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Background: ADAMTS5 has different roles in multiple types of cancers and participates in various molecular mechanisms. However, the prognostic value of ADAMTS5 in patients with hepatocellular carcinoma (HCC) still remains unclear. We carried the study to evaluate the prognostic value and identified underlying molecular mechanisms in HCC. Methods: Firstly, the association of ADAMTS5 expression and clinicopathological parameters was evaluated by in GSE14520. Next, ADAMTS5 expression in HCC was performed using GSE14520, GSE36376, GSE76427 and The Cancer Genome Atlas (TCGA) profile. Furthermore, Kaplan-Meier analysis, Univariate and Multivariate Cox regression analysis, subgroup analysis was performed to evaluate the prognostic value of ADAMTS5 in HCC. Finally, GO enrichment analysis, gene set enrichment analysis (GSEA) and weighted gene co-expression network analysis (WGCNA) were performed to revealed underlying molecular mechanisms. Result: The expression of ADAMTS5 was positively correlated with the development of HCC. Next, high ADAMTS5 expression was significantly associated with poorer survival (all P < 0.05) and the impact of ADAMTS5 on all overall survival (OS), disease-free survival (DFS), relapse-free survival (RFS), disease specific survival (DSS) and progression free interval (PFI) was specific for HCC among other 29 cancer types. Subgroup analysis showed that ADAMTS5 overexpression was significantly associated with poorer OS in patients with HCC. Finally, ADAMTS5 might participate in the status conversion from metabolic-dominant to extracellular matrix-dominant, and the activation of ECM-related biological process might contribute to high higher mortality risk for patients with HCC. Conclusion: ADAMTS5 may play an important role in the progression of HCC, and may be considered as a novel and effective biomarker for predicting prognosis for patients with HCC.

Background Zinc-finger E-box binding homeobox 1 (ZEB-1) plays crucial roles in epithelial-to-mesenchymal transition during tumor carcinogenesis. Published studies have examined the potential value of ZEB-1 as a biomarker for the prognosis of cancer. Nevertheless, the prognostic significance of ZEB-1 in human solid tumor remains inconclusive. Therefore, we performed the present meta-analysis to evaluate the prognostic value of ZEB-1 in patients with solid tumors. Methods The 13 included studies (1616 patients) were exact electronic searched from Web of Science, PubMed and EBSCO until September 2018. Pooled hazard ratios (HR) and the corresponding 95% confidence intervals (CI) for overall survival (OS) were analyzed through random or fixed effects models. Univariate and multivariate analyses were independently performed. Subgroup analyses, heterogeneity and publication bias were investigated to further enhance reliability. Results This research indicated that elevated expression of ZEB-1 significantly predicted worse OS in patients with solid tumors. In the univariate analysis, the pooled HR for OS was 1.66 (95% CI: 1.45–1.90; P  < 0.01). Meanwhile, in multivariate analysis, the pooled HR for OS was 2.28 (95% CI: 1.58–3.30; P  < 0.01). Begg’s funnel plot and Begg’s test did not show evidence of significant publication bias, both in univariate analysis and multivariate analysis. Conclusions High expression of ZEB-1 was associated with poorer OS, suggesting that ZEB-1 may be a potential biomarker for the prediction of prognosis, and a novel therapeutic target in human solid tumors.

Background Additional studies comparing laparoscopic gastrectomy (LG) versus open gastrectomy (OG) for advanced gastric cancer (AGC) have been published, and it is necessary to update the systematic review of this subject. Objective We conducted the meta-analysis to find some proof for the use of LG in AGC and evaluate whether LG is an alternative treatment for AGC. Method Randomized controlled trials (RCT) and high-quality retrospective studies (NRCT) compared LG and OG for AGC, which were published in English between January 2010 and May 2019, were search in PubMed, Embase, and Web of Knowledge by three authors independently and thoroughly. Some primary endpoints were compared between the two groups, including intraoperative time, intraoperative blood loss, harvested lymph nodes, first flatus, first oral intake, first out of bed, post-operative hospital stay, postoperative morbidity and mortality, rate of disease recurrence, and 5-year over survival (5-y OS). Besides, considering for this 10-year dramatical surgical material development between 2010 and 2019, we furtherly make the same analysis based on recent studies published between 2016 and 2019. Result Thirty-six studies were enrolled in this systematic review and meta-analysis, including 5714 cases in LAG and 6094 cases in OG. LG showed longer intraoperative time, less intraoperative blood loss, and quicker recovery after operations. The number of harvested lymph nodes, hospital mortality, and tumor recurrence were similar. Postoperative morbidity and 5-y OS favored LG. Furthermore, the systemic analysis of recent studies published between 2016 and 2019 revealed similar result. Conclusion A positive trend was indicated towards LG. LG can be performed as an alternative to OG for AGC.

Objective Lung cancer with the highest incidence and mortality in the world. Immune checkpoint inhibitors (ICIs), can bring long-term survival benefits to patients, but also can bring immune-related adverse events (irAEs) in some patients during therapy. Therefore, the aim of this study was to investigate the predictive effect of peripheral blood WBC, NLR, sATP CD4 and nATP CD4 on irAEs in advanced non-small cell lung cancer (NSCLC). Methods Clinical data of 112 patients with advanced NSCLC who were treated with PD -1/PD -L1 inhibitor in the Fifth Affiliated Hospital of Guangzhou Medical University from December 15, 2019 to April 30, 2023 were retrospectively analyzed. These patients were divided into the irAEs group (n = 27) and non-irAEs group (n = 85). The clinical data of the two groups were compared. Receiver operating characteristic (ROC) curves were drawn to determine the threshold value of baseline peripheral blood parameters to predict the occurrence of irAEs. Multivariate logistic regression analysis was used to explore the relationship between peripheral blood markers and the incidence of irAEs. Results The patient characteristics have no significant difference between irAEs and non-irAEs group. But the baseline peripheral blood WBC, sATP CD4 and nATP CD4 of patients in the irAEs group were higher than those in the non-irAEs group ( p  < 0.05), and the NLR in irAEs group was similar to in the non-irAEs group ( p  = 0.639).Univariate analysis showed that high WBC, sATP CD4 and nATP CD4 may the risk factors for the occurrence of irAEs ( p  < 0.05). Multivariate logistic regression analysis showed that high sATP CD4 and nATP CD4 were independent risk factors for the occurrence of irAEs ( p  < 0.05). The best critical values of WBC, sATP CD4 and nATP CD4 before treatment for predicting the occurrence of irAEs were 8.165 × 10 9 cells/L (AUC = 0.705) ,484.5 ng/mL (AUC = 0.777), and 156 ng/mL (AUC = 0.840), respectively. Conclusions sATP CD4 and nATP CD4 were independent risk factors for the occurrence of irAEs in advanced NSCLC patients. This discovery provides a new method to predict the occurrence of irAEs in patients. Based on the prediction results, corresponding treatment measures can be taken to reduce the incidence of adverse events.

Due to the complicated molecular and cellular heterogeneity in hepatocellular carcinoma (HCC), the morbidity and mortality still remains high level in the world. However, the number of novel metabolic biomarkers and prognostic models could be applied to predict the survival of HCC patients is still small. In this study, we constructed a metabolic gene signature by systematically analyzing the data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and International Cancer Genome Consortium (ICGC). Differentially expressed genes (DEGs) between tumors and paired non-tumor samples of 50 patients from TCGA dataset were calculated for subsequent analysis. Univariate cox proportional hazard regression and LASSO analysis were performed to construct a gene signature. The Kaplan-Meier analysis, time-dependent receiver operating characteristic (ROC), Univariate and Multivariate Cox regression analysis, stratification analysis were used to assess the prognostic value of the gene signature. Furthermore, the reliability and validity were validated in four types of testing cohorts. Moreover, the diagnostic capability of the gene signature was investigated to further explore the clinical significance. Finally, Go enrichment analysis and Gene Set Enrichment Analysis (GSEA) have been performed to reveal the different biological processes and signaling pathways which were active in high risk or low risk group. Ten prognostic genes were identified and a gene signature were constructed to predict overall survival (OS). The gene signature has demonstrated an excellent ability for predicting survival prognosis. Univariate and Multivariate analysis revealed the gene signature was an independent prognostic factor. Furthermore, stratification analysis indicated the model was a clinically and statistically significant for all subgroups. Moreover, the gene signature demonstrated a high diagnostic capability in differentiating normal tissue and HCC. Finally, several significant biological processes and pathways have been identified to provide new insights into the development of HCC. The study have identified ten metabolic prognostic genes and developed a prognostic gene signature to provide more powerful prognostic information and improve the survival prediction for HCC.

Breast carcinoma (BRCA) is the most common carcinoma among women worldwide. Despite the great progress achieved in early detection and treatment, morbidity and mortality rates remain high. In the present study, we make a systematic analysis of BRCA using TCGA database by applying CIBERSORT and ESTIMATE computational methods, uncovered CD3D as a prognostic biomarker by intersection analysis of univariate COX and protein–protein interaction (PPI). It revealed that high CD3D expression was strongly associated with poor survival of BRCA, based on The Cancer Genome Atlas (TCGA) database and online websites. Gene Set Enrichment Analysis (GSEA) revealed that the high CD3D expression group was mainly enriched for the immune-related pathways and the low CD3D expression group was mainly enriched for metabolic-related activities. Based on CIBERSORT analysis, the difference test and correlation test suggested that CD3D had a strong correlation with T cells, particularly CD8 + T cells, which indicated that CD3D up-regulation may increase T cell immune infiltration in the TME and induce antitumor immunity by activating T lymphocytes. Furthermore, the correlation analysis showed that CD3D expression had a strongly positive correlation with immune checkpoints, which indicating that the underlying mechanism involves CD3D mediated regulation of T cell functions in BRCA, and single cell RNA-seq analysis revealed that CD3D correlate with CD8 + T cells and it is itself highly expressed in CD8 + T cells. In summary, we identified a prognostic biomarker CD3D in BRCA, which was associated with lymphocyte infiltration, immune checkpoints and could be developed for innovative therapeutics of BRCA.

Background Hepatitis B virus (HBV) X protein (HBx) is a type of oncogenic protein involved in the progression of hepatocellular carcinoma (HCC) via interacting with host genes. Dysregulation of microRNAs (miRNAs) has been observed in HCC. This study aimed to investigate the role of HBx protein in the regulation of miR-19a, miR-122 and miR-223, and examine if these miRNAs involve in progression of malignant hepatocytes. Methods Quantitative real time PCR (qRT-PCR) was used to measure the expression of miR-19a, miR-122 and miR-223 in patient samples and in HepG2 cells transfected with HBx or 1.3 fold HBV genome and also in HepG2.2.15 cells, which stably produces HBV. Their target mRNAs and proteins-PTEN, cyclin G1 and c-myc were measured by qRT-PCR and western blot, respectively. The effect of miR-19a, miR-122 and miR-223, and their respective target genes, on cell proliferation was analyzed using 5-ethynyl-2-deoxyuridine incorporation and MTT assay. Results MiR-19a showed an up-regulation in HBV-positive HCC patients compared to healthy controls and HBV-negative HCC patients, while miR-122 and miR-223 showed a down-regulation compared to healthy controls, and miR-122 in HBV-positive HCC patients was also down-regulated when compared to HBV-negative HCC patients. MiR-19a was found to be up-regulated in HepG2 cells transfected with HBx or 1.3 fold HBV genome, but down-regulated in HepG2.2.15 cells. MiR-122 and miR-223 were down-regulated in HBx or 1.3 fold HBV transfected HepG2 cells as well as in HepG2.2.15 cell. Their target mRNAs and corresponding proteins-PTEN was down-regulated, while cyclin G1 and c-myc were found to be up-regulated. Modulated expression of miR-19a, miR-122 and miR-223 enhanced cell proliferation of HBx-transfected HepG2 cells, and rescue experiment further showed that their target genes-PTEN, cyclin G1and c-myc involved in cell proliferation of HBx-transfected HepG2 cells. Conclusions The expression of miR-19a, miR-122 and miR-223 were differentially regulated by HBx protein, the differential expression of miR-19a, miR-122 and miR-223 plays an important role in cell proliferation of HCC. This study provides new insight into understanding how HBx protein interacts with miRNAs and subsequently regulates host function.

Purpose: Using the gastric cancer cell line SGC7901 and gastric cancer stem cell (CSC-G), we conducted this study to investigate the role of cancer stem cells in invasion, metastasis and tumor angiogenesis. Methods: Stem cell markers (OCT4, SOX2, C-Myc and Klf4) expression was detected by RT-PCR and Western blotting. The proliferation, migration, invasion abilities, L-OHP and 5-FU resistance, angiogenesis were assessed using in vitro spherical clone formation assays, plate cloning experiments, transwell migration, transwell invasion, drug resistance, scratch-wound migration, ring formation assay, and their tumorigenic and ability were assessed using a tumor formation experiment in mice. Results: Compared with the SGC7901, the expression of Oct4, Sox2, Klf4 and CD44 mRNA was significantly higher in CSC-G, the mRNA relative expression of E-cadherin in CSC-G was lower than SGC7901, while the expression of c-Myc did not significantly change. The proliferation, drug resistance, migration, and invasion abilities were significantly higher in CSC-G, and the tumorigenic ability in mice was also significantly higher. Conclusion: The proliferation, drug resistance, migration, invasion, and tumorigenic abilities of CSC-G significantly were higher than SGC7901. CSC-G plays important roles in proliferation, migration, invasion, and tumorigenicity.

Using the gastric cancer cell line SGC7901, we constructed a cell line that overexpressed octamer-binding protein 4 (Oct4) and SRY-box 2 (Sox2) to explore the stem cell oncological and biological characteristics of these cells and to elucidate the mechanisms of Oct4 and Sox2 in cancer. A lentiviral vector containing the Sox2 gene was constructed and transfected into a gastric cancer cell line overexpressing Oct4 (SGC7901-Oct4) to obtain a stably transfected cell line (SGC7901-Oct4-Sox2). Oct4 and Sox2 expression was detected by RT-PCR and Western blotting. The proliferation, drug resistance, migration, and invasion abilities of the cells were assessed using in vitro (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium), drug resistance, scratch-wound migration, transwell migration, transwell invasion, and spherical clone formation assays, and their tumorigenic ability was assessed using a tumor formation experiment in mice. Compared with the control group, the expression of Oct4, Sox2, CD44, and E-cadherin was significantly higher in the group that overexpressed Oct4 and Sox2, while the expression of c-Myc and Klf4 did not significantly change. The proliferation, drug resistance, migration, and invasion abilities were significantly enhanced in the overexpression group, and the tumorigenic ability in mice was also significantly enhanced, with significantly increased tumor size and weight. The proliferation, drug resistance, migration, invasion, and tumorigenic abilities of SGC7901 cells overexpressing Oct4 and Sox2 were significantly improved. Oct4 and Sox2 play important roles in the proliferation, migration, invasion, and tumorigenicity of gastric cancer cells, and the two genes may be synergistic to a certain degree.

Cisplatin is a vital chemotherapy regimen for gastric cancer (GC), while partial response is observed (approximately 40%) because of drug resistance. Thus, it is urgent to improve drug sensitivity to improve the therapeutic effect of cisplatin on GC. The study was performed to explore the synergistic effect of decitabine and cisplatin in GC. Cancer and matched adjacent tissues from patients with GC were obtained and quantitative real-time PCR (qRT-PCR), Western blot and immunohistochemistry were performed to evaluate Sox2 expression level. Methylation-specific PCR (MSP) was performed to assess the effect of 5-aza-2'-deoxycytidine (5-Aza-CdR) on Sox2 promoter. Cell proliferation assay, scratch-wound migration assay and Transwell invasion ability were performed to assess the effect of 5-Aza-CdR on proliferation, migration and invasion ability. Meantime, the effect of 5-Aza-CdR was also investigated in gastric cell lines BGC-823 and nude mouse xenograft tumor model. Finally, the anti-cancer effect of decitabine, cisplatin and their combination treatment were investigated in a BGC-823 and nude mouse xenograft tumor model, Sox2 methylation level, Sox2 expression of BGC-823 and xenograft tumors were analyzed by MSP, qRT-PCR and Western blot. Sox2 expression was significantly associated with different differentiated degrees, depth of invasion (0.0011), lymph node metastasis (0.0013), and TNM stage (0.0002). Next, methylation inhibitor 5-Aza-CdR restored Sox2 expression to promote proliferation, migration and invasion in vitro and in vivo. Finally, cisplatin and decitabine was found to be synergistic to inhibit proliferation of xenograft tumors. Likewise, cisplatin and decitabine were also synergistic to induce Sox2 DNA demethylation to promote Sox2 mRNA and protein expression in BGC-823 and xenograft tumors. Cisplatin and decitabine could be synergistic to induce Sox2 DNA demethylation to promote expression of the Sox2 gene, which exerted an anti-tumor effect on GC. It may suggest an insight for innovative therapeutics of GC.