Downregulation of ABLIM3 confers to the metastasis of neuroblastoma via regulating the cell adhesion molecules pathway.

Neuroblastoma (NB) is the most prevalent extracranial solid tumor in pediatric patients, and its treatment failure often associated with metastasis. In this study, LASSO, SVM-RFE, and random forest tree algorithms, was used to identify the pivotal gene involved in NB metastasis. NB cell lines (SK-N-AS and SK-N-BE2), in conjunction with NB tissue were used for further study. ABLIM3 was identified as the hub gene and can be an independent prognostic factor for patients with NB. The immunohistochemical analysis revealed that ABLIM3 is negatively correlated with the metastasis of NB. Patients with low expression of ABLIM3 had a poor prognosis. High ABLIM3 expression correlated with APC co-stimulation and Type1 IFN response, and TIDE analysis indicated that patients with low ABLIM3 expression exhibited enhanced responses to immunotherapy. Downregulation of ABLIM3 by shRNA transfection increased the migration and invasion ability of NB cells. Gene Set Enrichment Analysis (GSEA) revealed that genes associated with ABLIM3 were primarily enriched in the cell adhesion molecules (CAMs) pathway. RT-qPCR and western blot analyses demonstrated that downregulation of ABLIM3 led to decreased expression of ITGA3, ITGA8, and KRT19, the key components of CAMs. This study indicated that ABLIM3 can be an independent prognostic factor for NB patients, and CAMs may mediate the effect of ABLIM3 on the metastasis of NB, suggesting that ABLIM3 is a potential therapeutic target for NB metastasis, which provides a novel strategy for future research and treatment strategies for NB patients.

Novel small molecule DMAMCL induces differentiation in rhabdomyosarcoma by downregulating of DLL1.

Rhabdomyosarcoma (RMS), a mesenchymal tumor occurring in the soft tissue of children, is associated with a defect in differentiation. This study unveils a novel anti-tumor mechanism of dimethylaminomicheliolide (DMAMCL), which is a water-soluble derivative of Micheliolide. First, we demonstrate that DMAMCL inhibits RMS cell growth without obvious cell death, leading to morphological alterations, enhanced expression of muscle differentiation markers, and a shift from a malignant to a more benign metabolic phenotype. Second, we detected decreased expression of DLL1 in RMS cells after DMAMCL treatment, known as a pivotal ligand in the Notch signaling pathway. Downregulation of DLL1 inhibits RMS cell growth and induces morphological changes similar to the effects of DMAMCL. Furthermore, DMAMCL treatment or loss of DLL1 expression also inhibits RMS xenograft tumor growth and augmented the expression of differentiation markers. Surprisingly, in C2C12 cells DMAMCL treatment or DLL1 downregulation also induces cell growth inhibition and an elevation in muscle differentiation marker expression. These data indicated that DMAMCL induced RMS differentiation and DLL1 is an important factor for RMS differentiation, opening a new window for the clinical use of DMAMCL as an agent for differentiation-inducing therapy for RMS treatment.

SESN1 functions as a new tumor suppressor gene via Toll-like receptor signaling pathway in neuroblastoma.

AIMS: Neuroblastoma (NB) is the most common extracranial solid tumor in children, with a 5-year survival rate of <50% in high-risk patients. MYCN amplification is an important factor that influences the survival rate of high-risk patients. Our results indicated MYCN regulates the expression of SESN1. Therefore, this study aimed to investigate the role and mechanisms of SESN1 in NB. METHODS: siRNAs or overexpression plasmids were used to change MYCN, SESN1, or MyD88's expression. The role of SESN1 in NB cell proliferation, migration, and invasion was elucidated. Xenograft mice models were built to evaluate SESN1's effect in vivo. The correlation between SESN1 expression and clinicopathological data of patients with NB was analyzed. RNA-Seq was done to explore SESN1's downstream targets. RESULTS: SESN1 was regulated by MYCN in NB cells. Knockdown SESN1 promoted NB cell proliferation, cell migration, and cell invasion, and overexpressing SESN1 had opposite functions. Knockdown SESN1 promoted tumor growth and shortened tumor-bearing mice survival time. Low expression of SESN1 had a positive correlation with poor prognosis in patients with NB. RNA-Seq showed that Toll-like receptor (TLR) signaling pathway, and PD-L1 expression and PD-1 checkpoint pathway in cancer were potential downstream targets of SESN1. Knockdown MyD88 or TLRs inhibitor HCQ reversed the effect of knockdown SESN1 in NB cells. High expression of SESN1 was significantly associated with a higher immune score and indicated an active immune microenvironment for patients with NB. CONCLUSIONS: SESN1 functions as a new tumor suppressor gene via TLR signaling pathway in NB.

Optimal combination of MYCN differential gene and cellular senescence gene predicts adverse outcomes in patients with neuroblastoma.

Introduction: Neuroblastoma (NB) is a common extracranial tumor in children and is highly heterogeneous. The factors influencing the prognosis of NB are not simple. Methods: To investigate the effect of cell senescence on the prognosis of NB and tumor immune microenvironment, 498 samples of NB patients and 307 cellular senescence-related genes were used to construct a prediction signature. Results: A signature based on six optimal candidate genes (TP53, IL-7, PDGFRA, S100B, DLL3, and TP63) was successfully constructed and proved to have good prognostic ability. Through verification, the signature had more advantages than the gene expression level alone in evaluating prognosis was found. Further T cell phenotype analysis displayed that exhausted phenotype PD-1 and senescence-related phenotype CD244 were highly expressed in CD8+ T cell in MYCN-amplified group with higher risk-score. Conclusion: A signature constructed the six MYCN-amplified differential genes and aging-related genes can be used to predict the prognosis of NB better than using each high-risk gene individually and to evaluate immunosuppressed and aging tumor microenvironment.

Identification of NCAPG as an Essential Gene for Neuroblastoma Employing CRISPR-Cas9 Screening Database and Experimental Verification.

Neuroblastoma is the most common extracranial solid tumor in children. Patients with neuroblastoma have a poor prognosis. The development of therapy targets and the ability to predict prognosis will be enhanced through further exploration of the genetically related genes of neuroblastoma. The present investigation utilized CRISPR-Cas9 genome-wide screening based on the DepMap database to determine essential genes for neuroblastoma cells' continued survival. WGCNA analysis was used to determine the progression-related genes, and a prognostic signature was constructed. The signature gene, NCAPG, was downregulated in neuroblastoma cells to explore its impact on various cellular processes. This research used DepMap and WGCNA to pinpoint 45 progression-related essential genes for neuroblastoma. A risk signature comprising NCAPG and MAD2L1 was established. The suppression of NCAPG prevented neuroblastoma cells from proliferating, migrating, and invading. The results of flow cytometric analysis demonstrated that NCAPG inhibition caused cell cycle arrest during the G2 and S phases and the activation of apoptosis. Additionally, NCAPG downregulation activated the p53-mediated apoptotic pathway, inducing cell apoptosis. The present work showed that NCAPG knockdown reduced neuroblastoma cell progression and may serve as a basis for further investigation into diagnostic indicators and therapy targets for neuroblastoma.

1,5,6-Trimethoxy-2,7-dihydroxyphenanthrene from Dendrobium officinale Exhibited Antitumor Activities for HeLa Cells.

Natural products are irreplaceable reservoirs for cancer treatments. In this study, 12 phenanthrene compounds were extracted and isolated from Dendrobium officinale. Each chemical structure was identified using comprehensive NMR analysis. All compounds were evaluated for their cytotoxic activities against five tumor cell lines, i.e., HeLa, MCF-7, SK-N-AS, Capan-2 and Hep G2. Compound 5, 1,5,6-trimethoxy-2,7-dihydroxyphenanthrene, displayed the most significant cytotoxic effect against HeLa and Hep G2 cells, with an IC50 of 0.42 and 0.20 µM. For Hela cells, further experiments demonstrated that compound 5 could obviously inhibit cell migration, block cell cycle in the G0/G1 phase and induce apoptosis. Expression measurements for p53 indicated that knock down of p53 by siRNA could mitigate the apoptosis induced by compound 5. Therefore, the compound 5 is a potential candidate drug for HeLa cells in cervical cancer.

Pan-cancer analysis of cuproptosis-promoting gene signature from multiple perspectives.

Cuproptosis is a newly discovered cell death form with a unique mechanism. Seven genes have been identified to facilitate the process. To explore the roles of cuproptosis in different cancers, we first used Gene Expression Profiling, Interactive Analysis, version 2, and cBioPortal to analyze expression, prognosis and mutation conditions in different cancers from The Cancer Genome Atlas (TCGA). Then, we conducted single sample gene set enrichment analysis to combine the signature of the cuproptosis-promoting genes for all TCGA cancers. Moreover, we performed a survival analysis to explore if cuproptosis-score could independently influence clinical outcomes. Next, we compared pathway enrichment, immune infiltration, gene set activity and gene mutation between different cuproptosis-score groups. Finally, based on the intersected genes from difference analysis and weighted gene co-expression network analysis, consensus clustering and Least Absolute Shrinkage and Selection Operator Cox regression were performed and nomograms were constructed. Cuproptosis-score was associated with a favorable prognosis in eight TCGA cancers. Cancer-associated fibroblasts, B cells, neutrophils and mast cells were generally less abundant, and ferroptosis activity was higher in high cuproptosis-score groups. The novel classifications could differentiate patients' overall survival, and the risk models could effectively predict patients' outcomes in kidney, renal clear cell carcinoma, liver hepatocellular carcinoma, mesothelioma and stomach adenocarcinoma. Cuproptosis activity was closely related to the prognosis of several cancers. Its effects on the immune microenvironment and its relationship with other cell death modes, especially ferroptosis, may become the focus of further research.

SOX4 Mediates ATRA-Induced Differentiation in Neuroblastoma Cells.

Neuroblastoma (NB), which is considered to be caused by the differentiation failure of neural crest cells, is the most common extracranial malignant solid tumor in children. The degree of tumor differentiation in patients with NB is closely correlated with the survival rate. To explore the potential targets that mediate NB cell differentiation, we analyzed four microarray datasets from GEO, and the overlapping down- or upregulated DEGs were displayed using Venn diagrams. SOX4 was one of the overlapping upregulated DEGs and was confirmed by RT-qPCR and Western blot in ATRA-treated NGP, SY5Y, and BE2 cells. To clarify whether SOX4 was the target gene regulating NB cell differentiation, the correlation between the expression of SOX4 and the survival of clinical patients was analyzed via the R2 database, SOX4 overexpression plasmids and siRNAs were generated to change the expression of SOX4, RT-qPCR and Western blot were performed to detect SOX4 expression, cell confluence or cell survival was detected by IncuCyte Zoom or CCK8 assay, immunocytochemistry staining was performed to detect cells' neurites, and a cell cycle analysis was implemented using Flow cytometry after PI staining. The results showed that the survival probabilities were positively correlated with SOX4 expression, in which overexpressing SOX4 inhibited NB cell proliferation, elongated the cells' neurite, and blocked the cell cycle in G1 phase, and that knockdown of the expression of SOX4 partially reversed the ATRA-induced inhibition of NB cell proliferation, the elongation of the cells' neurites, and the blocking of the cell cycle in the G1 phase. These indicate that SOX4 may be a target to induce NB cell differentiation.

B3GALT4 remodels the tumor microenvironment through GD2-mediated lipid raft formation and the c-met/AKT/mTOR/IRF-1 axis in neuroblastoma.

BACKGROUND: Beta-1,3-galactosyltransferase-4 (B3GALT4) plays a critical regulatory role in tumor biology. However, the role of B3GALT4 in modulating the tumor microenvironment (TME) of neuroblastoma (NB) remains unknown. METHODS: Public datasets and clinical NB samples were collected to evaluate the expression and clinical significance of GD2 and B3GALT4 in NB patients. CCK-8, colony formation, and transwell assays and experiments in tumor-bearing mouse models were conducted to investigate the function of B3GALT4. Flow cytometry, ELISA, immunohistochemistry, immunofluorescence, western blotting, and chemotaxis assays were conducted to ascertain the immunomodulatory mechanism of B3GALT4. The combined therapeutic effect of the lipid raft inhibitor MßCD and anti-GD2 mAb was validated in a murine model of NB. RESULTS: GD2 was overexpressed in NB tissues and high expression of GD2 was associated with poor prognosis in NB patients. B3GALT4 was downregulated in NB tissues, and low expression of B3GALT4 indicated poor prognosis in NB patients. Silencing B3GALT4 significantly enhanced tumor progression both in vitro and in vivo. Meanwhile, the overexpression of B3GALT4 increased the recruitment of CD8+ T lymphocytes via the chemokines CXCL9 and CXCL10. Additionally, B3GALT4 regulated NB-cell GD2 expression and lipid raft formation. Mechanistically, B3GALT4 regulated the expression of CXCL9 and CXCL10 via the c-Met signaling in the lipid rafts and the downstream AKT/mTOR/IRF-1 pathway. The lipid raft inhibitor, MßCD, attenuated B3GALT4 deficiency-induced tumor progression and immune evasion. Last, MßCD combined with anti-GD2 mAb treatment significantly enhanced the antitumor effect and the infiltration of CD8+ T cells. CONCLUSIONS: Upregulation of B3GALT4 promotes the secretion of CXCL9 and CXCL10 to recruit CD8+ T lymphocytes via the GD2-mediated lipid rafts and the c-Met/AKT/mTOR/IRF-1 pathway. Moreover, lipid raft inhibitors may enhance the efficacy of anti-GD2 immunotherapy for NB.

Corrigendum: Downregulation of ATXN3 enhances the sensitivity to AKT inhibitors (Perifosine or MK-2206), but decreases the sensitivity to chemotherapeutic drugs (etoposide or cisplatin) in neuroblastoma cells.

[This corrects the article DOI: 10.3389/fonc.2021.686898.].

Pan-cancer analysis of necroptosis-related gene signature for the identification of prognosis and immune significance.

BACKGROUND: Necroptosis is a novel programmed cell death mode independent on caspase. A number of studies have revealed that the induction of necroptosis could act as an alternative therapeutic strategy for drug-resistant tumors as well as affect tumor immune microenvironment. METHODS: Gene expression profiles and clinical data were downloaded from XENA-UCSC (including The Cancer Genome Atlas and Genotype-Tissue Expression), Gene Expression Omnibus, International Cancer Genome Consortium and Chinese Glioma Genome Atlas. We used non-negative matrix factorization method to conduct tumor classification. The least absolute shrinkage and selection operator regression was applied to establish risk models, whose prognostic effectiveness was examined in both training and testing sets with Kaplan-Meier analysis, time-dependent receiver operating characteristic curves as well as uni- and multi-variate survival analysis. Principal Component Analysis, t-distributed Stochastic Neighbor Embedding and Uniform Manifold Approximation and Projection were conducted to check the risk group distribution. Gene Set Enrichment Analyses, immune infiltration analysis based on CIBERSORT, EPIC, MCPcounter, ssGSEA and ESTIMATE, gene mutation and drug sensitivity between the risk groups were also taken into consideration. RESULTS: There were eight types of cancer with at least ten differentially expressed necroptosis-related genes which could influence patients' prognosis, namely, adrenocortical carcinoma (ACC), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), acute myeloid leukemia (LAML), brain lower grade glioma (LGG), pancreatic adenocarcinoma (PAAD), liver hepatocellular carcinoma (LIHC), skin cutaneous melanoma (SKCM) and thymoma (THYM). Patients could be divided into different clusters with distinct overall survival in all cancers above except for LIHC. The risk models could efficiently predict prognosis of ACC, LAML, LGG, LIHC, SKCM and THYM patients. LGG patients from high-risk group had a higher infiltration level of M2 macrophages and cancer-associated fibroblasts. There were more CD8+ T cells, Th1 cells and M1 macrophages in low-risk SKCM patients' tumor microenvironment. Gene mutation status and drug sensitivity are also different between low- and high-risk groups in the six cancers. CONCLUSIONS: Necroptosis-related genes can predict clinical outcomes of ACC, LAML, LGG, LIHC, SKCM and THYM patients and help to distinguish immune infiltration status for LGG and SKCM.

A novel ganglioside-related risk signature can reveal the distinct immune landscape of neuroblastoma and predict the immunotherapeutic response.

Introduction: Gangliosides play an essential role in cancer development and progression. However, the involvement of gangliosides in the prognosis and tumor microenvironment (TME) of neuroblastoma is not entirely understood. Methods: Consensus clustering analysis was performed to identify ganglioside-mediated molecular subtypes. LASSO-Cox analysis was conducted to identify independent prognostic genes, and a novel risk signature was constructed. The risk signature was validated internally and externally. We further explored the independent prognosis value, immune landscape, drug susceptibility, and tumor dedifferentiation of the risk signature. The role of the signature gene B3GALT4 in neuroblastoma was explored in vitro. Results: Seventeen ganglioside-related genes were differentially expressed between INSS stage 4 and other stages, and two ganglioside-related clusters with distinct prognoses were identified. A novel risk signature integrating ten ganglioside-related prognostic genes was established. Across the train set and external validation sets, the risk signature presented high predictive accuracy and discrimination. The risk signature was an independent prognostic factor and constructed a nomogram combining multiple clinical characteristics. In the high-score group, the deficiency in antigen processing and presenting machinery, lack of immune cell infiltration, and escaping NK cells contributed substantially to immune escape. The low-score group was more responsive to immune checkpoint blockade therapy, while the high-score group showed substantial sensitivity to multiple chemotherapeutic drugs. Besides, the risk score was significantly positively correlated with the stemness index and reduced considerably in all-trans retinoic acid-treated neuroblastoma cell lines, indicating high dedifferentiation in the high-score group. Additionally, neuroblastoma cells with downregulation of B3GALT4 present with increased proliferation, invasion, and metastasis abilities in vitro. Conclusion: The novel ganglioside-related risk signature highlights the role of ganglioside in neuroblastoma prognosis and immune landscape and helps optimize chemotherapy and immunotherapy for neuroblastoma.

Downregulation of ATXN3 Enhances the Sensitivity to AKT Inhibitors (Perifosine or MK-2206), but Decreases the Sensitivity to Chemotherapeutic Drugs (Etoposide or Cisplatin) in Neuroblastoma Cells.

BACKGROUND: Chemotherapy resistance is the major cause of failure in neuroblastoma (NB) treatment. ATXN3 has been linked to various types of cancer and neurodegenerative diseases; however, its roles in NB have not been established. The aim of our study was to explore the role of ATXN3 in the cell death induced by AKT inhibitor (perifosine or MK-2206) or chemotherapy drugs (etoposide or cisplatin) in NB cells. METHODS: The expressions of ATXN3 and BCL-2 family members were detected by Western blot. Cell survival was evaluated by CCK8, cell confluence was measured by IncuCyte, and apoptosis was detected by flow cytometry. AS and BE2 were treated with AKT inhibitors or chemotherapeutics, respectively. RESULTS: Downregulation of ATXN3 did not block, but significantly increased the perifosine/MK-2206-induced cell death. Among the BCL-2 family members, the expression of pro-apoptotic protein BIM and anti-proapoptotic protein Bcl-xl expression increased significantly when ATXN3 was down-regulated. Downregulation of BIM protected NB cells from the combination of perifosine/MK-2206 and ATXN3 downregulation. Downregulation of ATXN3 did not increase, but decrease the sensitivity of NB cells to etoposide/cisplatin, and knockdown of Bcl-xl attenuated this decrease in sensitivity. CONCLUSION: Downregulation of ATXN3 enhanced AKT inhibitors (perifosine or MK-2206) induced cell death by BIM, but decreased the cell death induced by chemotherapeutic drugs (etoposide or cisplatin) via Bcl-xl. The expression of ATXN3 may be an indicator in selecting different treatment regimen.

Downregulation of fibronectin 1 attenuates ATRA-induced inhibition of cell migration and invasion in neuroblastoma cells.

Neuroblastoma (NB) is the most common malignant extra cranial solid tumors in children. It has been well established that retinoic acid (RA) inhibits proliferation of neuroblastoma (NB) by blocking cells at G1 phase of the cell cycle. Clinically, RA has been successfully used to treat NB patients. However, the precise mechanism underlying the potent action of RA-treated NB is not fully explored. In this work, we carried out a gene expression profiling by RNA sequencing on all-trans retinoic acid (ATRA)-treated NB cells. Cancer-related pathway enrichment and subsequent protein-protein interaction (PPI) network analysis identified fibronectin 1 (FN1) as one of the central molecules in the network, which was significantly upregulated during ATRA treatment. In addition, we found that although downregulation of FN1 had no significant effects on either cell proliferation or cell cycle distributions in the presence or absence of ATRA, it increased cell migration and invasion in NB cells and partially blocked ATRA-induced inhibition of cell migration and invasion in SY5Y NB cells. Consistent with this finding, FN1 expression levels in NB patients positively correlate with their overall survivals. Taken together, our data suggest that FN1 is a potential target for effective ATRA treatment on NB patients, likely by facilitating ATRA-induced inhibition of cell migration and invasion.

Downregulation of PIF1, a potential new target of MYCN, induces apoptosis and inhibits cell migration in neuroblastoma cells.

Neuroblastoma (NB) is one of the most common malignant tumors in children. Chemotherapy resistance is one of the significant challenges in the treatment of high-risk NB patients, and it is necessary to search for new valid targets for NB treatment. This study aims to explore the possible role of PIF1 in NB by using bioinformatic analysis and downregulation of PIF1 with specific siRNA. Kyoto genome encyclopedia and R language based gene ontology was used to analyze the differentially expressed genes (DEGs) (including PIF1) when MYCN expression was silenced in NB cells. Analysis based on the R2 database showed a lower expression of PIF1 correlated with good prognosis in NB patients. Downregulation of MYCN expression by transfecting MYCN siRNA (#1, #2) into NB cells decreased the PIF1 expression at both mRNA and protein levels, while upregulation of MYCN expression by transfecting MYCN overexpressed plasmid increased the PIF1 expression. We further found that downregulation of PIF1 expression by transfecting PIF1 siRNA (#1, #2) into NB cells, increased the number of apoptotic cells, inhibited the cell survival, decreased the ability of cell migration and induced a cell cycle arrest at G1 phase. These data indicated that PIF1, as a potential new target of MYCN, maybe a novel target for NB treatment.

Novel prognostic biomarkers of gastric cancer based on gene expression microarray: COL12A1, GSTA3, FGA and FGG.

Gastric cancer (GC) is the fifth most common malignancy and the third leading cause of cancer­associated mortality in the world. However, its mechanisms of occurrence and development have not been clearly elucidated. Furthermore, there is no effective tumor marker for GC. Using DNA microarray analysis, the present study revealed genetic alterations, screened out core genes as novel markers and discovered pathways for potential therapeutic targets. Differentially expressed genes (DEGs) between GC and adjacent normal tissues were identified, followed by pathway enrichment analysis of DEGs. Next, the protein­protein interaction (PPI) network of DEGs was built and visualized. Analyses of modules in the PPI network were then performed to identify the functional core genes. Finally, survival analysis of core genes was conducted. A total of 256 genes were identified as DEGs between the GC samples and normal samples, including 169 downregulated and 87 upregulated genes. Through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, the present study identified a total of 143 GO terms and 21 pathways. Six clusters of functional modules were identified, and the genes associated with these modules were screened out as the functional core genes. Certain core genes, including collagen type 12 α1 chain (COL12A1), glutathione S­transferase α3 (GSTA3), fibrinogen α chain (FGA) and fibrinogen γ chain (FGG), were the first reported to be associated with GC. Survival analysis suggested that these four genes, COL12A1 (P=0.002), GSTA3 (P=3.4x10­6), FGA (P=0.00075) and FGG (P=1.4x10­5), were significant poor prognostic factors and therefore, potential targets to improve diagnosis, optimize chemotherapy and predict prognostic outcomes.

Development of a risk-scoring system to evaluate the serosal invasion for macroscopic serosal invasion positive gastric cancer patients.

BACKGROUND: The status of serosal invasion is often discordance between pathological and intraoperative evaluation. Our study sought to develop a risk-scoring system (RSS) to predict the probability of pT4a for macroscopic serosal invasion (MSI) positive patients and reevaluate the serosal invasion status. PATIENTS AND METHODS: A total of 1301 pT3/pT4a gastric cancer patients with curative surgery were reviewed. We constructed the RSS to predict the probability of pT4a and assigned MSI-positive patients into different risk groups based on the risk scores. The prognostic significance of these risk groups was also evaluated. RESULTS: Univariate and multivariate analyses identified that tumor location, Lauren type, Borrmann type, tumor size, lymphovascular invasion and pN stage were risk factors related to pT4a. Survival analyses showed that pT3 MSI-positive patients in high-risk group had similar survival with pT4a patients. We incorporated these two groups into one stage and proposed a novel revised-T stage. Two-step multivariate analyses indicated that the revised-T stage showed better prediction ability for prognosis and peritoneal recurrence assessment than original pT stage and MSI status. CONCLUSIONS: In our present study, we developed a RSS to predict the probability of pT4a for MSI-positive patients. Based on our RSS, we proposed a treatment algorithm to reevaluate the tumor invasion for MSI-positive patients in clinical practice. Future studies should include other preoperative predictors to improve the clinical utility of our model.

The clinicopathological and prognostic significances of CDC73 expression in cancers: a bioinformatics analysis.

CDC73 interacts with human PAF1 complex, histone methyltransferase complex and RNA polymerase II for transcription elongation and 3' end processing. Its down-regulated expression was immunohistochemically detected in gastric, colorectal, ovarian and head and neck cancers, and positively correlated with aggressive behaviors and unfavorable prognosis of malignancies. We performed a bioinformatics analysis by using Oncomine, TCGA and KM plotter databases. It was found that CDC73 mRNA was overexpressed in gastric, lung, breast and ovarian cancers, even stratified by histological subtypes (p<0.05). CDC73 mRNA expression was stronger in gastric intestinal- than diffuse-type carcinomas (p<0.05), and positively correlated with distant metastasis and TNM staging of lung cancer (p<0.05). CDC73 mRNA expression was positively related to both overall and progression-free survival rates of the patients with gastric cancer, even stratified by gender, lymph node involvement, or treatment (p<0.05), while versa for breast cancer (p<0.05). The prognostic significance of CDC73 mRNA was dependent on the datasets and pathological grouping in lung and ovarian cancers. These findings indicated the CDC73 mRNA overexpression was positively linked to carcinogenesis. It is cautious to employ CDC73 mRNA to evaluate the clinicopathological behaviors and prognosis of cancers.

Alcohol drinking and gastric cancer risk: a meta-analysis of observational studies.

BACKGROUND: Many studies investigated the association between alcohol drinking and gastric cancer risk, but the results were controversial. We performed a meta-analysis of observational studies to explore the association. MATERIALS AND METHODS: We searched PubMed to identify the relevant studies that reported the association between alcohol drinking and gastric cancer risk up to December 31, 2016. We pooled relative risks (RRs) in random effects model and performed dose-response analysis to quantify the association. Cochran Q test and I2 analyses were used to evaluate the heterogeneity. Meta-regression, subgroup, sensitivity and publication bias analyses were also performed. RESULTS: 75 studies were included in our study. The pooled RR of high vs low total alcohol drinking was 1.25 (95% CI, 1.15-1.37, P < 0.001), and a nonlinear association was further observed. Subgroup analysis showed that alcohol drinking significantly associated with the risk of gastric noncardia cancer (RR, 1.19; 95% CI, 1.01-1.40, P = 0.033), but not with the risk of gastric cardia cancer (RR, 1.16; 95% CI, 0.98-1.39, P = 0.087). Notably, the pooled RRs of high vs low analyses were 1.13 (95% CI, 1.03-1.24, P = 0.012) for beer drinking, 1.22 (95% CI, 1.06-1.40, P = 0.005) for liquor drinking, and 0.99 (95% CI, 0.84-1.16, P = 0.857) for wine drinking. CONCLUSIONS: Our meta-analysis found a nonlinear association between alcohol drinking and gastric cancer risk, and heavy drinking level was strongly related to gastric cancer risk. Beer and liquor had significant positive associations with gastric cancer risk, while wine drinking would not increase gastric cancer risk. These results need to be verified in future research.