Decreased expression of microRNA-200b is an independent unfavorable prognostic factor for glioma patients

Background and aimAs a member of the microRNA (miR)-200 family, miR-200b has been recognized as one of the fundamental regulators of epithelial–mesenchymal transition, chemosensitivity, cell proliferation, and cell cycle. Especially in glioma, miR-200b targets the CREB1 gene and suppresses the tumor cell growth in vitro. However, its involvement in human glioma has not yet been determined. The aim of this study was to investigate the clinical significance of miR-200b expression in this disease.MethodsmiR-200b expression in 266 pairs of human gliomas and matched nonneoplastic brain tissues was measured by real-time quantitative RT-PCR assay.ResultsCompared with nonneoplastic brain tissues, the expression level of miR-200b was significantly decreased in glioma tissues (tumor vs. normal: 2.87 ± 2.05 vs. 8.78 ± 2.50, P < 0.001). Of 266 patients with gliomas, 166 (62.41%) were in low miR-200b expression group. In addition, we found that the glioma tissues from high-grade tumors (grade III and IV) had much lower miR-200b expression than glioma tissues from low grade tumors (grade I and II). Moreover, the expression level of miR-200b was positively correlated with Karnofsky performance status (KPS) scores of glioma tissues. The results of a 60-month follow-up in 266 glioma patients further demonstrated that lower miR-200b expression was correlated with worse progression-free survival and overall survival in the patients with grade III and IV gliomas. Both univariate and multivariate analyses revealed that miR-200b was an independent prognostic indicator for glioma.ConclusionThese findings prove that the decreased expression of miR-200b may be associated with malignant tumor progression and poor prognosis in patients with gliomas, suggesting the potential role of miR-200b in glioma management. miR-200b may be a novel and valuable signature for predicting the clinical outcome of patients with gliomas.     

脑胶质瘤组织miR-211、miR-374、miR-510表达水平与临床病理特征及预后的关系研究

摘要 目的：探讨脑胶质瘤组织微小RNA（miR）-211、miR-374、miR-510表达水平与临床病理特征及预后的关系。方法：选择2013年8月至2015年8月我院诊治的83例脑胶质瘤患者作为研究对象,选择同期由于脑外伤在我院行内减压术切除的正常脑组织样本31份作为对照样本。采用荧光定量PCR检测miR-211、miR-374、miR-510表达水平,生存分析采用Kaplan-Meier法,应用Cox比例风险回归模型分析预后的影响因素。结果：与正常脑组织相比,脑胶质瘤组织中miR-211、miR-374表达水平明显下降,miR-510表达水平明显升高（P<0.05）。脑胶质瘤组织miR-211、miR-374、miR-510表达均与WHO分级和卡氏功能状态量表(KPS)评分有关（P<0.05）。miR-211、miR-374低表达患者的5年总生存率明显低于高表达患者,miR-510低表达患者的5年总生存率明显高于高表达患者（P<0.05）。WHO分级、KPS评分、miR-211、miR-374和miR-510表达是脑胶质瘤患者预后的影响因素（P<0.05）。结论：脑胶质瘤组织中miR-211和miR-374表达下调,而miR-510表达上调,miR-211、miR-374和miR-510表达均与WHO分级、KPS评分和预后相关,检测miR-211、miR-374和miR-51在脑胶质瘤患者的诊断和治疗中具有一定临床意义。     

MicroRNA-215 enhances invasion and migration by targeting retinoblastoma tumor suppressor gene 1 in high-grade glioma

Objective

To elucidate the molecular mechanism of microRNA-215 (miR-215) in the migration and invasion of high grade glioma.

Results

42 Patients were analysed for clinicopathological characteristics. qRT-PCR showed that miR-215 was up-regulated in glioma tissues compared with non-neoplastic brain tissues (P < 0.05). The up-regulated miR-215 was closely associated with high grade glioma (P < 0.01) and poor overall survival (P < 0.01). Transwell assay showed that re-expression of miR-215 enhanced migration and invasion of glioma cells. miR-215 also down-regulated retinoblastoma tumor suppressor gene 1 (RB1) expression by targeting its 3′-UTR. Reversely, re-expression of RB1 inhibited partial effect of miR-215 on migration and invasion in vitro.

Conclusions

Re-expression of miR-215 promoted cell migration and invasion of glioma by targeting RB1. miR-215 can thus be used as a biomarker for tumor progression and prognosis in human high grade glioma.

     

Kinesin family member 14 is a candidate prognostic marker for outcome of glioma patients

Background & aim: Human kinesin superfamily proteins (KIFs) are a conserved class of microtubule-dependent molecular motor proteins with adenosine triphosphatase activity and motion characteristics. As a member of KIFs, KIF14 plays an important role in the regulation of cell cycle and mitotic progression. Deregulation of KIF14 has been found in several human malignancies and also has been demonstrated to be involved in tumor progression and related to patient survival. The aim of this study was to investigate the clinicopathological significance of KIF14 expression in glioma. Methods: Real-time quantitative RT-PCR assay was performed to detect KIF14 mRNA expression, and Western blot and immunohistochemistry analyses were performed to detect KIF14 protein expression in human gliomas and non-neoplastic brain tissues, respectively. Then, the association of KIF14 immunostaining with clinicopathological factors and prognosis of glioma patients was also statistically analyzed. Results: KIF14 mRNA and protein expression were respectively increased 5.5- and 4.2-fold on average in glioma tissues relative to non-neoplastic brain tissues (both P < 0.001). Additionally, both KIF14 mRNA and protein expression increased with ascending pathological grade. Then, the high KIF14 immunostaining in glioma tissues was significantly associated with advanced pathological grade (P = 0.008), low Karnofsky performance score (KPS) (P = 0.02), high mitotic index (P = 0.005) and Ki-67 index (P = 0.008). Furthermore, both univariate and multivariate Cox regression analyses determined that KIF14 overexpression effectively predicted decreased overall survival in patients with gliomas. Conclusions: These findings offer the first convinced evidence that KIF14 expression in gliomas is tumor-specific and increased in more aggressive tumors. KIF14 might function as a candidate prognostic marker for human gliomas.     

miR-145 is a potential biomarker for predicting clinical outcome in glioblastomas

miR-145 has been found to be significantly downregulated in gliomas, and overexpression of miR-145 increases glioma cell apoptosis and enhances chemosensitivity or herpes simplex virus thymidine kinase gene therapy. However, the correlation between miR-145 and the clinical prognosis of glioblastomas has never been explored. In this study, a retrospective study was conducted in 86 cases of patients with glioblastoma after neurosurgery combined with chemoradiotherapy, and 36 cases with traumatic brain injury. Our results showed that miR-145 was significantly lower in glioblastoma tissues than that in normal brain tissue (P < 0.05). Furthermore, miR-145 was lower in patients with lower Karnofsky Performance Scale (KPS) scores than in patients with higher KPS scores ( P < 0.05). Cox Regression analysis showed that low miR-145 expression was associated with poor patient survival ( P < 0.05). These data suggested that patients with glioblastoma with lower miR-145 expression are prone to shorter overall survival.     

长链非编码RNA HOXA11-AS在胶质瘤中的表达及其临床意义的研究

目的:探讨长链非编码RNA HOXA11-AS在胶质瘤组织中的表达以及与胶质瘤患者临床预后的相关性。方法:首先,应用RT-PCR法检测人胶质瘤组织以及正常脑组织中HOXA11-AS的表达情况;其次,分析HOXA11-AS的表达水平与胶质瘤患者临床病理学特征之间的关系;最后,探讨HOXA11-AS的表达水平与胶质瘤患者预后之间的相关性。结果:RT-PCR显示,较之于正常脑组织(1.00±0.17),HOXA11-AS在胶质瘤组织(3.89±0.34)中的表达水平显著升高(P0.001),且随着肿瘤学分级的增高,HOXA11-AS的表达水平也随着升高(Grade Ⅰ-Ⅱ, 2.96±0.21 vs. Grade Ⅲ-Ⅳ, 4.83±0.50, p=0.003)。x~2检验提示HOXA11-AS表达水平与胶质瘤患者的肿瘤学分级、KPS评分以及患者的复发情况具有显著相关性,而与患者的年龄、性别、肿瘤大小等无相关性。Kaplan-Meier分析患者生存率,结果显示,HOXA11-AS低表达组患者的生存率明显高于HOXA11-AS高表达组患者,差异具有统计学意义(P0.001)。最后,我们的研究结果发现,HOXA11-AS的高表达水平、肿瘤学分级的增高、KPS评分80分均为影响胶质瘤患者预后的独立危险因素(P0.05)。结论:HOXA11-AS与胶质瘤患者预后密切相关,且为预测患者预后的独立因素。     

miR-324-5p、miR-605-3p在脑胶质瘤组织的表达及与临床病理参数和预后的关系

摘要 目的：探讨微小核糖核酸（miRNA）-324-5p、miR-605-3p在脑胶质瘤组织的表达及与临床病理参数和预后的关系。方法：选取2018年1月～2019年12月徐州医科大学附属医院收治的90例脑胶质瘤患者。收集术中部分瘤组织和瘤旁组织,采用实时荧光定量聚合酶链式反应（qRT-PCR）检测miR-324-5p、miR-605-3p表达。根据脑胶质瘤组织中miR-324-5p、miR-605-3p表达的平均值分为高表达组和低表达组,采用Kaplan-Meier法分析不同miR-324-5p、miR-605-3p表达脑胶质瘤患者生存情况,采用多因素Cox回归分析脑胶质瘤患者预后的影响因素。结果：与瘤旁组织比较,脑胶质瘤组织中miR-324-5p、miR-605-3p表达降低（P＜0.05）。不同分化程度、淋巴结转移、世界卫生组织（WHO）中枢神经系统肿瘤分类的脑胶质瘤患者miR-324-5p、miR-605-3p表达比较有差异（P＜0.05）。90例脑胶质瘤患者3年总生存率为36.67%（33/90）。Kaplan-Meier生存曲线分析显示,miR-324-5p高表达组、miR-605-3p高表达组总生存率高于miR-324-5p低表达组、miR-605-3p低表达组（P＜0.05）。多因素Cox回归分析显示,低分化、淋巴结转移和WHO中枢神经系统肿瘤分类Ⅲ～Ⅳ级为脑胶质瘤患者死亡的独立危险因素,miR-324-5p和miR-605-3p升高为独立保护因素（P＜0.05）。结论：脑胶质瘤组织中miR-324-5p、miR-605-3p呈低表达,与分化程度、淋巴结转移、WHO中枢神经系统肿瘤分类有关,miR-324-5p、miR-605-3p低表达还可导致不良预后。     

High Bone Sialoprotein (BSP) Expression Correlates with Increased Tumor Grade and Predicts a Poorer Prognosis of High-Grade Glioma Patients

Objectives

To investigate the expression and prognostic value of bone sialoprotein (BSP) in glioma patients.

Methods

We determined the expression of BSP using real-time RT-PCR and immunohistochemistry in tissue microarrays containing 15 normal brain and 270 glioma samples. Cumulative survival was calculated by the Kaplan-Meier method and analyzed by the log-rank test. Univariate and multivariate analyses were performed by the stepwise forward Cox regression model.

Results

Both BSP mRNA and protein levels were significantly elevated in high-grade glioma tissues compared with those of normal brain and low-grade glioma tissues, and BSP expression positively correlated with tumor grade (P<0.001). Univariate and multivariate analysis showed high BSP expression was an independent prognostic factor for a shorter progression-free survival (PFS) and overall survival (OS) in both grade III and grade IV glioma patients [hazard ratio (HR) = 2.549 and 3.154 for grade III glioma, and HR = 1.637 and 1.574 for grade IV glioma, respectively]. Patients with low BSP expression had a significantly longer median OS and PFS than those with high BSP expression. Small extent of resection and lineage of astrocyte served as independent risk factors of both shorter PFS and OS in grade III glioma patients; GBM patients without O⁶-methylguanine (O⁶-meG) DNA methyltransferase (MGMT) methylation and Karnofsky performance score (KPS) less than 70 points were related to poor prognosis. Lack of radiotherapy related to shorter OS but not affect PFS in both grade III and grade IV glioma patients.

Conclusion

High BSP expression occurs in a significant subset of high-grade glioma patients and predicts a poorer outcome. The study identifies a potentially useful molecular marker for the categorization and targeted therapy of gliomas.     

Upregulation of microRNA-372 associates with tumor progression and prognosis in hepatocellular carcinoma

MicroRNA-372 (miR-372) has been demonstrated to play a crucial role in cellular proliferation and apoptosis of cancer cells. However, its effects in hepatocellular carcinoma (HCC) have not been explored. The aim of this study was to investigate the clinical significance of miR-372 in human HCC. Quantitative RT-PCR was performed to detect miR-372 expression in HCC clinical samples and cell lines. Then, Kaplan–Meier and Cox proportional regression analyses were performed to determine the association of miR-372 expression with survival of HCC patients. Moreover, the effects of miR-372 on tumorigenicity of HCC cell lines were evaluated by in vitro assays. miR-372 expression in HCC tissues was significantly higher than in the corresponding normal adjacent liver tissues (P < 0.001). There was a correlation between miR-372 upregulation and advanced TNM stage of HCC patients (P = 0.02). In addition, HCC patients with higher miR-372 expression had significantly poorer recurrence-free survival (P = 0.006) and overall survival (P = 0.001). Multivariate analysis revealed that high miR-372 expression was an independent predictor of poor prognosis (for recurrence-free survival: Hazard Ratio [HR] 6.826, P = 0.01; for overall survival: HR 9.533, P = 0.008). Moreover, in vitro assays demonstrated that the ectopic expression of miR-372 may significantly promote the cellular proliferation, invasion, and migration of HCC cell lines. Our findings showed that miR-372 may serve as a potent prognostic marker for tumor recurrence and survival of HCC patients. Furthermore, miR-372 has been identified as a promoter for tumorigenicity of HCC cells, suggesting that it might be a prospective therapeutic target for HCC.     

Oncogenic reg IV is a novel prognostic marker for glioma patient survival

ABSTRACT: Aim The aberrant expression of regenerating islet-derived family member, 4 (Reg IV) has been found in various human cancers. However, the roles of Reg IV gene and its encoding product in human glioma have not been clearly understood. Therefore, the aim of this study was to investigate the clinicopathological significance of Reg IV expression in glioma. METHODS: Reg IV mRNA and protein expression in human gliomas and non-neoplastic brain tissues were respectively detected by real-time quantitative RT-PCR assay, Western blot, and immunohistochemistry. The association of Reg IV immunostaining with clinicopathological factors and prognosis of glioma patients was also statistically analyzed. RESULTS: Reg IV mRNA and protein expression levels in glioma tissues were both significantly higher than those in the corresponding non-neoplastic brain tissues (both P?相似文献   

Relative expressions of miR-205-5p, miR-205-3p, and miR-21 in tissues and serum of non-small cell lung cancer patients

Objective was to assess and compare the relative expressions of miR-205-5p, miR-205-3p, and miR-21-3p in tissues and serum among non-small cell lung carcinoma (NSCLC) patients, benign pulmonary conditions patients, and healthy volunteers. Serum samples were obtained between October 2011 and September 2012 from 20 NSCLC patients undergoing surgical treatment, 20 patients diagnosed with a benign lung disease (pulmonary tuberculosis, pneumonia, chronic obstructive pulmonary disease, or interstitial pneumonia) (lesion group), and 20 healthy volunteers (control group). NSCLC patients provided cancer tissues and cancer-adjacent normal tissues during surgery (paired specimens). Quantitative RT-PCR was used to assess miR-205-5p, miR-205-3p, and miR-21-3p expressions in serum and tissue samples. The relative expressions of miR-205-5p and miR-205-3p were significantly higher in NSCLC tissues compared with cancer-adjacent paired specimens (both P < 0.001). In the serum, significantly higher miR-205-5p, miR-205-3p, and miR-21-3p relative expressions were observed in the NSCLC group compared with the two other groups (all P < 0.001). The relative expressions of miR-205-5p and miR-21-3p in NSCLC tissues and serum were significantly correlated (r = 0.553, P = 0.011; and r = ?0.541, P = 0.014, respectively), while no significant correlation was observed for miR-205-3P (P = 0.120). Expressions of miR-205-5p and miR-205-3P in squamous cell carcinoma specimens were significantly higher than in lung adenocarcinoma specimens (both P = 0.001). Similarly, higher serum miR-205-5p and miR-205-3p levels were observed in squamous cell carcinoma patients (P = 0.033 and P = 0.002, respectively). In this preliminary and novel study, miR-205-5p was more useful as a marker for NSCLC than miR-205-3p or miR-21, indicating a potential for future applications in NSCLC diagnosis and prognosis.     

The Impact of MMP-2 and Its Specific Inhibitor TIMP-2 Expression on the WHO Grade and Prognosis of Gliomas in Chinese Population: a Meta-Analysis

So far, the prognostic value of matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of matrix metalloproteinase 2 (TIMP-2) expressions in patients with gliomas has been widely reported, especially in China. But, the results were inconsistent. Thus, we conducted a meta-analysis to determine the correlation of MMP-2 and TIMP-2 expressions with the prognosis of patients with gliomas. Identical search strategies were used to search relevant literature in electronic databases updated to May 1, 2015, and odds ratios (ORs) with 95 % confidence intervals (95 % CIs) were estimated. Funnel plots and Egger’s tests were conducted for the evaluation of publication bias, and heterogeneity and sensitivity were also analyzed. Finally, a total of 25 studies involving 1572 patients were included in the meta-analysis. Coincidentally, all these studies were conducted in Chinese population. It was found that MMP-2 expression was significantly associated with high-WHO grade gliomas (n?=?24, OR?=?6.54, CI?=?4.98–8.60; I ²?=?0 %, P?=?0.911) and poor overall survival (OS), while it did not correlate to age (n?=?2, OR?=?0.78, CI?=?0.35–1.74; I ²?=?0 %, P?=?0.621) and gender (n?=?2, OR?=?1.15, CI?=?0.51–2.62; I ²?=?0 %, P?=?0.995). Moreover, the results of the pooled analysis indicated that there was no association between TIMP-2 expression and the WHO grade of gliomas (n?=?7, OR?=?1.02, 95 % CI?=?0.68–1.54; I ²?=?71.4 %, P?=?0.002), but the ratio of MMP-2 and TIMP-2 (MMP-2/TIMP-2) rose with the increase of the WHO grade of gliomas. In conclusion, there was no correlation between TIMP-2 expression and the WHO grade of gliomas, while MMP-2 expression was potently associated with high-WHO grade of gliomas.     

Upregulation of microRNA-375 is associated with poor prognosis in pediatric acute myeloid leukemia

A genome-wide serum miRNA expression analysis previously showed the upregulation of microRNA-375 (miR-375) in acute myeloid leukemia (AML) patients compared with healthy controls. The aim of this study was to investigate the expression patterns and the prognostic relevance of miR-375 in pediatric AML. Expression levels of miR-375 in bone marrow mononuclear cells were detected by real-time quantitative PCR in a cohort of 106 patients with newly diagnosed pediatric AML. Expression levels of miR-375 in the bone marrow of pediatric AML patients were significantly higher than those in normal controls (P < 0.001). Then, miR-375 upregulation occurred more frequently in French–American–British classification subtype M7 than in other subtypes (P < 0.001). Regarding to cytogenetic risk, the expression levels of miR-375 in pediatric AML patients with unfavorable karyotypes were dramatically higher than those in intermediate and favorable groups (P = 0.002). Moreover, high miR-375 expression was significantly associated with shorter relapse-free survival (P < 0.001) and overall survival (P < 0.001) in pediatric AML patients. Multivariate analysis further identified miR-375 expression and cytogenetics risk as independent prognostic factors for both relapse-free survival and overall survival. In particular, the prognostic relevance of miR-375 expression was more obvious in the subgroup of patients with intermediate-risk cytogenetics. Our findings suggest for the first time that the upregulation of miR-375 may be one of the molecular mechanisms involved in the development and progression of pediatric AML. Since its correlation with poor relapse-free survival and overall survival, miR-375 may be a novel biomarker to improve the management of pediatric AML patients.     

Differential Expression of Circular RNAs in Glioblastoma Multiforme and Its Correlation with Prognosis

OBJECTIVE: The present study aimed to explore the expression profiles of circular RNAs (circRNAs) in glioblastoma multiforme (GBM) in an attempt to identify potential core genes in the pathogenesis of this tumor. METHODS: Differentially expressed circRNAs were screened between tumor tissues from five GBM patients and five normal brain samples using Illumina Hiseq. Bioinformatics analysis was used to analyze their potential function. CircBRAF was further detected in different WHO grades glioma tissues and normal brain tissues. Kaplan-Meier curves and multivariate Cox's analysis were used to analyze the association between circBRAF expression level and prognosis of glioma patients. RESULTS: A total of 1411 differentially expressed circRNAs were identified in GBM patients including 206 upregulated circRNAs and 1205 downregulated circRNAs. Differential expression of circRNAs was closely associated with the biological process and molecular function. The downregulated circRNAs were mainly associated with ErbB and Neurotrophin signaling pathways. Moreover, the expression level of circBRAF in normal brain tissues was significantly higher than that in glioma tissues (P < .001). CircBRAF was significantly lower in glioma patients with high pathological grade (WHO III & IV) than those with low grade (WHO I & II) (P < .001). Cox analysis revealed that high circBRAF expression was an independent biomarker for predicting good progression-free survival and overall survival in glioma patients (HR = 0.413, 95% CI 0.201-0.849; HR = 0.299, 95% CI 0.135-0.661; respectively). CONCLUSION: The present study identified a profile of dysregulated circRNAs in GBM. Bioinformatics analysis showed that dysregulated circRNAs might be associated with tumorigenesis and development of GBM. In addition, circBRAF could severe as a biomarker for predicting pathological grade and prognosis in glioma patients.     

脑胶质瘤组织CMTM1、ME2表达与临床病理特征和复发的关系研究

摘要 目的：探讨脑胶质瘤组织含CKLF样MARVEL跨膜结构域的蛋白1（CMTM1）、苹果酸酶2（ME2）表达与临床病理特征和复发的关系。方法：选取2018年1月～2021年1月徐州医科大学附属医院接受切除手术的92例脑胶质瘤患者，根据术后是否复发分为复发组和未复发组。采用免疫组化法检测脑胶质瘤组织和瘤旁组织CMTM1、ME2表达，分析二者与临床病理特征的关系，采用多因素Logistic回归分析脑胶质瘤患者术后复发的影响因素。结果：与瘤旁组织比较，脑胶质瘤组织中CMTM1、ME2阳性表达率升高（P＜0.05）。不同分化程度、世界卫生组织（WHO）中枢神经系统肿瘤分类脑胶质瘤组织中CMTM1、ME2阳性表达率比较，差异有统计学意义（P＜0.05）。随访2年，92例脑胶质瘤患者术后复发率为47.83%（44/92）。多因素Logistic回归分析显示，低分化、WHO中枢神经系统肿瘤分类Ⅲ～Ⅳ级、部分切除和CMTM1、ME2阳性表达为脑胶质瘤患者术后复发的独立危险因素（P＜0.05）。结论：脑胶质瘤组织中CMTM1、ME2阳性表达率升高，与分化程度、WHO中枢神经系统肿瘤分类等级和术后复发有关，可能成为脑胶质瘤患者术后复发的辅助评估指标。     

Stathmin 在微血管内皮细胞的表达与胶质瘤恶性程度关系

目的:检测Stathmin在正常脑组织及不同级别胶质瘤微血管内皮细胞中的表达情况。方法:利用结合CD105单克隆抗体的免疫磁珠内皮细胞分选系统特异性分选出68例胶质瘤微血管内皮细胞(其中低级别胶质瘤(WHO分级Ⅰ-Ⅱ)24例,高级别胶质瘤(WHO分级Ⅲ-Ⅳ)44例)和20例正常脑组织微血管内皮细胞。应用免疫组化、RT-PCR和Western blot检测Stathmin在胶质瘤微血管内皮细胞和正常脑组织微血管内皮细胞中的表达。结果:免疫组化证实Stathmin在正常脑组织微血管内皮细胞、低级别胶质瘤微血管内皮细胞和高级别胶质瘤微血管内皮细胞的表达百分率分别是20%,66%和95%(P<0.05)。RT-PCR和Western blot法检测显示,Stathmin在胶质瘤微血管内皮细胞中的表达明显增高。低级别胶质瘤组、高级别胶质瘤组分别与正常组比较,均有显著性差异(P<0.01);且低级别胶质瘤组与高级别胶质瘤组比较,有显著性差异(P<0.01),随着胶质瘤恶性程度的增加,Stathmin表达上调,具有统计学意义。结论:Stathmin在脑胶质瘤微血管内皮细胞中表达随肿瘤恶性程度增高而增加,可能为脑胶质瘤的生物治疗提供一个新靶点。