Overexpression of retinoic acid-induced protein 3 predicts poor prognosis for hepatocellular carcinoma

Aim

To investigate clinical significance of retinoic acid-induced protein 3 (RAI3) in hepatocellular carcinoma (HCC).

Methods

Expression of RAI3 at both mRNA and protein levels in tumor, para-tumor and normal liver tissues was detected in 106 HCC patients by real-time quantitative RT-PCR, Western blot and immunohistochemistry. Then, the correlation of RAI3 expression with clinicopathological characteristics and survivals of HCC patients was analyzed.

Results

Our data first found that RAI3 mRNA and protein expression were both significantly higher in HCC than in para-tumor (both P < 0.001) and normal liver tissues (both P < 0.001). The correlation analysis showed a positive correlation between RAI3 mRNA level and RAI3 protein level in HCC tissues (r = 0.8, P < 0.001). Immunohistochemistry data also revealed that overexpression of RAI3 was present in 73.6 % (78/106) of HCC tissues. In addition, high RAI3 protein expression was correlated with advanced TNM stage (P = 0.001), high serum AFP (P = 0.008), vascular invasion (P = 0.01) and tumor recurrence (P = 0.008). Moreover, HCC patients with overexpression of RAI3 had significantly shorter overall (P = 0.01) and disease-free survival (P = 0.01). Furthermore, multivariate analysis showed that overexpression of RAI3 was an independent prognostic factor for both overall (P = 0.02) and disease-free survival (P = 0.03) in HCC.

Conclusion

Our data for the first time provide a basis for the concept that overexpression of RAI3 may contribute to the malignant progression of HCC and predict poor prognosis for patients with this deadly disease after curative hepatectomy. RAI3 might be an important marker for tumor progression and prognosis, as well as a potential therapeutic target of HCC.     

EIF5A2在人肝细胞癌中的表达及其与术后生存期的关系

目的 检测真核翻译起始因子5A2(EIF5A2)在肝细胞癌(HCC)中的表达,探讨其与临床病理特征及预后的关系.方法 qRT-PCR和Western blot法分别检测12对新鲜HCC及癌旁非瘤组织中EIF5A2 mRNA和蛋白水平的表达;免疫组织化学检测284对HCC及癌旁非瘤组织中EIF5A2的表达水平,并分析其与...     

联合检测ANXA2和RACK1在肝细胞肝癌预后判断中的价值

  目的  联合检测膜联蛋白A2（ANXA2）和活化的蛋白激酶C的受体1（RACK1）在肝癌及癌旁组织中的表达及其预后价值。  方法  收集2010年1月至2011年12月南通大学附属医院行肝癌根治性切除术100例患者的石蜡标本。通过免疫组织化学染色检测ANXA2和RACK1在肝细胞癌中的表达,分析其与生存和复发时间的相关性,探讨两者联合表达在肝细胞癌中的预后价值。  结果  免疫组织化学结果提示ANXA2与RACK1的联合表达水平与肿瘤分化、TNM分期和脉管癌栓有关（均P<0.05）。在100例组织中,ANXA2在HCC组织中的表达（42%）明显高于邻近正常组织（11%,P<0.001）,RACK1在HCC组织中的表达（38%）明显高于邻近正常组织（18%,P=0.002）。ANXA2 表达强度与 AFP（P=0.027）、肿瘤大小（P=0.018）、脉管癌栓（P=0.035）、肿瘤分化（P<0.001）和 TNM 分期（P<0.001）有相关性,与性别、年龄、肿瘤数目、HBV 感染、Child 分级和肝硬化等因素无相关（均P>0.05）。RACK1 表达与肿瘤分化（P<0.001）、脉管癌栓（P=0.009）和 TNM 分期（P<0.001）有关,与其他临床特征无关（均P>0.05）;双变量Kendall检验结果显示,ANXA2和RACK1的表达水平存在显著正相关（Z=0.419,P<0.01）。ANXA2或RACK1的高表达提示有早期复发的倾向,在 12 例早期复发患者（复发时间<12 个月）中, 11 例患者高表达ANXA2（11/12,91.7%）和RACK1（11/12,91.7%）。Kaplan-Meier分析结果提示,ANXA2-/RACK1-患者的总生存率显著高于ANXA2+/RACK1-、ANXA2-/RACK1+和ANXA2+/RACK1+患者;ANXA2+/RACK1+患者较ANXA2+/RACK1-、ANXA2-/RACK1+和ANAX2-/RACK1-患者更易早期复发。  结论  ANXA2和RACK1是预测肝癌患者生存和复发的独立因素,两者联合检测更加有助于预后的判断。      

Validity of plasma macrophage migration inhibitory factor for diagnosis and prognosis of hepatocellular carcinoma

We performed our study to determine whether plasma macrophage migration inhibitory factor (MIF) levels have diagnostic and prognostic value in hepatocellular carcinoma (HCC) patients. Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were used to measure the expression of MIF in plasma and tissues, respectively. Plasma MIF levels were compared to HCC occurrence, clinicopathological features and outcomes. Cutpoints of plasma MIF levels for diagnosis and prognosis were, respectively, determined by receiver operating characteristic analysis and X-tile in corresponding training cohort, and then were confirmed in the validation cohort. The postoperative plasma MIF levels of HCC patients were detected in an independent cohort (80 HCC patients). As a result, MIF expression in situ was mainly observed in the cytoplasm of HCC cells. Intratumoral MIF expression was positively correlated with plasma MIF levels (r = 0.759, p < 0.001). Compared to serum α-fetoprotein (AFP), plasma MIF had a higher diagnostic value for discrimination of HCC from controls at 35.3 ng/ml. With determined cutpoints, plasma MIF levels demonstrated a significant association with overall survival (OS) and disease-free survival (DFS) of HCC patients even in patients with normal serum AFP levels and Tumor Node Metastasis (TNM) stage I. In addition, the plasma MIF levels were identified as an independent factor for OS [hazard ratio (HR) = 1.754; p = 0.012] and DFS (HR = 2.121; p < 0.001). Plasma MIF levels decreased markedly within 30 days after tumor resection (p < 0.001). Therefore, plasma MIF levels have potential as a diagnostic and prognostic factor for HCC.     

LRG1 expression indicates unfavorable clinical outcome in hepatocellular carcinoma

Leucine-rich-alpha-2-glycoprotein1 (LRG1) is a novel oncogene-associated protein which has been clarified vital to the progression of human cancers, but its role in hepatocellular carcinoma (HCC) remains unclear. Here, we showed that the expression of LRG1 was noticeably increased in HCC tissues, compared to the nontumorous tissues. High LRG1 expression was significantly associated with tumor size (P = 0.004), tumor differentiation (P = 0.010), TNM stage (P < 0.001) and vascular invasion (P = 0.019). Kaplan-Meier analysis showed that LRG1 expression was closely correlated to overall survival and disease-free survival in a training cohort of 474 patients with HCC. The correlation was further validated in an independent cohort of 303 HCC patients. The prognostic implication of LRG1 was confirmed by stratified survival analyses. Multivariate Cox regression model indicated LRG1 as an independent poor prognostic indicator for overall survival (Hazard ratio = 1.582, 95% confident interval: 1.345–1.862, P < 0.001) and disease-free survival (Hazard ratio = 1.280, 95% confident interval: 1.037–1.581, P = 0.022) in HCC. In vitro data showed that LRG1 markedly promoted cell migration but has no effect on cell proliferation. Collectively, our data show that LRG1 is markedly up-regulated and serves as an independent factor of poor outcomes in HCC. Our study therefore provides a promising biomarker for prognostic prediction in clinical management of HCC.     

Decreased expression of cytochrome P450 2E1 is associated with poor prognosis of hepatocellular carcinoma

Cytochrome P450-2E1 (CYP2E1) is one of the major hepatic enzymes involved in the metabolism of procarcinogen. Our study aimed to investigate the differential expression level of CYP2E1 and its clinicopathological significance in hepatocellular carcinoma (HCC). CYP2E1 revealed low level of expression in 70% of the tumor tissues, when compared to the adjacent nontumor tissues, at both mRNA and protein levels. The low expression of CYP2E1 was significantly correlated with the aggressive tumor phenotype, including poor differentiation status (by the Edmondson grading system) (p=0.038), absence of tumor capsule (p=0.030) and younger age of the patients (p=0.002). Multivariate analysis indicated that CYP2E1 expression level and pTNM stage were independent prognostic factors for disease-free survival. CYP2E1 was also shown to have a differential expression level in different liver tissues. The level of CYP2E1 was significantly higher in nontumor tissues from HCC patients compared to the intermediate level in cirrhosis livers from noncancer patients and normal livers from healthy persons. Tumor tissues were shown to have the lowest expression level. In conclusion, our results have shown that CYP2E1 is upregulated in the nontumor tissue and downregulated in tumor tissue, which is associated with aggressive tumor type and poor prognosis of the patients. It suggested that the differential expression of CYP2E1 may play an important role in HCC tumorigenesis.     

Expression of microRNA-218 and its Clinicopathological and Prognostic Significance in Human Glioma Cases

Background: MicroRNAs are a class of noncoding RNAs which regulate multiple cellular processes duringtumor development. The purpose of this report is to investigate the clinicopathological and prognostic significanceof miR-218 in human gliomas. Materials and Methods: Quantitative RT-PCR (qRT-PCR) was conducted todetect the expression of miR-218 in primary normal human astrocytes, three glioma cell lines and 98 pairedglioma and adjacent normal brain tissues.Associations of miR-218 with clinicopathological variables of gliomapatients were statistically analyzed. Finally, a survival analysis was performed using the Kaplan-Meier methodand Cox’s proportional hazards model. Results: The expression level of miR-218 in primary normal humanastrocytes was significantly higher than that in glioma cell lines (p<0.01). Also, the expression level of miR-218in glioma tissues was significantly downregulated in comparison with that in the adjacent normal brain tissues(p<0.001). Statistical analyses demonstrated that low miR-218 expression was closely associated with advancedWHO grade (p=0.002) and low Karnofsky performance score (p=0.010) of glioma patients. Kaplan-Meier analysiswith the log-rank test showed that patients with low-miR-218 expression had poorer disease-free survival andoverall survival (p=0.0045 and 0.0124, respectively). Multivariate analysis revealed that miR-218 expressionwas independently associated with the disease-free survival (p=0.009) and overall survival (p=0.004) of gliomapatients. Conclusions: Our results indicate that miR-218 is downregulated in gliomas and that its status mightbe a potential valuable biomarker for glioma patients.     

Mina53与CBX8在肝细胞肝癌中的表达及其与临床病理特征和预后的关系

目的 探讨Mina53与CBX8在肝细胞肝癌中的表达,并分析两者与肝细胞肝癌患者临床病理特征及预后的关系。方法 收集121例肝细胞肝癌患者术后切除标本制作组织芯片,采用免疫组织化学PV6000法检测Mina53与CBX8在肝细胞肝癌及相应癌旁相对正常组织中的表达,应用SPSS23.0软件对数据进行统计分析。结果 Mina53、CBX8在肝细胞肝癌中的表达水平高于癌旁相对正常组织（均P<0.001）。Mina53表达与肿瘤大小、被膜侵犯、脉管侵犯、病理分级、TNM分期有关（均P<0.05）;CBX8表达与乙肝表面抗原（HBsAg）、肿瘤大小、被膜侵犯、TNM分期有关（均P<0.05）。肝细胞肝癌中Mina53与CBX8表达呈正相关（r=0.574, P<0.01）。Mina53与CBX8均高表达患者的OS和DFS较Mina53或CBX8高表达者和两者均低表达者更短（均P<0.001）。多因素分析显示,Mina53、CBX8的表达水平是肝细胞肝癌患者术后OS和DFS的独立预后影响因素（P<0 . 0 5 ） 。结论 Mina53及CBX8在肝细胞肝癌组织中高表达, 可能与肝细胞肝癌的发生发展和浸润转移有关,Mina53和CBX8高表达提示患者预后不良,联合检测Mina53和CBX8有助于肝细胞肝癌的预后判断。     

IQGAP2 inactivation through aberrant promoter methylation and promotion of invasion in gastric cancer cells

Invasion and metastases of cancer cells are the main causes of treatment failure in cancer. IQ motif-containing GTPase activating protein 1 (IQGAP1), plays pivotal roles in intercellular adhesion, migration, invasion and metastases in various cancer cells. However, the role of another family member, IQGAP2, in carcinogenesis remains unknown. Here, we investigated IQGAP2 functions in gastric cancers. We found that IQGAP2 protein expression was lost in 5 of the 9 gastric cancer cell lines. Through analysis by the methylation-specific PCR, aberrant IQGAP2 methylation was detected in 3 gastric cancer cell lines. IQGAP2 mRNA was found to be activated after 5-aza-2'-deoxycytidine treatment of the methylation-positive cells. Moreover, IQGAP2 methylation was detected in 28 of the 59 (47%) primary gastric cancer tissues, but not in 12 normal gastric mucosa samples. Immunohistochemical staining revealed that 7 of the 8 (88%) gastric cancer tissues without methylation signals displayed IQGAP2 expression, whereas among 10 with methylation signals none expressed IQGAP2 (p = 0.0002), indicating that IQGAP2 methylation is highly associated with loss of the IQGAP2 expression in the primary gastric cancer tissues as well as gastric cancer cell lines. Furthermore, IQGAP2 methylation was also associated with tumor invasion and a poor prognosis. IQGAP2 knockdown with small interfering RNA increased the invasive capacity of a gastric cancer cell line. These results suggest that silencing of IQGAP2 by promoter methylation may contribute to gastric cancer development.     

NRP-1在肝细胞癌组织中的表达及其临床意义

目的 明确神经纤毛蛋白质1(NRP-1)在肝细胞癌(HCC)组织中的表达情况及其临床意义.方法 收集151例HCC组织和89例正常肝组织标本,应用免疫组织化学染色法检测其中NRP-1蛋白的表达情况.单因素及多因素统计分析NRP-1表达与HCC患者临床病理指标的关系,并以生存分析比较不同NRP-1表达水平患者的生存情况.结果 失访或随访期间因非HCC疾病死亡的病例共11例,最终进入研究的有效病例为140例.NRP-1在HCC组织和正常肝组织中的阳性表达率分别为65.00％、35.96％,差异有统计学意义(x2=18.843,P＜0.001).按照NRP-1的表达水平,将140例HCC患者分为阴性表达组49例,阳性表达组91例.单因素分析结果显示,NRP-1在HCC中的表达与肿瘤数目(x22=8.025,P=0.005)、TNM分期(x2=26.467,P ＜0.001)、分化程度(x2=15.296,P ＜0.001)、门脉侵袭(x2=9.054,P=0.003)以及肝静脉侵袭(x2=5.928,P=0.015)有关.多因素分析结果显示,TNM分期(OR=1.392,95％ CI为1.121 ～1.730,x2=8.950,P=0.003)、分化程度(OR=1.469,95％ CI为1.102 ～1.958,x2 =6.862,P =0.009)、门脉侵袭(OR=1.829,95％ CI为1.157 ～ 2.893,x2=6.665,P=0.010)及肝静脉侵袭(OR =2.161,95％ CI为1.172 ～3.987,x2=6.084,P=0.014)是NRP-1表达的影响因素.NRP-1阴性组HCC患者的中位生存时间显著长于阳性组患者(44个月∶23个月),差异有统计学意义(x2=21.922,P＜0.001).结论 NRP-1在HCC组织中呈过表达趋势,与HCC的恶性程度密切相关,其表达增高提示患者预后不良.     

A novel prognostic biomarker SPC24 up-regulated in hepatocellular carcinoma

SPC24 is an important component of the nuclear division cycle 80 (Ndc80) kinetochore complex, which plays an essential role in the coupling of kinetochore to spindle microtubules (MTs) and the accurate segregation of chromosomes during mitosis. However, the functional role of SPC24 in hepatocellular carcinoma (HCC) remains unknown. Here, we detected the expression of SPC24 in HCC and analyzed its association with clinicopathologic features and prognosis of HCC patients. The expression of SPC24 mRNA was investigated in 212 cases of paired HCC and adjacent liver tissues by quantitative real-time PCR (qRT-PCR) and in the tissues of 20 HCC patients by semi-quantitative RT-PCR. Additionally, the expression of SPC24 protein was detected in 69 cases of HCC by immunohistochemistry (IHC) or in 2 cases of HCC tissues by Western-blotting. Furthermore, small interfering RNA (siRNA)-mediated silencing of SPC24 was employed in SMMC7721 and HepG2 human HCC cells to investigate cell proliferation, invasion and apoptosis. Survival curves were plotted using the Kaplan-Meier method, and differences in survival probability were obtained using the log-rank test. Independent predictors associated with disease-free survival (DFS) and overall survival (OS) were analyzed using the Cox proportional-hazards regression model. In this study, we showed that SPC24 was noticeably increased in HCC tissues compared to normal adjacent noncancerous tissues, at both mRNA and protein levels. High expression of SPC24 was significantly correlated with alpha-fetoprotein (AFP) (p = 0.044), median size (p = 0.030), tumor number (p = 0.019), and Barcelona-Clinic Liver Cancer (BCLC) stage (p = 0.015). Kaplan-Meier analysis showed that the DFS and OS of high SPC24 expression group was significantly shorter than that of low SPC24 expression group (p < 0.001; p = 0.001; respectively). The prognostic impact of SPC24 was further confirmed by stratified survival analysis. Importantly, multivariate analysis identified SPC24 upregualtion (p = 0.001), PVTT (p = 0.007), size of tumor > 5 cm (p < 0.001) as independent risk factors of DFS after resection, and SPC24 upregualtion (p < 0.001), PVTT (p = 0.029), size of tumor > 5 cm (p = 0.002), recurrence (p < 0.001) as independent prognostic factors for the OS of HCC patients. Additionally, siRNA-mediated silencing of SPC24 dramatically suppressed cell growth, adhesion, invasion and increased apoptosis in HCC cells. In conclusion, these results showed for the first time that SPC24 expression was significantly up-regulated in HCC, which may act as a novel prognostic biomarker for patients suffering from this deadly disease. Additionally, silence of SPC24 inhibiting HCC cell growth indicated that SPC24 may be a promising molecular target for HCC therapy.     

Prognostic Value of Matrix Metalloproteinase-1/ Proteinase-Activated Receptor-1 Signaling Axis in Hepatocellular Carcinoma

Matrix metalloproteinase-1 (MMP-1) is proposed to be involved in both tumor cell invasion and metastasis. MMP-1 proteolytically activates protease activated receptor-1 (PAR-1), which also plays an important role in tumor development and progression. However, it is currently unknown whether MMP-1 activation of PAR-1 has relevance to the progression of hepatocellular carcinoma (HCC). To address this problem, we investigate the clinicopathological and prognostic value of MMP-1/PAR-1 signaling axis in HCC. Immunohistochemistry assay was used to determine the expression of MMP-1 and PAR-1 proteins in normal and HCC tissues. The correlations of MMP-1 and PAR-1 expression with clinicopathological parameters were assessed by Chi-squared test. Patient survival and their differences were determined by Kaplan-Meier method and log-rank test. Cox regression was adopted for multivariate analysis of prognostic factors. MMP-1 and PAR-1 immunoreactivities were negative or low in normal liver tissues, but high in HCC tissues. PAR-1 expression was significantly correlated with that of MMP-1 (r?=?0.896, p?P?P?P?P?相似文献   

PD-1在肝细胞癌肿瘤浸润淋巴细胞中的表达及与预后的相关性

背景与目的:程序性死亡[蛋白]-1(programmed death-1,PD-1)在调节外周免疫耐受中发挥重要作用,PD-1在肝细胞癌(hepatocellular carcinoma,HCC)肿瘤浸润淋巴细胞中的表达状态与效应细胞CD8+T淋巴细胞的关系尚不清楚,探讨HCC肿瘤浸润淋巴细胞中PD-1的表达及预后意义...     

Upregulation of vasohibin-1 expression with angiogenesis and poor prognosis of hepatocellular carcinoma after curative surgery

Vasohibin-1 has recently been found and is known as an endogenous angiogenesis inhibitor, but the role of vasohibin-1 in hepatocellular carcinoma (HCC) is unknown. This study investigated the expression pattern of vasohibin-1, its correlation with clinicopathological features, and its potential role in tumor angiogenesis and prognosis of HCC. Expression of vasohibin-1, vascular endothelial growth factor-A (VEGF-A), and intratumoral microvessel density (MVD, labeled by CD34) were assessed by immunohistochemistry in 117 HCC specimens and adjacent nontumor liver tissues (ANLT). Correlation between vasohibin-1 and VEGF-A, MVD, and clinicopathological features was then investigated. Prognostic value of these factors was determined using Kaplan-Meier analysis and a Cox proportional hazards regression model. Cytoplasm high expression of vasohibin-1 was detected in 38.5% (45/117) of the HCC tissues, which was significantly higher than that in 16.2% (19/117) of ANLT (P?相似文献   

Tumor Associated Glycoprotein-72 is a Novel Marker for Poor Survival in Hepatocellular Carcinoma

To investigate the relationship of tumor associated glycoprotein-72 (TAG-72) expression with clinicopathological features in hepatocellular carcinoma (HCC) patients. Sixty pairs of HCC and paracarcinomatous (PCLT) tissues, and 10 nomral liver (NL) tissues were collected for Western blot analysis, and 244 pairs of HCC and PCLT tissues were collected for immunohistochemistry analysis. TAG-72 protein expression was elevated significantly in HCC tissues compared with PCLT and NL tissues. Its increased expression was correlated with TNM stage, Edmondson-Steiner grade, vein invasion and multiple tumor nodes. It is noteworthy that the HCC patients with high TAG-72 expression had shorter overall survival and disease-free survival than the patients with low expression. Multivariate Cox regression analysis revealed that TAG-72 expression was an independent prognostic factor for HCC patients. The current study demonstrated for the first time that the increased expression of TAG-72 was correlated with poor survival in patients with HCC, indicating that TAG-72 is a novel prognostic marker for HCC.     

Prognostic significance of BMP7 as an oncogene in hepatocellular carcinoma

This study aims to evaluate the association between BMP7 tissue expression and patient prognosis in hepatocellular carcinoma (HCC). The expression of BMP7 mRNA in HCC was characterized using real-time PCR and 30 pairs of fresh frozen HCC tissues and corresponding noncancerous tissues. BMP7 protein expression in HCC was confirmed using immunohistochemistry on a tissue microarray chip. Finally, BMP7 expression was correlated with conventional clinicopathological features of HCC and patient outcome. The expression of BMP7 mRNA and protein in HCC cells was much higher than in normal hepatic cells. Our results showed that the high expression of BMP7 in HCC was related to tumor size (p?<?0.001), histological differentiation (p?=?0.041), serum AFP (p?=?0.007), and tumor stage (p?<?0.001). Kaplan–Meier survival analysis showed that a high-expression level of BMP7 resulted in a significantly poor prognosis of HCC patients. Multivariate analysis revealed that BMP7 expression level was an independent prognostic parameter for the overall survival rate of HCC patients. These findings provide evidence that a high-expression level of BMP7 serves as a biomarker for poor prognosis for HCC. Thus, we speculate that BMP7 may be a potential target of antiangiogenic therapy for HCC.     

FGFR1和MMP3在食管鳞状细胞癌中的表达及临床意义

目的:观察成纤维细胞成长因子受体1(fibroblast growth factor receptor1,FGFR1)和基质金属蛋白酶3(matrix metalloproteinase 3,MMP3)基因和蛋白在食管鳞癌、癌旁及正常食管组织中的表达情况,探讨它们与食管鳞癌患者临床病理特征之间的关系.方法:采用RT-qPCR、Western blot和免疫组织化学染色检测78例食管鳞癌组织(鳞癌组)、35例食管鳞癌癌旁组织(癌旁组)及35例正常食管组织(正常组)中FGFR1和MMP3 mRNA及蛋白的表达,并分析其与肿瘤临床病理特征之间的关系.结果:FGFR1和MMP3 mRNA在食管鳞癌组表达水平显著高于癌旁组和正常组,差异具有统计学意义(P＜0.05).在癌旁组和正常组表达差异无统计学意义(P＞0.05).FGFR1和MMP3蛋白在食管鳞癌组中的表达率和表达水平明显高于癌旁组和正常组,差异具有统计学意义(P＜0.05).在癌旁组及正常组表达率及表达水平差异均无统计学意义(P＞0.05).FGFR1和MMP3蛋白在食管鳞癌中的表达与患者性别、年龄、肿瘤分化程度无关(P＞0.05),而与肿瘤浸润深度、淋巴结是否转移及TNM分期相关(P＜0.05).食管鳞癌中,FGFR1和MMP3的蛋白表达呈正相关(r=0.303,P＜0.05).结论:FGFR1和MMP3在食管鳞癌中均高表达,两者可能与食管癌的侵袭和转移有关.