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.     

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。     

CDKN1B Val 109 Gly variant is not related to risk of prostate cancer

Association between CDKN1B gene Val 109 Gly polymorphism and prostate cancer (PCa) susceptibility has been investigated in several studies but with inconsistent conclusions. We adopted odds ratios (ORs) and 95% confidence intervals (CIs) to assess the correlation between CDKN1B Val 109 Gly variant and PCa susceptibility. Moreover, we used in-silico tools to evaluate the relationship of CDKN1B expression and overall survival (OS) or disease free survival (DFS) time in PCa patients. The overall results demonstrated no association of the CDKN1B variant on PCa risk [allelic contrast (OR = 0.78, 95% CI = 0.45 − 1.35, P_{heterogeneity} = 0.038); GV vs VV (OR = 0.83, 95% CI = 0.56 − 1.25, P_{heterogeneity} = 0.253); GG vs VV (OR = 0.48, 95% CI = 0.23 − 1.01, P_{heterogeneity} = 0.161); GG+GV vs VV (OR = 0.75, 95% CI = 0.52 −1.08, P_{heterogeneity} = 0.132) and GG vs GV+VV (OR = 0.63, 95% CI = 0.25 − 1.11, P_{heterogeneity} = 0.152)]. In subgroup analysis by ethnicity and source of control, we also identified similar results. In-silico results showed that expression of CDKN1B was decreased in PCa tissue, especially in less advanced PCa (Gleason score = 6 or 7). No significant difference of OS or DFS time was indicated between the low and high expression of CDKN1B. Our present study showed evidence that CDKN1B Val 109 Gly variant is not related to PCa risk. Future studies with large sample size are needed to confirm this correlation in more details.     

Lysosomal-Associated Protein Transmembrane 4 Beta-35 Overexpression Is a Novel Independent Prognostic Marker for Gastric Carcinoma

ObjectiveThe purpose of this work was to analyze the relationships between the expression status of Lysosomal-associated protein transmembrane-4 beta 35 (LAPTM4B-35) in cancerous tissues and clinicopathological characteristics and prognosis of the patients with gastric carcinoma (GC).MethodsThe GC samples from 157 patients in a discovery cohort and 148 patients in a testing cohort with follow-up data were used to validate the feasibility of expression of LAPTM4B-35 protein in predicting GC prognosis. Immunohistochemical staining was used to determine the expression of LAPTM4B-35 protein in precancerous gastric lesions and gastric carcinomas. The correlation between the expression of LAPTM4B-35 and clinicopathologic characteristics of patients with gastric carcinoma was analyzed using chi-square test. Univariate and multivariate analyses were performed to determine the association between LAPTM4B-35 expression and prognosis.ResultsLAPTM4B-35 expression was increased steadily in sequential stages of precancerous gastric lesions. Positive LAPTM4B-35 expression was more frequently detected in patients with distant metastasis (P = 0.023) and III+IV TNM stages (P = 0.042) in the discovery cohort. Kaplan-Meier survival curves and univariate analysis showed that expression of LAPTM4B-35 had a significant impact on overall survival of patients with gastric carcinoma in discovery cohort (P<0.001) and testing cohort (P = 0.001). LAPTM4B-35 expression was an independent prognostic indicator for the overall survival of patients with gastric carcinoma in both cohorts.ConclusionsThe present research demonstrated that LAPTM4B-35 over-expression was an independent factor in gastric carcinoma prognosis. LAPTM4B gene may be a useful target of interventions slowing the progression of precancerous gastric lesions and a new therapy method to improve the prognosis of gastric carcinoma.     

Preoperative albumin-to-globulin ratio predicts survival in patients with non-small-cell lung cancer after surgery

The prognostic value of the preoperative albumin-to-globulin ratio (AGR) has not been investigated in non-small-cell lung cancer (NSCLC). Therefore, we aimed to assess the clinical applicability of the preoperative AGR to predict the prognosis in patients with NSCLC. We retrospectively enrolled 545 patients with stage I/II/III NSCLC who underwent surgery at our institution. The cutoff value for preoperative AGR was calculated by using a receiver operating characteristic curve analysis. A low AGR was associated with several clinicopathological variables related to tumor progression. In the multivariate analyses, the preoperative AGR was identified as an independent prognostic factor for disease-free survival (DFS; P = 0.003) and overall survival (OS; P = 0.005). For patients with stage II and III with a preoperative AGR ≤ 1.43, the surgery plus chemotherapy group had a significantly longer DFS and OS than the surgery alone group (P = 0.002 and P = 0.001, respectively); however, a significant difference in DFS and OS between these two groups was not observed in patients with stage II and III with an AGR > 1.43 (P = 0.808 and P = 0.842, respectively). The preoperative AGR is an independent, significant predictor of DFS and OS in patients with NSCLC. Our results also demonstrate that the preoperative AGR might be a predictive marker of the therapeutic effect of postoperative chemotherapy in patients with stage II and III NSCLC.     

Clinical and prognostic effects of CDKN2A,CDKN2B and CDH13 promoter methylation in ovarian cancer: a study using meta-analysis and TCGA data

Abstract

Background: Promoter methylation of tumour suppressor genes (TSGs) CDKN2A, CDKN2B and CDH13 has been reported in ovarian cancer. However, the clinicopathological characteristics and prognostic role of CDKN2A, CDKN2B and CDH13 promoter methylation in ovarian carcinoma remained unclear.

Methods: The pooled odds ratio (OR) or hazard ratios (HRs) with their 95% confidence intervals (95% CIs) were calculated in this meta-analysis. The Cancer Genome Atlas data were obtained to confirm the role of CDKN2A, CDKN2B and CDH13 methylation in ovarian cancer.

Results: CDKN2A, CDKN2B and CDH13 promoter methylation was higher in ovarian cancer than in normal ovarian tissues. CDH13 promoter methylation was correlated with tumour histology (serous vs. non-serous type: OR?=?0.33, p?=?0.031). CDKN2A promoter methylation was not linked to overall survival (OS), but it was correlated with a poor prognosis in progression-free survival (HR?=?1.55, p?=?0.004). TCGA data showed no correlation between CDKN2A, CDKN2B and CDH13 methylation and OS as well as disease-free survival (DFS).

Conclusions: CDKN2A, CDKN2B and CDH13 promoter methylation may correlate with the increased risk of ovarian cancer. CDKN2A promoter methylation may be an independent prognostic biomarker for predicting progression-free survival.     

Loss of circadian clock gene expression is associated with tumor progression in breast cancer

Several studies suggest a link between circadian rhythm disturbances and tumorigenesis. However, the association between circadian clock genes and prognosis in breast cancer has not been systematically studied. Therefore, we examined the expression of 17 clock components in tumors from 766 node-negative breast cancer patients that were untreated in both neoadjuvant and adjuvant settings. In addition, their association with metastasis-free survival (MFS) and correlation to clinicopathological parameters were investigated. Aiming to estimate functionality of the clockwork, we studied clock gene expression relationships by correlation analysis. Higher expression of several clock genes (e.g., CLOCK, PER1, PER2, PER3, CRY2, NPAS2 and RORC) was found to be associated with longer MFS in univariate Cox regression analyses (HR<1 and FDR-adjusted P < 0.05). Stratification according to molecular subtype revealed prognostic relevance for PER1, PER3, CRY2 and NFIL3 in the ER+/HER2- subgroup, CLOCK and NPAS2 in the ER-/HER2- subtype, and ARNTL2 in HER2+ breast cancer. In the multivariate Cox model, only PER3 (HR = 0.66; P = 0.016) and RORC (HR = 0.42; P = 0.003) were found to be associated with survival outcome independent of established clinicopathological parameters. Pairwise correlations between functionally-related clock genes (e.g., PER2-PER3 and CRY2-PER3) were stronger in ER+, HER2- and low-grade carcinomas; whereas, weaker correlation coefficients were observed in ER- and HER2+ tumors, high-grade tumors and tumors that progressed to metastatic disease. In conclusion, loss of clock genes is associated with worse prognosis in breast cancer. Coordinated co-expression of clock genes, indicative of a functional circadian clock, is maintained in ER+, HER2-, low grade and non-metastasizing tumors but is compromised in more aggressive carcinomas.     

Expression and Prognostic Value of miR-486-5p in Patients with Gastric Adenocarcinoma

MicroRNA (miR)-486-5p expression is often reduced in human cancers. However, its expression in gastric carcinoma and its relation to clinicopathological features and prognosis are unclear. Tissue microarrays were constructed from 84 patients with gastric adenocarcinoma (GC) who were undergoing radical resection. miR-486-5p expression was detected by miRNA-locked nucleic acid in situ hybridization, and its correlations with clinicopathological features and overall survival were analyzed. Bioinformatic studies predict that fibroblast growth factor 9 (FGF9) is a potential target gene of miR-486-5p. miR-486-5p was mainly located in the cytoplasm of GC cells and neighboring normal tissues. Compared with paracancerous normal tissue, miR-486-5p expression was decreased in 63.1% (53/84) of the GC samples, increased in 32.1% (27/84) and unchanged in 4.8% (4/84). FGF9 expression was decreased in 69.0% (58/84) of GC samples and increased in 31.0% (26/84) compared with normal paracancerous tissues using immunohistochemical analysis. Low or unchanged miR-486-5p expression (P = 0.002), tumor stage (P = 0.001), tumor status (P = 0.001), node status (P = 0.001), tumor size (P = 0.004), and depth of tumor invasion (P = 0.013) were significant negative prognostic predictors for overall survival in patients with GC. After stratification according to American Joint Committee on Cancer (AJCC) stage, low/unchanged miR-486-5p expression remained a significant predictor of poor survival in stage II (P = 0.024) and stage III (P = 0.003). Cox regression analysis identified the following predictors of poor prognosis: tumor status (hazard ratio [HR], 7.19; 95% confidence interval [CI], 1.75–29.6; P = 0.006), stage (HR, 2.62; 95%CI, 1.50–4.59; P = 0.001), lymph node metastasis (HR, 2.52; 95% CI, 1.27–4.99; P = 0.008), low/unchanged miR-486-5p (HR, 2.47; 95% CI, 1.35–4.52; P = 0.003), high level of FGF9 (HR, 2.41; 95% CI, 1.42–4.09; P = 0.001) and tumor size (HR, 2.50; 95% CI, 1.30–4.82; P = 0.006). Low or unchanged expression of miR-486-5p compared with neighboring normal tissues was associated with a poor prognosis, while high expression was associated with a good prognosis in GC. miR-486-5p may thus be useful for evaluating prognosis and may provide a novel target treatment in patients with GC.     

大肠癌组织中TS和COX-2的表达及其与患者无病生存期的关系

目的:探讨大肠癌患者癌组织中环氧化酶-2(COX-2)、胸苷酸合成酶(TS)的表达及其与患者无病生存期的关系。方法:筛选我院收治的大肠癌根治术患者,选择无病生存期大于48个月者30例和无病生存期小于48个月者29例。采用免疫组化法检测大肠癌组织中COX-2和TS的表达,并分析其与患者无病生存期的关系。结果:49例结直肠癌患者中,TS的阳性表达率为91.84%,COX-2的阳性表达率为77.55%。不同无病生存期的大肠癌患者TS的表达水平比较无统计学差异(P=0.646)。COX-2在无病生存期48个月的患者癌组织中表达水平明显低于无病生存期48个月的患者,差异有统计学意义(P=0.033)。结论:COX-2与大肠癌患者的无病生存期显著相关,可能成为预测大肠癌预后的参考指标。     

Presence of cancer cells in gastric lavage of gastric cancer patients as an indicator of advanced disease,predictor of tumour aggressive phenotype and independent prognostic factor for poor survival: The endoluminal metastatic pathway of gastric cancer and GL0/GL1 classification

Objective

As of 2017, the pathobiology of gastric cancer (GC) is far from fully understood; consequently, new methods of basic and advanced research have been proposed and tested. The presence (GL1) vs absence (GL0) of malignant cells exfoliated in gastric lavage (GL) of GC patients was formerly evaluated with diagnostic intent but not for staging or prognostic assessment. We investigated this hitherto unreported application of cytopathology.

Methods

GL was preoperatively and prospectively collected from 80 GC patients and cytologically analysed. The results were compared with the classic clinicopathological features of GC and related to survival. The prognostic value of GL1 was assessed through univariate and multivariate analyses.

Results

GL1 was detected in 36 samples (45%) and correlated with advanced tumour depth (T3‐T4), lymphatic metastasis (N+), distant metastasis (M1) and lymphovascular invasion (LVI1; P=.0317, .0024, .003 and .0028, respectively). Overall survival (OS) was significantly shorter for GL1 (23 months) vs GL0 patients (42 months; P=.005) and GL1 vs GL0 T1 subjects (12.6 vs 47.8 months, P=.0029). Univariate analysis revealed that GL1, N+, M1, LVI1 and advanced stage were significantly associated with OS. Multivariate analysis assessed GL1 as the only independent prognostic factor for worse OS and progression‐free survival (P=.0013 and .0107).

Conclusions

In the present study, GL1 was correlated with advanced disease, aggressive tumour behaviour and poor prognosis. Although additional studies are needed to confirm these findings, the GL0/GL1 classification can be applied to GC patients to achieve higher accuracy in staging, prognostic stratification and treatment selection.     

Development of a novel gene signature in patients without Helicobacter pylori infection gastric cancer

Gastric cancer (GC) is one of the most fatal common cancers in worldwide. Helicobacter pylori (H. pylori) infection is closely related to the development of GC, although the mechanism is still unclear. In our study, we aim to develop a robust messenger RNA (mRNA) signature associated with H. pylori (-) GC that can sensitively and efficiently predict the prognostic. The RNA-seq expression profile and corresponding clinical data of 598 gastric cancer samples and 63 normal samples obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus database. Using gene set enrichment analysis H. pylori (+) GC and H. pylori (-) GC patients and normal samples to select certain genes for further analysis. Using univariate and multivariate Cox regression model to establish a gene signature for predicting the overall survival (OS). Finally, we identified G2/M related seven-mRNA signature (TGFB1, EGF, MKI67, ILF3, INCENP, TNPO2, and CHAF1A) closely related to the prognosis of patients with H. pylori (-) GC. The seven-mRNA signature was identified to act as an independent prognostic biomarker by stratified analysis and multivariate Cox regression analysis. It was also validated on two test groups from TCGA and GSE15460 and shown that patients with high-risk scores based on the expression of the seven mRNAs had significantly shorter survival times compared to patients with low-risk scores (P < .0001). In this study, we developed a seven-mRNA signature related to G2/M checkpoint from H. pylori (-) GCs that as an independent biomarker potentially with a good performance in predicting OS and might be valuable for the clinical management for patients with GC.     

Prognostic implication and functional annotations of Rad50 expression in patients with prostate cancer

Increasing evidence has shown that Rad50, a protein involved in the DNA damage repair process, significantly correlated with tumor prognosis. This study focused on Rad50 expression in tumor samples and its prognostic value for patients with prostate cancer (PCa). In this study, significantly elevated Rad50 expression in PCa tissues compared to normal tissues (P < .01). Five independent Oncomine databases validated significant differential expression of Rad50 (P < .001). Hence, 80 patients with PCa from Fudan University Shanghai Cancer Center (FUSCC) and 351 patients with PCa with available protein expression data from The Cancer Genome Atlas (TCGA) were included to investigate the survival benefit. Univariate and multivariate Cox regression analyses were performed to investigate the significance of clinicopathological factors on disease-free survival (DFS) and overall survival (OS). Kaplan-Meier analysis indicated that elevated Rad50 protein expression levels significantly correlated with unfavorable DFS (P = .005) in the FUSCC cohort and poorer OS (P = .04) in TCGA cohort. Furthermore, coregulation analysis of proteins indicated that 76 coregulated proteins were associated with Rad50, while 11 most highly involved hub proteins, including Rad50, MRE11A, DUT, POLR3A, MCM3AP, RECQL, PNPT1, RANBP3, DDX1, SNRPB, and UGN, were significantly coregulated in the protein-protein interaction network. Functional enrichment analysis consecutively indicated significant functions and signaling pathways including DNA replication, spliceosome, DNA geometric change, homologous recombination, and G2M checkpoint. This study first reveals that elevated Rad50 expression is significantly associated with aggressive progression and poor survival for patients with PCa. Together, these data suggest that Rad50 may act as an oncoprotein, guide the molecular diagnosis, and may shed light on novel individual therapeutic strategies for progressive PCa patients.     

Pre-treatment systemic immune-inflammation index is a useful prognostic indicator in patients with breast cancer undergoing neoadjuvant chemotherapy

The systemic immune-inflammation index (SII = N × P/L) based on neutrophil (N), platelet (P) and lymphocyte (L) counts is used to predict the survival of patients with malignant tumours and can fully reflect the balance between host inflammatory and immune status. This study is conducted to explore the potential prognostic significance of SII in patients with breast cancer undergoing neoadjuvant chemotherapy (NACT). A total of 262 patients with breast cancer received NACT were enrolled in this study. According to the receiver operating characteristic curve, the optimal cut-off value of SII was divided into two groups: low SII group (<602 × 10⁹/L) and high SII group (≥602 × 10⁹/L). The associations between breast cancer and clinicopathological variables by SII were determined by chi-squared test or Fisher's exact test. The Kaplan-Meier plots and log-rank test were used to determine clinical outcomes of disease-free survival (DFS) and overall survival (OS). The prognostic value of SII was analysed by univariate and multivariate Cox proportional hazards regression models. The toxicity of NACT was accessed by National Cancer Institute Common Toxicity Criteria (NCICTC). According to univariate and multivariate Cox regression survival analyses, the results showed that the value of SII had prognostic significance for DFS and OS. The patients with low SII value had longer DFS and OS than those with high SII value (31.11 vs 40.76 months, HR: 1.075, 95% CI: 0.718-1.610, P = .006; 44.47 vs 53.68 months, HR: 1.051, 95% CI: 0.707-1.564, P = .005, respectively). The incidence of DFS and OS in breast cancer patients with low SII value was higher than that in those patients with high SII value in 3-, 5- and 10-year rates. The common toxicities after NACT were haematological and gastrointestinal reaction, and there were no differences by SII for the assessment of side effects of neoadjuvant chemotherapy. Meanwhile, the results also proved that breast cancer patients with low SII value and high Miller and Payne grade (MPG) survived longer than those breast cancer with high SII value and low MPG grade. In patients without lymph vessel invasion, these breast cancer patients with low SII value had better prognosis and lower recurrence rates than those with high SII value. Pre-treatment SII with the advantage of reproducible, convenient and non-invasive was a useful prognostic indicator for breast cancer patients undergoing neoadjuvant chemotherapy and is a promising biomarker for breast cancer on treatment strategy decisions.     

A novel autophagy-related lncRNA survival model for lung adenocarcinoma

Long non-coding RNA (lncRNA) is an important regulatory factor in the development of lung adenocarcinoma, which is related to the control of autophagy. LncRNA can also be used as a biomarker of prognosis in patients with lung adenocarcinoma. Therefore, it is important to determine the prognostic value of autophagy-related lncRNA in lung adenocarcinoma. In this study, autophagy-related mRNAs-lncRNAs were screened from lung adenocarcinoma and a co-expression network of autophagy-related mRNAs-lncRNAs was constructed by using The Cancer Genome Atlas (TCGA). The univariate and multivariate Cox proportional hazard analyses were used to evaluate the prognostic value of the autophagy-related lncRNAs and finally obtained a survival model composed of 11 autophagy-related lncRNAs. Through Kaplan-Meier analysis, univariate and multivariate Cox regression analysis and time-dependent receiver operating characteristic (ROC) curve analysis, it was further verified that the survival model was a new independent prognostic factor for patients with lung adenocarcinoma. In addition, based on the survival model, gene set enrichment analysis (GSEA) was used to illustrate the function of genes in low-risk and high-risk groups. These 11 lncRNAs were GAS6-AS1, AC106047.1, AC010980.2, AL034397.3, NKILA, AL606489.1, HLA-DQB1-AS1, LINC01116, LINC01806, FAM83A-AS1 and AC090559.1. The hazard ratio (HR) of the risk score was 1.256 (1.196-1.320) (P < .001) in univariate Cox regression analysis and 1.215 (1.149-1.286) (P < .001) in multivariate Cox regression analysis. And the AUC value of the risk score was 0.809. The 11 autophagy-related lncRNA survival models had important predictive value for the prognosis of lung adenocarcinoma and may become clinical autophagy-related therapeutic targets.     

Effect of Fenofibrate on Adiponectin and Inflammatory Biomarkers in Metabolic Syndrome Patients

Adiponectin is an adipose‐secreted hormone with anti‐inflammatory properties mediated by inhibition of nuclear factor‐κB (NF‐κB) signaling. This study investigates whether fenofibrate alters adiponectin levels in patients with hypertriglyceridemia and the metabolic syndrome, and examines the association of adiponectin with circulating inflammatory markers and whole blood cytokine production. The effects of fenofibrate (160 mg/day) on adiponectin and other inflammatory markers were investigated in a 12‐week randomized, placebo‐controlled trial in 55 patients with hypertriglyceridemia (plasma triglycerides ≥1.7 mmol/l and <6.8 mmol/l), central obesity and other characteristics of the metabolic syndrome who were not receiving lipid‐altering therapies. In the fenofibrate group, adiponectin levels increased from 4.10 to 4.50 µg/ml (+7.7%); in the placebo group, adiponectin levels increased by 1.8%; (P = 0.0005). In multivariate models including age, gender, and waist circumference, there were inverse correlations between changes in adiponectin and vascular cell adhesion molecule‐1 (VCAM‐1) (r = −0.54, P < 0.0001) and intercellular adhesion molecule‐1 (ICAM‐1) (r = −0.57, P < 0.0001), and C‐reactive protein (CRP) (r = −0.40, P = 0.0041); lipopolysaccharide (LPS)‐stimulated production of tumor necrosis factor‐α (TNF‐α) (r = −0.30, P = 0.035), interleukin (IL)‐1β (r = −0.44, P = 0.0016), monocyte chemotactic protein‐1 (MCP‐1) (r = −0.46, P = 0.001), and macrophage inflammatory protein‐1α (MIP‐1α) (r = −0.45, P = 0.0012). Fenofibrate (160 mg/day) raised adiponectin levels in patients with hypertriglyceridemia and the metabolic syndrome. Changes in adiponectin were significantly and inversely associated with changes in multiple inflammatory markers. These data suggest that adiponectin may contribute to the anti‐inflammatory effects of fenofibrate.     

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.     

Identification of key lncRNAs in the carcinogenesis and progression of colon adenocarcinoma by co-expression network analysis

Colon adenocarcinoma (COAD) is one of the most common cancers, and its carcinogenesis and progression is influenced by multiple long non-coding RNAs (lncRNA), especially through the miRNA sponge effect. In this study, more than 4000 lncRNAs were re-annotated from the microarray datasets through probe sequence mapping to obtain reliable lncRNA expression profiles. As a systems biology method for describing the correlation patterns among genes across microarray samples, weighted gene co-expression network analysis was conducted to identify lncRNA modules associated with the five stepwise stages from normal colonic samples to COAD (n = 94). In the most relevant module (R² = −0.78, P = 4E-20), four hub lncRNAs were identified (CTD-2396E7.11, PCGF5, RP11-33O4.1, and RP11-164P12.5). Then, these four hub lncRNAs were validated using two other independent datasets including GSE20916 (n = 145) and GSE39582 (n = 552). The results indicated that all hub lncRNAs were significantly negatively correlated with the three-stage colonic carcinogenesis, as well as TNM stages in COAD (one-way analysis of variance P < 0.05). Kaplan-Meier survival curve showed that patients with higher expression of each hub lncRNA had a significantly higher overall survival rate and lower relapse risk (log-rank P < 0.05). In conclusion, through co-expression analysis, we identified and validated four key lncRNAs in association with the carcinogenesis and progression of COAD, and these lncRNAs might have important clinical implications for improving the risk stratification, therapeutic decision and prognosis prediction in COAD patients.     

Clinicopathological and prognostic value of lncRNA PANDAR expression in solid tumors: Evidence from a systematic review and meta-analysis

PANDAR (promoter of CDKN1A antisense DNA damage activated RNA) has been shown to be aberrantly expressed in many types of cancer. Considering conflicting data, the current study was aimed to assess its potential role as a prognostic marker in malignant tumors. A comprehensive literature search of PubMed, Medline, and Web of Science was performed to identify all eligible studies describing the use of PANDAR as a prognostic factor for different types of cancer. Data related to overall survival (OS) and clinicopathologic features were collected and analyzed. The pooled hazard ratio (HR) and odds radio (OR) with a 95% confidence interval (CI) were used to estimate associations. Ten original studies containing 1,231 patients were included. The results showed that in patients with cancer, high PANDAR expression is correlated with lymph node metastasis (LNM; OR = 2.57; 95% CI, 1.76–3.81; p < 0.001), tumor stage (OR = 2.90; 95% CI, 1.25–6.75; p = 0.013), and tumor size (OR = 1.79; 95% CI, 1.11–2.91; p = 0.018). However, sensitivity analysis further demonstrated a significant association between high PANDAR expression and OS, both in multivariate and univariate analysis models (pooled HR 2.01; 95% CI, 1.17–3.44 and pooled HR 2.62; 95% CI, 1.98–3.47, respectively), after omitting one study. These results suggested that PANDAR expression might be indicative of advanced disease and poor prognosis in patients with cancer. Further studies are necessary to determine the value of this risk stratification biomarker in clinical management of patients with cancer.     

High CCNB2 expression correlates with poor prognosis in hepatocellular carcinoma

Cyclin B2 (CCNB2), a member of the cyclin protein family, has a key role in the progression of G2/M transition. However, the clinical value of CCNB2 in hepatocellular carcinoma (HCC) is still unknown. The aim of our study is to identify the role of CCNB2 in HCC patients. Immunohistochemical analysis using tissue microarray (TMA) was employed to evaluate the expression of CCNB2 in HCC and the correlation between CCNB2 expression and clinicopathological features in HCC patients. The relationship between CCNB2 expression and the prognosis of HCC patients was analyzed using Oncomine and Kaplan-Meier Plotter online resources. High CCNB2 cytoplasmic expression was observed in 77.22% of patients with HCC, which was related to differentiation (P<0.001), tumor diameter (P=0.025), and hepatitis B virus infection (P=0.008). High CCNB2 nuclear expression was seen among 43.43% of cases, which was associated with differentiation (P=0.001). CCNB2 levels were inversely proportional to patient prognosis. The study suggests that CCNB2 expression could be an effective prognostic biomarker for HCC.     

Microarray-based identification of genes associated with prognosis and drug resistance in ovarian cancer

The outcome for patients with ovarian cancer (OC) is poor because of drug resistance. Therefore, identification of factors that affect drug resistance and prognosis in OC is needed. In the present study, we identified 131 genes significantly dysregulated in 90 platinum-resistant OC tissues compared with 197 sensitive tissues, of which 30 were significantly associated with disease-free survival (DFS; n = 16), overall survival (OS; n = 6), or both (n = 8) in 489 OC patients of the The Cancer Genome Atlas cohort. Of these 30 genes, 17 were significantly upregulated and 13 were downregulated in the 90 resistant tissues, and with one exception, all of the up-/downregulated genes in resistant tissues were predictors of shorter DFS or/and OS. LAX1, MECOM, and PDIA4 were independent risk factors for DFS, and KLF1, SLC7A11, and PDIA4 for OS; combining these genes provided more accurate predictions for DFS and OS than any of the genes used individually. We further verified downregulation of PDIA4 protein in 51 specimens of patients with OC (24 drug resistant’s and 27 sensitive’s), which confirmed that downregulated PDIA4 predicted DFS and OS. PDIA4 also consistently predicted OS in a larger sample of 1656 patients with OC. These 30 genes, particularly the PDIA4, could be therapeutic targets or biomarkers for managing OC.