total of 23 (15 up‐ and 8 downregulated) significantly expressed SE‐LncRNAs were identified in CRC tissues. The top 8 upregulated SE‐LncRNAs were RP11‐893F2.9, PTCSC1, RP11‐803D5.4, AC005592.2, LINC00152, LINC01232, AC017002.1, and RP4‐673M15.1, and the top 8 downregulated SE‐LncRNAs were RP11‐569A11.1, RP11‐245G13.2, RP11‐556N21.1, U91328.19, {"type":"entrez-nucleotide","attrs":{"text":"AX748340","term_id":"32132728"}}AX748340, CTD‐2337J16.1, CATG00000108830.1, and RP11‐670E13.2. Of which, RP11‐569A11.1 was found to be significantly downregulated in CRC tissues and cells. ROC curve analysis showed the area under the curve (AUC) of 0.77 [95% confidence interval (CI), 0.660–0.884, p < 0.001], and the diagnostic sensitivity and specificity were 74.29% and 71.43%, respectively. Functionally, overexpression of RP11‐569A11.1 inhibited CRC cell proliferation, migration and invasion, and induced cell apoptosis, while knockdown of RP11‐569A11.1 generated an opposite effect. Mechanistically, RP11‐569A11.1 positively regulated IFIT2 expression in CRC cells.ConclusionRP11‐569A11.1 inhibited CRC tumorigenesis by IFIT2‐dependent and could serve as a promising diagnostic biomarker in CRC.