Oncomine Datasets Research Articles

Toll-interacting protein may affect doxorubicin resistance in hepatocellular carcinoma cell lines.

Liver cancer is the third leading cause of cancer-related deaths worldwide, and hepatocellular carcinoma (HCC) is the most common type of liver cancer. Transarterial interventions are among the chemotherapeutic approaches used in hardly operable regions prior to transplantation, and in electrochemotherapy, where doxorubicin is used. However, the efficacy of treatment is affected by resistance mechanisms. Previously, we showed that overexpression of the CUE5 gene results in doxorubicin resistance in Saccharomyces cerevisiae (S. cerevisiae). In this study, the effect of Toll-interacting protein (TOLLIP), the human ortholog of CUE5, on doxorubicin resistance was evaluated in HCC cells to identify its possible role in increasing the efficacy of transarterial interventions. The NIH Gene Expression Omnibus (GEO) and Oncomine datasets were analyzed for HCC cell lines with relatively low and high TOLLIP expression, and SNU449 and Hep3B cell lines were chosen, respectively. TOLLIP expression was increased by plasmid transfection and decreased by TOLLIP-siRNA in both cell lines and evaluated by RT-PCR and ELISA. Cell proliferation and viability were examined using xCELLigence and MTT assays after doxorubicin treatment, and growth inhibitory 50 (GI 50) concentrations were evaluated. Doxorubicin GI 50 concentrations decreased approximately 2-folds in both cell lines upon silencing TOLLIP after 48h of drug treatment. Our results showed for the first time that silencing TOLLIP in hepatocellular carcinoma cells may help sensitize these cells to doxorubicin and increase the efficacy of chemotherapeutic regimens where doxorubicin is used.

Identification of immune-related genes contributing to head and neck squamous cell carcinoma development using weighted gene co-expression network analysis.

This study aimed to identify genes related to the degree of immune cell infiltration in head and neck squamous cell carcinoma (HNSCC), explore their new biological functions, and evaluate their diagnostic and prognostic value in HNSCC. Transcriptomic data from The Cancer Genome Atlas (TCGA) HNSCC dataset was used to screen differentially expressed genes between tumors and normal tissues, followed by weighted correlation network analysis (WGCNA) to identify immune-related modules. Differential gene expression, immune cell infiltration, and survival analyses were performed to screen key genes. The expression of these key genes was validated in Oncomine and gene expression omnibus (GEO) datasets and by immunohistochemistry (IHC). 1869 and 1578 genes were significantly upregulated and downregulated in HNSCC. WGCNA showed that the brown module was associated with the most significant number of immune-related genes. PPI network analysis demonstrated that PPL, SCEL, KRT4, KRT24, KRT78, KRT13, SPRR3, TGM3, CRCT1, and CRNN were key components in the brown module. Furthermore, the expression levels of KRT4, KRT78, KRT13, and SPRR3 in HNSCC correlated with infiltration levels of CD8+ T cells and macrophages. Survival analyses revealed that the expression of KRT78, KRT13, and SPRR3 in HNSCC correlated with overall survival (OS). The IHC assay indicated that KRT13 (p=.042), KRT78 (p < .001), and SPRR3 (p=.022) protein expression levels in HNSCC were significantly lower than in normal tissues. Analysis of GSE65858 and GSE41613 datasets showed that a worse OS was associated with low expression of KRT78 (p=.0086, and p=.005) and SPRR3 (p=.017, and p=.02). Our findings suggest that KRT4, KRT78, KRT13, and SPRR3 are related to the occurrence and development of HNSCC. Importantly, KRT78 and SPRR3 might serve as diagnostic and prognostic biomarkers of HNSCC.

MYL5 as a Novel Prognostic Marker is Associated with Immune Infiltrating in Breast Cancer: A Preliminary Study.

Myosin light chain plays a vital regulatory function in a large-scale cellular physiological procedure, however, the role of myosin light chain 5 (MYL5) in breast cancer has not been reported. In this study, we aimed to elucidate the effects of MYL5 on clinical prognosis and immune cell infiltration, and further explore the potential mechanism in breast cancer patients. In this study, we first explored the expression pattern and prognostic value of MYL5 in breast cancer across multiple databases, including Oncomine, TCGA, GTEx, GEPIA2, PrognoScan, and Kaplan-Meier Plotter. The correlations of MYL5 expression with immune cell infiltration and associational gene markers in breast cancer were analyzed by using the TIMER, TIMER2.0, and TISIDB databases. The enrichment and prognosis analysis of MYL5-related genes were implemented by using LinkOmics datasets. We found that there was a low expression of MYL5 in breast cancer than in corresponding normal tissue by analyzing the data from Oncomine and TCGA datasets. Furthermore, research showed the prognosis of the MYL5 high-expression group was better than the low-expression group in breast cancer patients. Furthermore, MYL5 expression is markedly related to the tumor-infiltrating immune cells (TIICs), including cancer-associated fibroblast, B cell, CD8+ T cell, CD4+ T cell, macrophage, neutrophil, and dendritic cell, and related to immune molecules as well as the associated gene markers of TIICs. MYL5 can serve as a prognostic signature in breast cancer and is associated with immune infiltration. This study first offers a relatively comprehensive understanding of the oncogenic roles of MYL5 for breast cancer.

Glycoprotein M6A Suppresses Lung Adenocarcinoma Progression via Inhibition of the PI3K/AKT Pathway.

Lung adenocarcinoma is the most common subtype of lung cancer and has high morbidity and mortality. Glycoprotein M6A (GPM6A) is a neuronal membrane glycoprotein reported to be related with cancer. However, studies on GPM6A in lung adenocarcinoma are rare. This study aimed to investigate the role of GPM6A in lung adenocarcinoma and its potential mechanism. GPM6A mRNA expression was analysed in 33 types of cancers using The Cancer Genome Atlas (TCGA) datasets. It was compared among normal lung tissues, lung adenocarcinoma tissues, and adjacent tissues using the Oncomine database. Real-time quantitative polymerase chain reaction (RT-qPCR) was performed to detect GPM6A expression in human lung adenocarcinoma cell lines (A549 and H1299) and normal pulmonary epithelial cells (BEAS-2B). When GPM6A was inhibited, cell proliferative capacity was detected by Cell Counting Kit 8 (CCK8), EdU, and colony formation assays. Cell migration ability was detected by wound healing and transwell assays. The expression of epithelial-mesenchymal transition (EMT) markers was detected by Western blotting (WB) and RT-qPCR. When GPM6A was overexpressed, cell proliferation and migration were detected again. Ten nude mice were subcutaneously injected with cells overexpressing GPM6A or empty vector, and the tumor size was recorded on day 14 and then measured every 3 days thereafter. The final tumor weight was measured on day 36. Furthermore, the expressions of phosphoinositide 3-kinase (PI3K), phosphorylated PI3K, AKT, and phosphorylated AKT were detected by WB. Results showed that GPM6A mRNA expression decreased in 15 types of tumors in TCGA dataset. GPM6A expression was lower in lung adenocarcinoma than in normal lung tissues or adjacent tissues in the Oncomine dataset. Similar results were found in lung adenocarcinoma cells. The function study showed that GPM6A downregulation enhanced the proliferation, migration, and EMT of lung adenocarcinoma cells, while GPM6A upregulation inhibited their development. The xenograft results suggested that GPM6A upregulation delayed tumor growth and reduced tumor weight. Moreover, WB showed that GPM6A knockdown activated the PI3K/AKT pathway, while GPM6A upregulation inhibited the activation of the PI3K/AKT pathway. In conclusion, GPM6A suppresses lung adenocarcinoma progression via inhibition of the PI3K/AKT pathway. Thus, GPM6A could be a possible treatment target for lung cancer therapy.

Oncogenic Role of HMGB1 as An Alarming in Robust Prediction of Immunotherapy Response in Colorectal Cancer.

Simple SummaryThe high mobility group box1 (HMGB1) protein operates as an alarm for danger. We explore the correlation between HMGB1 expression and the clinical survival status of patients receiving antitumor immunotherapy toward assessing the prognostic value in a multicancer context. We further conducted screening and identified four interacting genes that are targeted for binding by HMGB1-proteins and validate and contextualize the results in vitro. Additionally, HMGB1 function is also remarkably related to the tumor immune microenvironment and immune infiltration, especially regarding the high purity of stromal and immune cells in the tumor microenvironment (TME). In multicancer analysis, HMGB1 is also found linked with frequently genetic mutations and deletions, including in TMB and MSI which lead to resistance against antitumor immunotherapy and worse clinical prognosis among patients. The combination of HMGB1 expression with immune checkpoint molecules (ICPs), such as PD-L1, might present a novel immunology-based antitumor immunotherapy strategy.Objective: To assess the correlation between HMGB1 expression and the patient prognosis in a multicancer context. Methods: The potential oncogenic role of HMGB1 was explored in forty tumors through the TCGA, GEO, and Oncomine datasets. We analyzed the clinical prognostic value and antitumor immunotherapy of HMGB1 in a multicancer context using GEO (GSE111636). Results: High expression of HMGB1 is present in multicancer cases, and its low expression is closely associated with the prognostic survival of patients, in terms of both overall and disease-free survival in ACC and LUAD. Further investigation revealed that the high expression of gastric and lung cancer is closely associated with low risk and better prognosis of patients based on COX and Kaplan–Meier analysis of OS, FP and PPS. HMGB1 expression was found to be significantly correlated with cancer-associated fibroblast and CD8+ T cell infiltration in the TME. The analysis of GO functional annotation/KEGG pathways indicates that HMGB1 may regulate tumor immunity-related pathways, such as the tumor immunotherapy response in colorectal cancer. The function of four genes as hubs are confirmed by in vitro HMGB1 knockdown which led to inhibition of cell proliferation and metastasis in SW620 and SW480 cells. Conclusion: HMGB1 is a potential novel biomarker for improving clinical prognosis and antitumor immunotherapy efficacy. CDK1, HMGB2, SSRP1, and H2AFV may serve as key nodes for HMGB1 in colorectal cancer.

High expression of HNRNPR in ESCA combined with 18F-FDG PET/CT metabolic parameters are novel biomarkers for preoperative diagnosis of ESCA

BackgroundThe aim of this study was to determine the expression and function of heterogeneous nuclear ribonucleoprotein R (HNRNPR) in esophageal carcinoma (ESCA), the correlation between its expression and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computerized tomography scan (PET/CT)-related parameters. We also investigated whether 18F-FDG PET/CT can be used to predict the expression of HNRNPR in ESCA.MethodsWe analyzed patients with ESCA who underwent 18F-FDG PET/CT before surgery, and their tissues were stained with HNRNPR IHC. The associated parameters were derived using the 18F-FDG PET imaging data, and the correlation with the IHC score was evaluated. The Oncomine, TCGA, and GEO datasets were used to investigate HNRNPR expression in the pan- and esophageal cancers, as well as its relationship with N6-methyladenosine (m6A) modification and glycolysis. The R software, LinkedOmics, GeneMANIA, and StringOnline tools were used to perform GO/KEGG, GGI, and PPI analyses on the HNRNPR.ResultsHNRNPR is highly expressed in the majority of pan-cancers, including ESCA, and is associated with BMI, weight, and history of reflux in patients with ESCA. HNRNPR is somewhat accurate in predicting the clinical prognosis of ESCA. HNRNPR expression was positively correlated with SUVmax, SUVmean, and TLG in ESCA (p < 0.05). The combination of these three variables provides a strong predictive value for HNRNPR expression in ESCA. GO/KEGG analysis showed that HNRNPR played a role in the regulation of cell cycle, DNA replication, and the Fannie anemia pathway. The analysis of the TCGA and GEO data sets revealed a significant correlation between HNRNPR expression and m6A and glycolysis-related genes. GSEA analysis revealed that HNRNPR was involved in various m6A and glycolysis related-pathways.ConclusionHNRNPR overexpression correlates with 18F-FDG uptake in ESCA and may be involved in the regulation of the cell cycle, m6A modification, and cell glycolysis. 18F-FDG PET/CT-related parameters can predict the diagnostic accuracy of HNRNPR expression in ESCA.

C chemokines are prognostic biomarkers correlated with diverse immune cell infiltrations in clear cell renal cell carcinoma.

BackgroundThe interplay between tumor-infiltrating immune cells and cancer cells affects cancer initiation, progression, and treatment. C chemokines are critically involved in immune cell chemotaxis, self-tolerance formation, antigen cross-presentation, and cytotoxic immune response. However, their roles in cancer development are still largely unknown.MethodsWe comprehensively analyzed the expression, prognostic value, functions, and immune implication of C chemokines in clear cell renal cell carcinoma (ccRCC) using multiple databases. Besides, we detected the expression of C chemokines in RCC cell lines using quantitative real-time polymerase chain reaction (qPCR).ResultsThrough analyzing The Cancer Genome Atlas (TCGA), Oncomine and Gene Expression Omnibus (GEO) ccRCC datasets, we found that C chemokines were significantly upregulated in ccRCC tumor tissues and associated with tumor progression. Besides, qPCR revealed the overexpression of C chemokines in RCC cell lines. Promoter hypomethylation was a potential factor causing the upregulation of C chemokines. ccRCC patients with higher levels of C chemokines had significantly poorer overall survival (OS), progression-free interval (PFI), and disease-specific survival (DSS). C chemokines and related genes were involved mainly in cytokine-cytokine receptor interactions and the chemokine signaling and Toll-like receptor signaling pathways. Correlation analysis revealed a positive correlation between C chemokines and the infiltration of 25 immune cell subtypes, many of which affected the prognosis of ccRCC. Moreover, C chemokines were positively correlated with the expression of genes associated with M2 macrophage polarization and T-cell exhaustion, and the expression of several immune checkpoints in ccRCC.ConclusionsOur research provides preliminary insights into the prognostic value and immune implication of C chemokines in ccRCC, which is conducive to the prediction of survival and immunotherapy response, and the development of novel therapeutic targets for ccRCC.

Comprehensive analysis of CXCR family members in lung adenocarcinoma with prognostic values

BackgroundThe expression profiles and molecular mechanisms of CXC chemokine receptors (CXCRs) in Lung adenocarcinoma (LUAD) have been extensively explored. However, the comprehensive prognostic values of CXCR members in LUAD have not yet been clearly identified.MethodsMultiple available datasets, including Oncomine datasets, the cancer genome atlas (TCGA), HPA platform, GeneMANIA platform, DAVID platform and the tumor immune estimation resource (TIMER) were used to detect the expression of CXCRs in LUAD, as well as elucidate the significance and value of novel CXCRs-associated genes and signaling pathways in LUAD.ResultsThe mRNA and/or protein expression of CXCR1, CXCR2, CXCR3, CXCR4, CXCR5 and CXCR6 displayed predominantly decreased in LUAD tissues as compared to normal tissues. On the contrary, compared with the normal tissues, the expression of CXCR7 was significantly increased in LUAD tissues. Subsequently, we constructed a network including CXCR family members and their 20 related genes, and the related GO functions assay showed that CXCRs connected with these genes participated in the process of LUAD through several signal pathways including Chemokine signaling pathway, Cytokine-cytokine receptor interaction and Neuroactive ligand-receptor interaction. TCGA and Timer platform revealed that the mRNA expression of CXCR family members was significantly related to individual cancer stages, cancer subtypes, patient’s gender and the immune infiltration level. Finally, survival analysis showed that low mRNA expression levels of CXCR2 (HR = 0.661, and Log-rank P = 1.90e−02), CXCR3 (HR = 0.674, and Log-rank P = 1.00e−02), CXCR4 (HR = 0.65, and Log-rank P = 5.01e−03), CXCR5 (HR = 0.608, and Log-rank P = 4.80e−03) and CXCR6 (HR = 0.622, and Log-rank P = 1.85e−03) were significantly associated with shorter overall survival (OS), whereas high CXCR7 mRNA expression (HR = 1.604, and Log-rank P = 4.27e−03) was extremely related with shorter OS in patients.ConclusionOur findings from public databases provided a unique insight into expression characteristics and prognostic values of CXCR members in LUAD, which would be benefit for the understanding of pathogenesis, diagnosis, prognosis prediction and targeted treatment in LUAD.

Prognostic value of p16, p53, and pcna in sarcoma and an evaluation of immune infiltration

Backgroundp16, p53, and proliferating cell nuclear antigen (pcna) genes play significant roles in many chromatin modifications and have been found to be highly expressed in a variety of tumor tissues. Therefore, they have been used as target genes for some tumor therapies. However, the differential expressions of the p16, p53, and pcna genes in human sarcomas and their effects on prognosis have not been widely reported.MethodsThe Oncomine dataset was used to analyze the transcription levels of p16, p53, and pcna genes, and the gene expression profile interactive analysis (GEPIA) dataset was used to analyze the differential expressions of p16, p53, and pcna. The expression levels of p16, p53, and pcna were further analyzed by Western Blotting. GEPIA and Kaplan–Meier analyses were used to analyze the prognostic value of p16, p53, and pcna. Furthermore, p16, p53, and pcna gene mutations and their association with overall survival (OS) and disease-free survival (DFS) were analyzed using cBioPortal datasets. In addition, genes co-expressed with p16, p53, and pcna were analyzed using Oncomine. The DAVID dataset was used to analyze the functional enrichment of p16, p53, pcna, and their co-expressed genes by Gene Ontology (GO) and Metascape were used to construct a network map. Finally, the immune cell infiltration of p16, p53, and pcna in patients with sarcoma was reported by Tumor Immune Estimation Resource (TIMER).Resultsp16, p53, and pcna were up-regulated in human sarcoma tissues and almost all sarcoma cell lines. Western Blotting showed that the expression of p16, p53, and pcna was elevated in osteosarcoma cell lines. The expression of pcna was correlated with OS, the expression of p16, p53, and pcna was correlated with relapse-free survival, and the genetic mutation of p16 was negatively correlated with OS and DFS. We also found that p16, p53, and pcna genes were positively/negatively correlated with immune cell infiltration in sarcoma.ConclusionsThe results of this study showed that p16, p53, and pcna can significantly affect the survival and immune status of sarcoma patients. Therefore, p16, p53, and pcna could be used as potential biomarkers of prognosis and immune infiltration in human sarcoma and provide a possible therapeutic target for sarcoma.

SQLE inhibition suppresses the development of pancreatic ductal adenocarcinoma and enhances its sensitivity to chemotherapeutic agents in vitro.

In this study, we sought to explore the function of seven important enzymes (MSMO1, EBP, HMGCS1, IDI2, DHCR7, FDFT1, and SQLE) involved in cholesterol biosynthesis especially SQLE in PDAC therapy. The TCGA and Oncomine dataset were used to explore the expression of the seven enzymes in normal and cancerous pancreatic individual, and their anti-proliferation efficiency against PDAC cells was measured by cell viability assay. Expression level and prognostic values of SQLE were evaluated by western blot and Kaplan-Meier analysis. The influence of SQLE knockdown by shRNA in PDAC cells was assessed by transwell, colony formation and cell cycle analysis. RNA-seq and GSEA were utilized to investigate the potential mechanisms. The synergistic effect of SQLE inhibitor, terbinafine, combined with six chemotherapeutic drugs in PDAC cells was tested by CCK-8 method. We demonstrated that downregulation of those enzymes especially SQLE significantly suppressed PDAC cells survival. SQLE was upregulated in PDAC cell lines, and the elevated level of SQLE was correlated with poor prognosis in pancreatic cancer samples. SQLE knockdown could significantly inhibit the proliferation and migration of PDAC cells. Cell cycle was blocked in S phase after SQLE silencing. Mechanistically, GSEA analysis with RNA-seq data revealed that SQLE silencing negatively mediated mTORC1 and TNFα/NF-κB signaling pathways. Besides, SQLE inhibitor terbinafine enhanced chemotherapeutic sensitivity of the six compounds. This study demonstrated that SQLE was a novel target for PDAC therapy. The synergism role of SQLE inhibition and chemotherapy may be potential therapeutic strategy for pancreatic cancer treatment.

Comprehensive analysis to identify noncoding RNAs mediated upregulation of maternal embryonic leucine zipper kinase (MELK) correlated with poor prognosis in hepatocellular carcinoma.

Object: Maternal embryonic leucine zipper kinase (MELK) is involved in the development and progression of various cancers. This work investigated the usefulness of MELK in the prediction of hepatocellular carcinoma (HCC) prognosis.Methods: Information on MELK expression was obtained by pan-cancer analysis using The Cancer Genome Atlas (TCGA) database. The TCGA-liver hepatic cancer (TCGA-LIHC), Oncomine datasets, International Cancer Genome Consortium (ICGC) datasets were used to investigate MELK expression in HCC. The prognostic roles of MELK in HCC were assessed by univariate and multivariate survival analyses. The underlying mechanism for noncoding RNAs (ncRNAs) involved in MELK expression was investigated by in silico studies, correlation, methylation, and survival analyses. The relationships between MELK expression and immune cells, immune markers, and checkpoint markers were also analyzed.Results: (1) MELK was identified as an independent predictor of overall survival (OS) in HCC patients (MELK high vs. low expression, HR 2.469; 95% CI 1.217–5.008; p = 0.012) in a multivariate Cox analysis, with a concordance index (C-index) value of 0.727 (95% CI 0.750–0.704). (2) The noncoding RNA miR3142HG and the LINC00265/has-miR-101-3p axis were found to regulate MELK expression in HCC tissue. (3) MELK levels were linked to various immune functions, including tumor infiltration and the expression of immune checkpoints and biomarkers in HCC.Conclusion: MELK may have an oncogenic function in HCC and was found to be up-regulated by ncRNAs and associated with immune cell infiltration and unfavorable prognosis.

Integrative analysis of expression, prognostic significance and immune infiltration of RFC family genes in human sarcoma.

Objective: To reveal the expression and prognostic value of replication factor C family genes (RFCs) in patients with sarcoma.Results: The results showed that the mRNA expression levels of RFC2, RFC3, RFC4, and RFC5 were increased in sarcoma tissues. In addition, Cancer Cell Line Encyclopedia (CCLE) dataset analysis indicated that RFC1, RFC2, RFC3, RFC4, and RFC5 were elevated expressed in sarcoma cell lines. Moreover, Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan-Meier Plotter showed that highly expressed RFC2-5 were associated with poor overall survival (OS) or relapse-free survival (RFS) in sarcoma patients. The results of the Tumor Immune Estimation Resource (TIMER) database indicated that the expression of RFCs was negatively correlated with the infiltration of CD4+ T cells and macrophages.Conclusions: There were significant differences in the expression of RFCs between normal tissue and sarcoma tissue, and RFC2, RFC3, RFC4, and RFC5 might be promising prognostic biomarkers for sarcoma.Methods: The expression of RFCs was analyzed using the ONCOMINE dataset and GEPIA dataset. CCLE dataset was used to assess the expression of RFCs in the cancer cell line. The prognostic value of RFCs was evaluated by GEPIA and Kaplan-Meier analysis. Furthermore, the association between RFCs and their co-expressed genes were explored via ONCOMINE and GEPIA datasets. We used the TIMER dataset to analyze the immune cell infiltration of RFCs in sarcoma.

Comprehensive analysis of expression and prognosis for LMNB family genes in human sarcoma.

Previous studies indicated that lamin proteins were thought to be related to gene expression, chromatin structure, and unclear stability. There are 2 types of vertebrate lamins, including A and B. The 2 B type proteins are encoded by lamin B1 (LMNB1) and lamin B2 (LMNB2). The LMNBs factor has been found to be associated with the development of multiple tumors, but its association with sarcoma has been barely mentioned.The transcription levels of LMNBs were analyzed via Oncomine database. Gene Expression Profiling Interactive Analysis (GEPIA) dataset was adopted to analyze the differential expression of LMNBs in sarcoma. Cancer Cell Line Encyclopedia dataset was used to explore the expression of LMNBs in sarcoma cell line. We analyzed the prognostic value of LMNBs in GEPIA and Kaplan-Meier Plotter. Oncomine and GEPIA datasets were also used to detect the relationship between LMNBs and their co-expressed genes. We used the Database for Annotation, Visualization and Integrated Discovery to conduct the Gene Ontology analysis of LMNBs and their co-expressed genes. Kyoto Encyclopedia of Genes and Genomes was also used to analyze the pathway of LMNBs.LMNB1 and LMNB2 were reported to be hyperexpressed in sarcoma. The expression of LMNBs was elevated in various sarcoma cell lines. According to the results, we observed that LMNBs were connected to the poor overall survival, recurrence-free survival, and disease-free survival of sarcoma patients.This study indicated that hyperexpression of LMNBs was significantly related to worse outcome of sarcoma, LMNB1 and LMNB2 were expected to become potential biomarkers for human.

The Pan-Cancer Crosstalk Between the EFNA Family and Tumor Microenvironment for Prognosis and Immunotherapy of Gastric Cancer.

Background: EFNA1–5 have important physiological functions in regulating tumorigenesis and metastasis. However, correlating EFNA genes in the tumor immune microenvironment (TIME), and the prognosis of patients with gastric cancer remains to be determined. Methods: Using public databases, the expression of EFNA1-5 in pan-cancer and gastric cancer was comprehensively analyzed using UCSC Xena, the Oncomine dataset and UALCAN. We further completed survival analysis by Kaplan-Meier plotter to evaluate the prognosis of the high and low expression groups of the EFNAs gene in patients with gastric cancer. The TIMER tool was used to reveal the correlation between immune cell infiltration and genes of interest. Spearman correlation was used to find an association between the EFNA genes and tumor stem cells, TIME, microsatellite instability (MSI) or tumor mutational burden (TMB). We also used cBioportal, GeneMANIA and STRINGS to explore the types of changes in these genes and the protein interactions. Finally, we described the TIME based on QUANTISEQ algorithm, predicted the relationship between the EFNA genes and half-maximal inhibitory concentration (IC50), and analyzed the relationship between the EFNA family genes and immune checkpoints. Results: The expression of EFNA1, EFNA3, EFNA4, and EFNA5 was elevated in pan-cancer. Compared with normal adjacent tissues, EFNA1, EFNA3, and EFNA4 were up-regulated in gastric cancer. In terms of the influence on the survival of patients, the expression of EFNA3 and EFNA4 were related to overall survival (OS) and disease-free survival (DFS) for patients with gastric cancer. High expression of EFNA5 often predicted poor OS and DFS. In gastric cancer, the expression of EFNA3 and EFNA4 showed a significant negative correlation with B cells. The higher the expression of EFNA5, the higher the abundance of B cells, CD4+T cells and macrophages. CD8+T cells, dendritic cells infiltration and EFNA1-4 expression were negatively correlated. The infiltration of CD4+T cells, macrophages and neutrophils was negatively correlated with the expression of EFNA1, EFNA3, and EFNA4. TMB and MSI were positively correlated with EFNA3/EFNA4 expression. In the tumor microenvironment and drug sensitivity, EFNA3/4/5 also showed a significant correlation. In addition, we explored the relationship between the EFNA family genes and the immune microenvironment (B cells, M2 macrophages, monocytes, CD8+ T cells, regulatory T cells, myeloid dendritic cells, natural killer cells, non-regulatory CD4+ T cells), immune checkpoint (PDCD1, PDCD1LG2, CD274, CTLA4), and IC50 of common chemotherapeutic drugs for gastric cancer (5-fluorouracil, cisplatin, docetaxel and gemcitabine). Conclusions: Our study provides new ideas for tumor treatment and prognosis from the perspective of TIME, and nominates EFNA1–5 to become potential therapeutic targets for gastric cancer.

Integrated Transcriptomic Analysis Reveals a Distinctive Role of YAP1 in Extramedullary Invasion and Therapeutic Sensitivity of Multiple Myeloma.

Multiple myeloma (MM) is the second most common hematologic malignancy. There are no standard therapeutic guidelines for extramedullary invasion (EM). We performed a retrospective integrated transcriptomic analysis based on GEO, TCGA, and Oncomine datasets with a total of over 2,500 cases enrolled. GSVA analysis was performed on GSE24080. The external validation cohorts include GSE9782, GSE2658, MMRF-COMPASS, and Oncomine. The data of MGUS to relapsed MM were acquired from GSE6477, GSE5900, and Oncomine. The data of EM were acquired from GSE39683 and GSE66291. Single-cell level transcriptome data of MM and EM were acquired from GSE106218. GSVA analysis revealed that 559 cases could be divided into 2 groups based on the expression of oncogenic pathways with prognostic significances. Group 1 with a specific phenotype of YAP1-MYC+ exhibited an unpromising prognosis. The univariate analysis revealed YAP1 as a tumor suppressor in MM. The activity of DNA repair, glycolysis, and oxidative phosphorylation was significantly higher in YAP1-MYC+ MM, which is in concordance with EM myeloma cells based on single-cell analysis. Furthermore, we discovered that YAP1-MYC+ MM patients exhibited an improved response for IMiD treatment. Collectively, YAP1-MYC+MM patients might suffer a worse prognosis and stronger propensity for EM progression.

M6A-induced lncDBET promotes the malignant progression of bladder cancer through FABP5-mediated lipid metabolism.

The limited effect of adjuvant therapy for advanced bladder cancer (BCa) leads to a poor prognosis. Increasing evidence has shown that RNA N6-methyladenosine (m6A) modification plays important functional roles in tumorigenesis. Nevertheless, the role and mechanism of m6A-modified noncoding RNAs (ncRNAs) in BCa remain largely unknown.Methods: RT-PCR, western blotting and ONCOMINE dataset were used to determine the dominant m6A-related enzyme in BCa. M6A-lncRNA epitranscriptomic microarray was used to screen candidate targets of METTL14. RT-PCR, MeRIP and TCGA dataset were carried out to confirm the downstream target of METTL14. CHIRP/MS was conducted to identify the candidate proteins binding to lncDBET. RT-PCR, western blotting, RIP and KEGG analysis were used to confirm the target of lncDBET. The levels of METTL14, lncDBET and FABP5 were tested in vitro and in vivo. CCK-8, EdU, transwell and flow cytometry assays were performed to determine the oncogenic function of METTL14, lncDBET and FABP5, and their regulatory networks.Results: We identified that the m6A level of total RNA was elevated and that METTL14 was the dominant m6A-related enzyme in BCa. m6A modification mediated by METTL14 promoted the malignant progression of BCa by promoting the expression of lncDBET. Upregulated lncDBET activated the PPAR signalling pathway to promote the lipid metabolism of cancer cells through direct interaction with FABP5, thus promoting the malignant progression of BCa in vitro and in vivo.Conclusions: Our study establishes METTL14/lncDBET/FABP5 as a critical oncogenic axis in BCa.

Investigating the Association between COMMD3 Expression and the Prognosis of Hepatocellular Carcinoma.

The Copper Metabolism MURR1 Domain (COMMD) family proteins are known to play roles in promoting or inhibiting the proliferation, migration and invasion of tumor cells. However, the role of COMMD3 in hepatocellular carcinoma are still unclear. By investigating the TCGA datasets, we found that the mRNA expression of COMMD3 was significantly upregulated in hepatocellular carcinoma tissue compared with normal liver tissue, which was further supported by Oncomine dataset, Western blot, qRT-PCR, and IHC analysis. Moreover, Kaplan-Meier survival analysis showed that the high expression of COMMD3 was associated with poor overall survival (OS) and disease-free survival (DFS). Consistently, the clinic-pathological analysis found that the overexpression of COMMD3 was correlated with advanced TNM stage, advanced T stage and vascular invasion. By performing multivariate analysis, we found that the expression of COMMD3 was an independent influencing factor on OS and DFS. Furthermore, we knocked down COMMD3 in HCC cells via RNA interference. The results showed that silencing COMMD3 could inhibit the migration, invasion, and angiogenesis of HCC cells. Finally, we established xenograft tumor model in nude mice, and the knockdown of COMMD3 suppressed tumor growth and angiogenesis. In summary, our study showed that the high expression of COMMD3 was correlated with poor prognosis in HCC patients and contributed to migration, invasion and angiogenesis of HCC cells.

NCAPH regulates gastric cancer progression through DNA damage response.

Gastric cancer (GC) is one of the most common devastating and deadly malignancies of the gastrointestinal tract in the world. GLOBOCAN data analysis showed that GC accounted for approximately 1,033,000 new cases of cancer and 78,200 deaths in 2018. Nonstructural maintenance of chromosomes (non-SMC) condensin I complex subunit H (NCAPH) is a regulatory subunit that encodes the non-SMC condensin I complex. Previous studies have demonstrated that NCAPH is highly expressed in multiple cancers. This study aimed to explore the function and potential mechanism of NCAPH in GC. Our study showed that NCAPH expression was significantly upregulated in The Cancer Genome Atlas (TCGA) and Oncomine datasets. Quantitative real-time polymerase chain reaction and western blotting were used to detect NCAPH expression in GC and paracarcinoma tissues. Cell Counting Kit-8 (CCK-8) and colony formation assays were used to examine cell proliferation. Cell scratch and Transwell invasion assays were performed to assess cell migration. In addition, western blotting was used to detect the expression of proteins related to the cell cycle, DNA damage repair, and epithelial-mesenchymal transition (EMT). Flow cytometry was applied for cell cycle and apoptosis detection. A xenograft model was employed to assess the effect of NCAPH in vivo. The results demonstrated that NCAPH expression was significantly increased in GC tissue samples and cell lines. Knockout of NCAPH notably inhibited cell proliferation, cell migration, cell invasion, cell cycle progression, and tumor growth in vitro and in vivo, and induced the G1-phase cell cycle arrest by regulating the DNA damage response. In addition, knockout of NCAPH promoted cell apoptosis and regulated the expression of EMT-related proteins. The results indicate that the knockout of NCAPH in GC cells inhibits proliferation and metastasis via the DNA damage response in vitro and in vivo. NCAPH plays an important role in GC and may be a potential therapeutic target for GC treatment.

Type IIA topoisomerase (TOP2A) triggers epithelial-mesenchymal transition and facilitates HCC progression by regulating Snail expression

ABSTRACT Type IIA topoisomerase (TOP2A) is upregulated in hepatocellular carcinoma (HCC) and its expression is positively correlated with poor prognosis. However, the underlying molecular mechanism of this connection are poorly understood. Hence, the present work aimed to examine the possible mechanisms which may be useful in identifying a potential therapeutic strategy. The differential expression of TOP2A mRNA in HCC as compared with adjacent normal tissue was analyzed using the Oncomine database. The expression levels of TOP2A in HCC specimens and cell lines were assessed by Western blot and RT-qPCR. Stable cell lines were generated to knockdown or overexpress TOP2A, and then cell growth, migration, and invasion were analyzed. Furthermore, this study examined epithelial-mesenchymal transition (EMT) as well as the activation of related pathways. Additionally, the correlation between TOP2A levels and E-cadherin/Snail expression was determined in 72 HCC specimens. Higher expression levels of TOP2A were observed in HCC in Oncomine datasets, and the results were verified using 40 pairs of HCC specimens and peritumoral tissues. TOP2A expression levels were remarkably elevated in cells with great metastatic capacity. In addition, HCC cell growth, migration, and invasion were suppressed after TOP2A knockdown in MHCC97H cells (MHCC97H-shRNA-TOP2A), while these capabilities were promoted in TOP2A-overexpressing Hep3B cells (Hep3B-TOP2A). Furthermore, EMT was inhibited in MHCC97H-shRNA-TOP2A cells, but induced in Hep3B-TOP2A cells. The induction of EMT by TOP2A was shown to be mediated by Snail, as TOP2A promoted Snail expression through the p-ERK1/2/p-SMAD2 signaling pathway. TOP2A level showed a negative correlation with E-cadherin, whereas a positive correlation with that of vimentin and Snail in human HCC specimens by immunohistochemistry analyses. Kaplan–Meier survival curves revealed that TOP2A upregulation showed a positive correlation with poor prognosis patients. Taken together, TOP2A possibly enhances the metastasis of HCC by promoting EMT through the mediation of the p-ERK1/2/p-SMAD2/Snail pathway. This indicates that TOP2A maybe a potential factor to predict the prognosis of HCC.

Identification of Therapeutic Targets and Prognostic Biomarkers Among Chemokine (C-C Motif) Ligands in the Liver Hepatocellular Carcinoma Microenvironment.

Background: Liver hepatocellular carcinoma (LIHC) is the third leading cause of cancer-related death and the sixth most common solid tumor worldwide. In the tumor microenvironment, the cross-talk between cancer cells, immune cells, and stromal cells exerts significant effects on neoplasia and tumor development and is modulated in part by chemokines. Chemokine (C-C motif) ligands (CCL) can directly target tumor cells and stromal cells, and they have been shown to regulate tumor cell proliferation, cancer stem-like cell properties, cancer invasiveness and metastasis, which directly and indirectly affect tumor immunity and influence cancer progression, therapy and patient outcomes. However, the prognostic values of chemokines CCL in LIHC have not been clarified. Methods: In this study, we comprehensively analyzed the relationship between transcriptional chemokines CCL and disease progression of LIHC using the ONCOMINE dataset, GEPIA, UALCAN, STRING, WebGestalt, GeneMANIA, TRRUST, DAVID 6.8, LinkedOmics, TIMER, GSCALite, and Open Targets. We validated the protein levels of chemokines CCL through western blot and immunohistochemistry. Results: The transcriptional levels of CCL5/8/11/13/15/18/20/21/25/26/27/28 in LIHC tissues were significantly elevated while CCL2/3/4/14/23/24 were significantly reduced. A significant correlation was found between the expression of CCL14/25 and the pathological stage of LIHC patients. LIHC patients with low transcriptional levels of CCL14/21 were associated with a significantly poor prognosis. The functions of differentially expressed chemokines CCL were primarily related to the chemokine signaling pathway, cytokine–cytokine receptor interactions, and TNF-α signaling pathway. Our data suggested that RELA/REL, NFKB1, STAT1/3/6, IRF3, SPI1, and JUN were key transcription factors for chemokines CCL. We found significant correlations among the expression of chemokines CCL and the infiltration of six types of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells) and immune checkpoints (PD-1. PD-L1, and CTLA-4). The western blot and immunohistochemistry results showed that protein expression levels of CCL5 and CCL20 were upregulated in LIHC. CCL5 and CCL20 were significantly correlated with the clinical outcome of patients with LIHC, and could be negatively regulated by some drugs or small molecules. Conclusions: Our results may provide novel insights for the potential suitable targets of immunological therapy and prognostic biomarkers for LIHC.