Overexpression of B7H5/CD28H is associated with worse survival in human gastric cancer

Gastric cancer (GC) is a common malignancy with low 5‐year overall survival (OS). Recently, immune therapy has been used to treat cancer. B7H5 and CD28H are novel immune checkpoint molecules. However, the prognostic value of B7H5/CD28H expression in patients with GC remains unclear. In this study, seventy‐one patients diagnosed with GC were included in this study. Patients' GC tissues and matched adjacent tissue constructed a tissue microarray. The expression levels of B7H5 and CD28H were examined using immunohistochemistry. Correlations between the expression of B7H5 and CD28H and the clinical data were evaluated. We found that the expression of B7H5 and CD28H (both P = .001) were higher in GC tumour tissues than in adjacent noncancerous tissues. B7H5/CD28H expression acted as an independent predictive factor in the OS of patients with GC. High expression of B7H5 and CD28H predicted poor outcome. Patients in the B7H5+CD28H+ group had a lower 5‐year OS compared with patients in the B7H5?CD28? group (4.5% vs 55.6%, P = .001). A significant difference was found in the 5‐year OS between patients in the B7H5+CD28H? and B7H5+CD28H+ groups (33.5% vs 4.5%, P = .006). However, there was no correlation between B7H5 and CD28H expression (P = .844). Therefore, B7H5 and CD28H expression are up‐regulated in GC and are independent prognostic factors for overall survival in patients with GC. Although there was no correlation between B7H5 and CD28H expression, high expression of B7H5 and CD28H predicts poor prognosis, especially when both are highly expressed.     

Aldolase A as a prognostic factor and mediator of progression via inducing epithelial–mesenchymal transition in gastric cancer

Glycolysis is regarded as the hallmark of cancer development and progression, which involves a multistep enzymatic reaction. This study aimed to explore the clinicopathological significance and potential role of glycolytic enzyme aldolase A (ALDOA) in the carcinogenesis and progression of gastric cancer (GC). ALDOA was screened from three paired liver metastasis tissues and primary GC tissues and further explored with clinical samples and in vitro studies. The ALDOA protein level significantly correlated with a larger tumor diameter (P = .004), advanced T stage (P < .001), N stage (P < .001) and lymphovascular invasion (P = .001). Moreover, the expression of ALDOA was an independent prognostic factor for the 5‐year overall survival and disease‐free survival of patients with GC in both univariate and multivariate survival analyses (P < .05). Silencing the expression of ALDOA in GC cell lines significantly impaired cell growth, proliferation and invasion ability (P < .05). Knockdown of the expression of ALDOA reversed the epithelial–mesenchymal transition process. Mechanically, ALDOA could affect the hypoxia‐inducible factor (HIF)‐1α activity as demonstrated by the HIF‐1α response element–luciferase activity in GC cells. Collectively, this study revealed that ALDOA was a potential biomarker of GC prognosis and was important in the carcinogenesis and progression of human GC.     

Epigenetic silencing of DACH1 induces the invasion and metastasis of gastric cancer by activating TGF‐β signalling

Gastric cancer (GC) is the fourth most common malignancy in males and the fifth most common malignancy in females worldwide. DACH1 is frequently methylated in hepatic and colorectal cancer. To further understand the regulation and mechanism of DACH1 in GC, eight GC cell lines, eight cases of normal gastric mucosa, 98 cases of primary GC and 50 cases of adjacent non‐tumour tissues were examined. Methylation‐specific PCR, western blot, transwell assay and xenograft mice were used in this study. Loss of DACH1 expression correlated with promoter region methylation in GC cells, and re‐expression was induced by 5‐Aza‐2′‐deoxyazacytidine. DACH1 is methylated in 63.3% (62/98) of primary GC and 38% (19/50) of adjacent non‐tumour tissues, while no methylation was found in normal gastric mucosa. Methylation of DACH1 correlated with reduced expression of DACH1 (P < 0.01), late tumour stage (stage III/IV) (P < 0.01) and lymph node metastasis (P < 0.05). DACH1 expression inhibited epithelial–mesenchymal transition and metastasis by inhibiting transforming growth factor (TGF)‐β signalling and suppressed GC cell proliferation through inducing G2/M phase arrest. The tumour size is smaller in DACH1‐expressed BGC823 cell xenograft mice than in unexpressed group (P < 0.01). Restoration of DACH1 expression also sensitized GC cells to docetaxel. These studies suggest that DACH1 is frequently methylated in human GC and expression of DACH1 was controlled by promoter region methylation. DACH1 suppresses GC proliferation, invasion and metastasis by inhibiting TGF‐β signalling pathways both in vitro and in vivo. Epigenetic silencing DACH1 may induce GC cells' resistance to docetaxel.     

Long noncoding RNAs expression in gastric cancer

Long noncoding RNAs (lncRNAs) have been involved in the pathogenesis of several human cancers including gastric cancer. In the current study, we selected five lncRNAs namely NEAT1, TUG1, PANDA, UCA1, and GHET1 to assess their expressions in gastric cancer samples compared with adjacent noncancerous tissues (ANCTs) from the same patients. Some previous reports have shown contribution of these lncRNAs in gastric cancer. However, we aimed to explore their associations with patients’ clinicopathological data and their potential as diagnostic biomarkers. Significant associations were found between site of primary tumor and relative expression of all lncRNAs in cancer samples compared with ANCTs. Besides, GHET1 relative expression was associated with lymph node status. The diagnostic power of GHET1 was higher from other lncRNAs. Combination of GHET1, TUG1, UCA1, and PANDA increased the diagnostic power and significance (AUC = 0.8; P < 0.0001). The current study supports participation of lncRNAs in the pathogenesis of gastric cancer and highlights their potential as diagnostic biomarkers.     

Epigenetic inactivation of the novel candidate tumor suppressor gene ITIH5 in colon cancer predicts unfavorable overall survival in the CpG island methylator phenotype

Inter-α-trypsin inhibitor heavy chain 5 (ITIH5) is supposed to be involved in extracellular matrix stability and thus may play a key role in the inhibition of tumor progression. The current study is the first to analyze in depth ITIH5 expression as well as its potential clinical and functional impact in colon cancer. Based on 30 tumor and 30 adjacent normal tissues we examined ITIH5 mRNA expression and promoter methylation, whose significance was further validated by independent data sets from The Cancer Genome Atlas (TCGA) platform. In addition, ITIH5 protein expression was evaluated using immunohistochemistry. ITIH5 mRNA expression loss was significantly associated (P < 0.001) with hypermethylation of the ITIH5 promoter in primary colon tumors. In addition, treatment of tumor cell lines with demethylating (DAC) and histone acetylating (TSA) agents induced ITIH5 expression. In line, independent TCGA data revealed a significant expression loss of ITIH5, particularly in the MSI-high and CIMP-positive phenotype concordant with an increased ITIH5 hypermethylation in CIMP-positive colon tumors (P < 0.001). In proximal, i.e., right-sided tumors, abundant ITIH5 expression was associated with longer overall survival (OS, P = 0.049) and the CIMP-positive (P = 0.032) subgroup. Functionally, ITIH5 re-expression mediated a reduced proliferation in HCT116 and CaCo2 cells. In conclusion, our results indicate that ITIH5 is a novel putative tumor suppressor gene in colon cancer with a potential impact in the CIMP-related pathway. ITIH5 may serve as a novel epigenetic-based diagnostic biomarker with further clinical impact for risk stratification of CIMP-positive colon cancer patients.     

胞质分裂作用因子10在肺癌诊断及预后中的意义

摘要 目的：探讨胞质分裂作用因子10（Dock10）在肺癌组织及癌旁组织中的表达及其在肺癌预后及诊断中的意义。方法：选取2010年6月至2015年6月期间我院收治的肺癌患者98例,检测其肺癌组织及癌旁组织中Dock10的表达情况。分析Dock10表达与患者临床病理特征的关系。分析患者预后的影响因素。分析Dock10在肺癌诊断中的价值及其表达与患者预后的关系。结果：肺癌组织中Dock10 mRNA及蛋白表达水平、平均表达量均高于癌旁组织（P<0.05）。Dock10表达与肿瘤大小、TNM分期、分化程度有关（P<0.05）。COX比例风险回归分析结果显示,吸烟史、TNM分期、分化程度、Dock10表达均为肺癌患者预后的影响因素（P<0.05）。受试者工作特征（ROC）曲线分析结果显示Dock10诊断肺癌的曲线下面积及最佳诊断临界值分别为0.894、1.877 ng/mL,具有一定诊断价值。Dock10低表达患者的5年生存率高于Dock10高表达患者（P<0.05）。结论：Dock10对肺癌的临床诊断和预后具有一定意义,可能作为一种潜在的肺癌诊断和预后评估辅助指标。     

乙醛脱氢酶1和肿瘤坏死因子相关诱导凋亡配体在膀胱癌组织中的表达及其临床意义

目的:探讨乙醛脱氢酶1(ALDH-1)和肿瘤坏死因子相关诱导凋亡配体(TRAIL)在膀胱癌组织中的表达及其临床意义。方法:选取2015年3月到2018年1月在河北北方学院附属第一医院进行治疗的膀胱癌患者70例,收集其手术切除的癌组织和癌旁正常组织,采用免疫组化法检测癌组织和癌旁正常组织中ALDH-1、TRAIL表达情况,分析ALDH-1、TRAIL的表达与膀胱癌患者的临床病理特征的关系及癌组织中ALDH-1、TRAIL表达的相关性。结果:癌组织中的ALDH-1的阳性表达率高于癌旁正常组织,TRAIL的阳性表达率低于癌旁正常组织(P0.05)。膀胱癌患者的ALDH-1阳性表达率与年龄、性别、分化程度、肿瘤数量无关(P0.05),临床分期为T2-T3期、有淋巴结转移的膀胱癌患者ALDH-1阳性表达率高于临床分期为Ta-T1期、无淋巴结转移的膀胱癌患者(P0.05)。膀胱癌患者的TRAIL阳性表达率与年龄、性别、临床分期、淋巴结转移、肿瘤数量无关(P0.05),高分化的膀胱癌患者TRAIL阳性表达率高于中低分化的膀胱癌患者(P0.05)。Pearson相关性分析显示,癌组织中ALDH-1、TRAIL表达无明显的相关性(P0.05)。结论:膀胱癌组织中ALDH-1的表达偏高且与临床分期和淋巴结转移有关,TRAIL的表达偏低且与分化程度有关,但ALDH-1和TRAIL之间无相关性,需进一步探讨与研究。     

氨基酸转运载体SLC1A5在胃癌组织中的表达及其临床病理学意义

目的:研究氨基酸转运载体溶质载体家族1成员5(Solute Carrier Family 1 Member 5, SLC1A5)蛋白在胃癌组织中的表达情况,并探讨其与胃癌临床病理特征及预后的相关性。方法:收集进展期胃癌组织及对应癌旁组织90例,应用免疫组化技术检测SLC1A5在上述组织中的表达情况,并统计分析其表达与胃癌临床病理特征及预后的关系。同时通过基因数据库分析SLC1A5在胃癌组织和癌旁组织中表达情况及其对胃癌患者预后的影响。结果:与癌旁组织相比,胃癌组织中SLC1A5表达明显上调(P0.0001)。数据库研究也显示SLC1A5在胃癌组织中表达明显上调(GSE 65801,P=0.0046;GSE 63809,P0.0001;GSE 27342,P=0.0147)。胃癌组织中SLC1A5高表达与肿瘤大小(P0.05)、肿瘤浸润深度(P0.01)、淋巴结转移(P0.05)、TNM分期(P0.05)和Ki-67(P0.01)相关,而与年龄、性别、肿瘤位置及分化程度均无显著相关性(P0.05)。胃癌组织中SLC1A5表达强度与患者预后相关,表达越高,患者预后越差(总体生存率,P=0.0131;无复发生存率,P=0.0293)。数据库分析也显示SLC1A5高表达可明显缩短患者的总体生存期(GSE 14210,P=0.011;GSE 22377,P=0.0015)和无进展生存期(GSE 14210,P=0.0095;GSE 22377,P=0.0012)。结论:SLC1A5蛋白表达在胃癌组织中明显上调,且与肿瘤大小、肿瘤浸润深度、淋巴结转移及TNM分期有关。SLC1A5高表达与胃癌患者预后不良密切相关。     

Expression analysis of selected miR-206 targets from the transforming growth factor-β signaling pathway in breast cancer

Breast cancer as a molecularly heterogeneous malignancy is associated with dysregulation of several signaling pathways, including transforming growth factor-β (TGF-β) signaling. On the other hand, several recent studies have demonstrated the role of microRNAs (miRNAs) in breast cancer pathogenesis. In the current study, we performed a computerized search to find miR-206 target genes that are functionally linked to the TGF-β signaling pathway. We selected LEF1, Smad2, and Snail2 genes to assess their expression in 65 breast cancer samples and their adjacent noncancerous tissues (ANCTs) in correlation with expression levels of miR-206 as well as clinicopathological characteristics of patients. miR-206 was significantly downregulated in (Estrogen receptor) ER-positive breast cancer samples compared with their corresponding ANCTs. Association analysis between expression levels of genes and demographic features of patients showed significant association between expressions of SMAD2 and LEF1 genes and body mass index ( P values of 0.03 and 0.02, respectively). miR-206 low-expression levels were associated with TNM stage, mitotic rate, and lymph node involvement ( P values of 0.02, 0.01, and 0.01 respectively). In addition, SMAD2 high-expression levels were associated with HER2 status ( P = 0.02). Consequently, our data highlight the role of TGF-β signaling dysregulation in the pathogenesis of breast cancer and warrant further evaluation of miRNAs and messenger RNA coding genes in this pathway to facilitate detection of cancer biomarkers and therapeutic targets.     

LAPTM4B-35, a Cancer-Related Gene,Is Associated with Poor Prognosis in TNM Stages I-III Gastric Cancer Patients

Background

Lysosome-associated transmembrane protein 4β-35 (LAPTM4B-35), a member of the mammalian 4-tetratransmembrane spanning protein superfamily, has been reported to be overexpressed in several cancers. However the expression of LAPTM4B-35 and its role in the progression of gastric cancer (GC) remains unknown. The aim of this study was to investigate LAPTM4B-35 expression in GC, its potential relevance to clinicopathologic parameters and role of LAPTM4B-35 during gastric carcinogenesis.

Methods

In the present study, paraffin-embedded specimens with GC (n = 240, including 180 paired specimens) and 24 paired fresh frozen tissues were analyzed. qRT-PCR and immunohistochemistry (IHC) were used to analyze the expression of LAPTM4B-35 in GC. The effects of LAPTM4B-35 on GC cell proliferation, migration and invasion were determined by overexpression and knockdown assays.

Results

IHC showed that LAPTM4B-35 was expressed in 68.3% (123/180) of GC tissues, while in 16.1% (29/180) of their paired adjacent noncancerous gastric tissues (P = 0.000). LAPTM4B-35 mRNA levels in GC tissues were also significantly elevated when compared with their paired adjacent noncancerous tissues (P = 0.017). Overexpression of LAPTM4B-35 was significantly associated with degree of differentiation, depth of invasion, lymphovascular invasion and lymph node metastasis (P<0.05). Kaplan-Meier survival curves revealed that patients with LAPTM4B-35 expression had a significant decrease in overall survival (OS) in stages I-III GC patients (P = 0.006). Multivariate analysis showed high expression of LAPTM4B-35 was an independent prognostic factor for OS in stage I-III GC patients (P = 0.025).

Conclusion

These findings indicate that LAPTM4B-35 overexpression may be related to GC progression and poor prognosis, and thus may serve as a new prediction marker of prognosis in GC patients.     

Downregulation of <Emphasis Type="Italic">AKR1B10</Emphasis> expression in colorectal cancer

Colorectal cancer is one of the most common cancers in the world. Changes in AKR1B1 and AKR1B10 expression levels, whose diagnostic value was previously shown for several other cancer types, were studied in colorectal tumors. These genes encode aldose reductases, members of the aldo-keto reductase superfamily, which comprises enzymes capable to reduce a range of aromatic and aliphatic aldehydes and ketones. They are also involved in retinoid metabolism and carcinogenesis. AKR1B1 and AKR1B10 mRNA levels were compared in paired specimens of normal and colorectal tumor tissues using RT-PCR and quantitative real-time PCR. For the first time, the downregulation of these genes was demonstrated in colorectal carcinoma. AKR1B10 expression was decreased in most tumor specimens (88%, 65/74) even at the early stages, and in more than 60% of cases mRNA levels were decreased more than 10-fold. AKR1B1 mRNA levels were decreased in 10% of specimens. Therefore, these two structurally similar genes show quite different mRNA expression patterns in colorectal cancer, suggestive of their different functional roles in the intestine. Significant downregulation of AKR1B10 expression can be considered a potential diagnostic marker of colorectal cancer.     

卵巢癌组织ERCC1、Vimentin表达与临床病理特征及预后的关系分析

目的:探讨卵巢癌组织切除修复交叉互补基因(ERCC1)、波形蛋白(Vimentin)表达与临床病理特征及预后的关系。方法:选取2015年3月～2016年2月期间首都医科大学附属北京世纪坛医院收治的卵巢癌患者83例为研究对象,收集每位患者的卵巢癌组织样本、癌旁正常组织样本,采用免疫组化SP法对各组织标本中的ERCC1、Vimentin的阳性表达率、表达水平进行检测,并分析ERCC1、Vimentin表达与卵巢癌临床病理特征间的关系,并对患者进行统一的手术治疗,分析ERCC1、Vimentin阳性表达组与阴性表达组患者的预后。结果:卵巢癌组织的ERCC1、Vimentin的阳性表达率分别为54.22%(45/83)、69.88%(58/83),高于癌旁正常组织的9.64%(8/83)、20.48%(17/83),差异有统计学意义(P0.05)。卵巢癌组织的ERCC1、Vimentin的表达水平均高于癌旁正常组织(P0.05)。ERCC1、Vimentin的阳性表达率与卵巢癌患者的年龄、病灶直径、病理分型无关,而与卵巢癌肿瘤的临床分期、分化程度、淋巴结转移有关。ERCC1、Vimentin阳性表达组患者的无进展生存期(PFS)、总体生存期(OS)均短于ERCC1、Vimentin阴性表达组(P0.05)。结论:ERCC1、Vimentin的表达水平与卵巢癌的分期、分化程度、淋巴结转移有关,在卵巢癌的发生发展过程中起重要作用,ERCC1、Vimentin可能作为卵巢癌患者预后评估的参考指标。     

Overexpression of Circular RNA ciRS‐7 Abrogates the Tumor Suppressive Effect of miR‐7 on Gastric Cancer via PTEN/PI3K/AKT Signaling Pathway

Gastric cancer (GC) has one of the highest mortality rates of malignancies globally. Currently, ciRS‐7, a novel circular RNA, has emerged as a potential sponge for miR‐7. However, few studies on ciRS‐7 in GC have been performed. In this study, we investigated the clinical significance and function of ciRS‐7 in GC. First, the expression levels of ciRS‐7 in 102 primary GC tissues and the matched para‐carcinoma tissues were evaluated and the clinical relevance was confirmed in an independent validation cohort (n = 154). Second, the effects of ciRS‐7 on miR‐7, PTEN, and PI3K were evaluated. Finally, the function of ciRS‐7 in GC was analyzed with cell lines and nude mice. The expression of ciRS‐7 was significantly upregulated in GC tissues compared with the matched para‐carcinoma tissues (P = 0.0023), and the upregulation of ciRS‐7 was linked to poor survival in the testing (P = 0.0143) and validation cohort (P = 0.0061). Multivariate survival analysis revealed that ciRS‐7 was probably an independent risk factor of overall survival (P < 0.05). Furthermore, overexpression of ciRS‐7 blocked the miR‐7‐induced tumor suppression in MGC‐803 and HGC‐27 cells and led to a more aggressive oncogenic phenotype, via antagonizing miR‐7‐mediated PTEN/PI3K/AKT pathway. ciRS‐7 may act as a prospective prognostic biological marker and a promising therapeutic target for GC. J. Cell. Biochem. 119: 440–446, 2018. © 2017 Wiley Periodicals, Inc.