Oncomine Database Research Articles

H2AFX might be a prognostic biomarker for hepatocellular carcinoma.

H2AFX can play a central role in DNA repair, replication, transcription regulation, and chromosomal stability. However, there is little research to explore the expression of H2AFX in cancers. Moreover, the correlation between the expression of H2AFX and tumor immunity, which affects the prognosis of hepatocellular carcinoma (HCC), is not clear. This article aimed to observe the correlation between H2AFX and tumor tissue infiltration biomarkers in HCC and its prognostic potential in HCC. Oncomine and TIMER database were used to assess the expression level of H2AFX mRNA, and GEPIA and Kaplan-Meier databases were used to evaluate its prognostic potential. The TIMER database analyzed the relationship between h2afx expression level and tumor immune cell infiltration markers in liver cancer tissues. The results showed that H2AFX was overexpressed in tumor tissues than normal tissues in HCC via analysis, and its expression level was correlated with the survival rate of HCC. Moreover, the expression level of H2AFX was related to various immune biomarkers. These results show that overexpression of H2AFX would reflect the poor prognosis of HCC, and these would also reflect that the gene H2AFX can affect the infiltration of HCC immune cells and then play a role in regulating tumor immunity. Our study showed that the gene H2AFX might be a potential poor prognostic biomarker in HCC and might be involved in the infiltration of HCC immune cells.

Exploration of the breast ductal carcinoma in situ signature and its prognostic implications.

Following the implementation of breast screening programs, the occurrence of ductal carcinoma in situ (DCIS) as an early type of neoplasia has increased. Although the prognosis is promising, 20%-50% of DCIS patients will progress to invasive ductal carcinoma (IDC) if not treated. It is essential to look for promising biomarkers for predicting DCIS prognosis. The Gene Expression Omnibus (GEO) database was used to explore the expression of genes that differed between DCIS and normal tissue in this investigation. Enrichment analysis was performed to characterize the biological role and intrinsic process pathway. The Cancer Genome Atlas Breast Cancer Dataset was used to categorize the hub genes, and the results were confirmed using the Cytoscape plugin CytoHubba and MCODE. The prognostic ability of the core gene signature was determined through time-dependent receiver operating characteristic (ROC), Kaplan-Meier survival curve, Oncomine databases, and UALCAN databases. In addition, the prognostic value of core genes was verified in proliferation assays. We identified 217 common differentially expressed genes (DEGs) in the present study, with 101 upregulated and 138 downregulated genes. The top genes were obtained from the PPI network (protein-protein interaction). A unique six-gene signature (containing GAPDH, CDH2, BIRC5, NEK2, IDH2, and MELK) was developed for DCIS prognostic prediction. Centered on the Cancer Genome Atlas (TCGA) cohort, the ROC curve showed strong results in prognosis prediction. The six core gene signatures is often overexpressed in DCIS, with a weak prognosis. Furthermore, when breast cancer cells are transfected with small interfering RNAs, downregulation of core gene expression substantially inhibits cell proliferation, revealing a high potential for employing core genes in DCIS prognosis. In conclusion, the current investigation verified the six core genes signatures for prospective DCIS biomarkers, which may aid clinical decision-making for individual care.

Mesenchymal stem cells derived from adipose accelerate the progression of colon cancer by inducing a MT-CAFs phenotype via TRPC3/NF-KB axis

BackgroundThere is increasing evidence that mesenchymal stem cells (MSCs) help shape the tumor microenvironment and promote tumor progression, and ion channels might play a critical role in this process. The objective of the present study was to explore the function and mechanism of MT-CAFs on progression of colon cancer.MethodsHere, a gene chip was used for a general analysis of gene expression changes in MSC-transformed CAF cells (MT-CAFs). Bioinformatic tool and western blot screened out the ion channel protein TRPC3 with significantly increased expression, and identify the function through two-photon microscope. The progression of cancer was detected via MTS, transwell and Wound Healing. ELISA deected the secretion of inflammation factors. TRPC3/NF-KB axis was identified by western blot and immunofluorescence.ResultsTRPC3 can caused calcium influx, which further activated the NF-KB signaling pathway. Knockdown or inhibition of TRPC3 in MSCs significantly reduced the activation of NF-KB, and decreased the growth, migration, and invasion of MT-CAFs. After TRPC3 knockdown, the ability of MT- CAFs to promote tumor migration and invasion was impaired. Conversely, the upregulation of TRPC3 expression in MT-CAFs had the opposite effect. In vivo, TRPC3 expressed on MSCs also contributed to the tumorigenesis and progression of cancer cells. In addition, the Oncomine and GEPIA databases showed that TRPC3 expression is higher in colon cancer tissues compared with normal colon tissues, and was positively correlated with the expression of the CAF genes alpha-smooth muscle (α-SMA/ACTA2) and fibroblast activation protein Alpha. The disease-free survival of patients with positive TRPC3 expression in MSCs was significantly shorter than those with negative expression.ConclusionsThese results indicate that TRPC3 expressed on MT-CAFs plays a critical role in tumor progression via the NF-KB signaling pathway, and is correlated with poor prognosis in colon cancer patients. Therefore, TRPC3 may be a novel therapeutic target for the treatment of colon cancer.

Targeting MYO1B impairs tumorigenesis via inhibiting the SNAI2/cyclin D1 signaling in esophageal squamous cell carcinoma.

Myosin-related proteins play an important role in cancer progression. However, the clinical significance, biological functions, and mechanisms of myosin 1B (MYO1B), in esophageal squamous cell carcinoma (ESCC) remain unclear. The clinical relevance of MYO1B, SNAI2, and cyclin D1 in ESCC was determined by immunohistochemistry, Oncomine, and GEPIA databases. The oncogenic roles of MYO1B were determined by CCK8, colony formation assays, wound healing, and Transwell assay. MYO1B, SNAI2, and cyclin D1 at mRNA and protein levels in ESCC cells were detected by qPCR and Western blot analysis. In our study, we found that MYO1B expression was increased in ESCC tissue samples and correlated with tumor stage, TNM stage, and poor outcomes. Functional assays indicated that depletion of MYO1B impaired oncogenesis, and enhanced chemosensitivity in ESCC. Bioinformatic analysis and mechanistic studies illustrated that SNAI2 was a key downstream effector of MYO1B. Suppression of MYO1B downregulated expression of SNAI2, thereby inhibiting the SNAI2/cyclin D1 pathway. Furthermore, a selective inhibitor of cyclin D1 activation reversed siMYO1B cells overexpressing SNAI2-elicited aggressive phenotypes of ESCC cells. MYO1B positively correlated with SNAI2 and cyclin D1 in ESCC samples, and higher SNAI2 expression was also associated with poor prognosis in ESCC patients. Our finding demonstrated that MYO1B activates the SNAI2/cyclin D1 pathway to drive tumorigenesis and cisplatin cytotoxicity in ESCC, indicating that MYO1B is a potential therapeutic target for patients with ESCC.

Deoxythymidylate Kinase as a Promising Marker for Predicting Prognosis and Immune Cell Infiltration of Pan-cancer.

Background: Deoxythymidylate kinase (DTYMK) serves as a pyrimidine metabolic rate-limiting enzyme that catalyzes deoxythymidine monophosphate (dTMP) to generate deoxythymidine diphosphate (dTDP). It remains unclear whether DTYMK expression has the potential to predict outcome and immune cell infiltration in cancers. Methods: DTYMK expression profile was analyzed using Oncomine, TIMER, GEPIA and UALCAN databases. The influence of DTYMK on immune infiltration was examined using TIMER and TISIDB databases. DTYMK interactive gene hub and co-expressing genes were obtained and analyzed by STRING and Linkedomics, respectively. The relationship between DTYMK expression and patient prognosis was validated using GEPIA, Kaplan-Meier plotter, and PrognoScan databases. The functions of DTYMK in cancer cells were also biologically validated in vitro. Results: DTYMK expression was elevated in tumor tissues compared with their control counterparts. DTYMK expression varied in different stages and discriminatorily distributed in different immune and molecular subtypes. Higher expression of DTYMK predicted worse outcome in several cancer types such as liver hepatocellular carcinoma (LIHC) and lung adenocarcinoma (LUAD). High DTYMK expression was positively or negatively correlated with immune cell infiltration, including B cell, CD8+ cell, CD4+ T cell, macrophage, neutrophil and dendritic cell, depending on the type of cancers. Additionally, DTYMK co-expressing genes participated in pyrimidine metabolism as well as in T helper cell differentiation in LIHC and LUAD. In vitro, knockdown of DTYMK suppressed cell migration of liver and lung cancer cells. Conclusion: DTYMK might be taken as an useful prognostic and immunological marker in cancers and further investigation is warrented.

High expression of eIF4A1 predicts unfavorable prognosis in clear cell renal cell carcinoma

BackgroundClear cell renal cell carcinoma (ccRCC) is a worldwide malignancy with high morbidity and mortality. Translation initiation factor 4A1 (eIF4A1), which is an ATP-dependent RNA helicase as a part of eIF4F complex, has been linked to malignant transformation and progression, and a variety of cancers display dysregulation of this enzyme. However, its role in ccRCC remains unclear. In our study, we examined its potential effects in ccRCC. MethodsBased on Proteomic data, TCGA and ONCOMINE database, RCC cell lines and tissues, the expression of eIF4A1 between ccRCC and normal tissues were investigated. A correlation was evaluated between the prognostic model for OS and ccRCC progression. Analysis of functional enrichment and PPI network were performed. After examining differentially expressed genes between the eIF4A1 high and low-expression groups, we performed GSEA analysis. Furthermore, we investigated immune cell infiltration of eIF4A1. Then we determined eIF4A1 functions in the establishment and maintenance of cell viability, migration and invasion of cell lines. Flow cytometry was utilized to detect cell cycle. ResultsThe eIF4A1 was up-regulated in ccRCC tissues and cell lines. An increased level of eIF4A1 was linked to lower survival rates and impaired immunity. Depletion of eIF4A1 could arrest tumor cells in G1 phase, so as to seriously limit cell proliferation and weaken the capacity of cell migration. ConclusionccRCC patients with high eIF4A1 expression are at increased risk of poor prognosis, furthermore eIF4A1 plays a prominent role in facilitating tumor cell proliferation and migration which may further be a potential prognostic biomarker and therapeutic target.

Bioinformatics analysis of the role of aldolase A in tumor prognosis and immunity

Aldolase A (ALDOA) is an enzyme that plays an important role in glycolysis and gluconeogenesis, which is closely related to tumor metabolism. In this study, the overall roles of ALDOA in pan-cancer have been investigated from several aspects using databases and online analysis tools. Using the ONCOMINE database, the expression of ALDOA in various cancers was analyzed. The prognostic role of ALDOA was explored by PrognoScan, GEPIA, and Kaplan–Meier Plotter. The immune-related role of ALDOA and its downstream substrates was decided by TIMER, cBioPortal and String. Our data indicate that ALDOA expression level in lung adenocarcinoma, liver hepatocellular carcinoma, head and neck squamous cell carcinoma is higher than that in normal tissues. Increased expression of ALDOA often indicates a poor prognosis for patients. The correlation between ALDOA and immune infiltration among different tumors is very different. We also investigate the relationship between ALDOA and its upstream/downstream proteins. Our results showed that ALDOA could be used as a biomarker for the tumor prognosis, and could be correlated with the infiltrating levels of macrophages, CD4+ T cells and CD8+ T cells.

ETV1 Positively Correlated With Immune Infiltration and Poor Clinical Prognosis in Colorectal Cancer.

ObjectiveNumerous studies recently suggested that the immune microenvironment could influence the development of colorectal cancer (CRC). These findings implied that the infiltration of immune cells could be a promising prognostic biomarker for CRC.MethodsFurthermore, the Oncomine database and R2 platform analysis were applied in our research to validate CRC clinical prognosis via expression levels of polyoma enhancer activator 3 (PEA3) members. We explored the correlation of ETV1, ETV4, and ETV5 with tumor-infiltrating immune cells (TIICs) in CRC tumor microenvironments via the Tumor Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA). Immunohistochemistry (IHC) was used to validate our CRC clinical data.ResultsOur findings indicated that the upregulation of PEA3 members including ETV1 and ETV5 was positively associated with poor prognosis in CRC patients. Meanwhile, ETV1 and ETV5 may play significant roles in the development progress of CRC. Furthermore, ETV1 tends to be associated with immune infiltration of CRC, especially with cancer-associated fibroblasts and M2 macrophages.ConclusionThese findings revealed that ETV1 and ETV5 played significant roles in the development of CRC. Moreover, ETV1 was significantly associated with the infiltration of cancer-associated fibroblasts and M2 macrophages in CRC. Targeting ETV1 can be a potential auspicious approach for CRC treatment.

Calponin 3 Acts as a Potential Diagnostic and Prognostic Marker and Promotes Glioma Cell Proliferation, Migration, and Invasion

Calponin 3 (CNN3) is involved in the proliferation and invasion of cervical cancer and osteosarcoma cells. However, the role of CNN3 in glioma tumorigenesis remains to be elucidated. CNN3 mRNA expression in normal brain tissue and gliomas, including glioblastoma multiforme and lower-grade glioma, was analyzed using GEPIA 2 and Oncomine. CNN3 levels in glioma tissues were identified using immunohistochemical data provided by the Human Protein Atlas website. The relationship between CNN3 mRNA expression and clinical characteristics of patients with glioma was analyzed using the Oncomine database and The Cancer Genome Atlas. The diagnostic value of CNN3 expression in glioma was analyzed using receiver operating characteristic analysis according to The Cancer Genome Atlas and Genotype-Tissue Expression data. The relationship between CNN3 and prognosis was analyzed using GEPIA 2. The function of CNN3 knockdown in glioma cell lines was analyzed using cell proliferation, Transwell, and Western blot assays. Both mRNA and protein levels of CNN3 were distinctly higher in lower-grade glioma and glioblastoma multiforme tissues than those in normal brain tissues, particularly glioblastoma. A higher CNN3 mRNA level had significant relationship with higher World Health Organization grade, isocitrate dehydrogenase wild-type status, and 1p/19q noncodeletion. CNN3 mRNA expression is a highly accurate marker for the diagnosis of glioma. Patients with glioma in the high-CNN3 group had significantly lower disease-free survival and survival rates. In addition, CNN3 silencing significantly inhibited cell proliferation, migration, invasion, and the phosphorylation of P65 NF-κB. CNN3 expression is increased in glioma, particularly glioblastoma. Silencing CNN3 expression inhibited the proliferation, migration, and invasion of glioma cell lines.

Bioinformatic analysis of the role of solute carrier-glutamine transporters in breast cancer.

BackgroundBreast cancer (BC) is a highly heterogeneous disease. Solute carriers (SLCs) have been involved in the tumor progression of various cancer types. This study aimed to evaluate the role of these SLC-related glutamine transporters in the prognosis of BC patients by bioinformatics analysis.MethodsThis study examined the transcription and prognostic data for glutamine-related transporters in BC from Oncomine Database, which is currently the largest oncogene microarray database platform in the world. As well as Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan-Meier (K-M), and cBioPortal online resources. The Tumor Immune Estimation Resource (TIMER) and GEPIA were also used to examine the relationship between SLCs and immune cell infiltration.ResultsThe expression levels of SLC1A5, SLC3A2, SLC7A5, SLC7A8, and SLC38A1 were higher in BC tissues than normal breast tissues, but the expression level of SLC6A14 was lower. The expression levels of SLC7A5, SLC7A8, SLC6A14, and SLC38A2 were related to a later clinical tumor stage. In the K-M analyses, The K-M curves revealed that patients with high SLC1A5 expression had a poor prognosis (OS HR =1.28, 95% CI: 1.06–1.54; P=0.01). The high expression of SLC3A2 was significantly correlated with a poor prognosis (DMFS HR =1.19, 95% CI: 1.02–1.39; P=0.027). Increased SLC7A5 mRNA levels and decreased SLC7A8 mRNA levels were significantly associated with a poor prognosis in terms of OS, RFS, DMFS and PPS. The high expression of SLC6A14 was significantly correlated with a poor prognosis (PPS HR =1.35, 95% CI: 1.07–1.7; P=0.011). The high expression of SLC38A1 was correlated with a better prognosis than low expression of SLC38A1 (RFS HR =0.84, 95% CI: 0.76–0.93; P=0.00077; DMFS HR =0.78, 95% CI: 0.67–0.91; P=0.0013). The infiltration of immune cells and their marker genes were associated with SLC1A5, SLC3A2, SLC7A5, SLC7A8, SLC6A14, SLC38A1, and SLC38A2 expression. SLC7A5, SLC7A8, SLC38A1, and SLC38A2 have the potential to regulate polarization in tumor-associated macrophages.ConclusionsSLC7A5, SLC7A8, SLC38A1, and SLC38A2 may regulate the polarization of tumor-associated macrophages (TAMs). SLC1A5, SLC3A2, SLC7A5, and SLC6A14 may be promising biomarkers for the BC diagnosis and may represent potential therapeutic targets for these patients.

Clinical significance and prospective molecular mechanism of NUF2 in gastric cancer exploration: A comprehensive study based on the GeneChip, GEO, Oncomine, and TCGA databases.

Nuf2 is a combination of silica and spindle microtubules during the cells in the cells, participating in regulatory cell proliferation and apoptosis. Previous studies have shown that the growth of gastric cancer (GC) cells is significantly inhibited after siRNA-mediated Nuf2 gene knockout. However, the expression, survival and molecular mechanism of nuf2 in patients with GC are still unclear.This study revealed the prognostic role of Nuf2 in GC and its relationship with immune cells. The expression of Nuf2 in GC by TIMER database and Oncomine database, and evaluated the relationship between the expression of Nuf2 and the survival and prognosis of patients with GC by Kaplan–Meier Plotter database and gene expression profiling interactive analysis database.Here, we revealed that Nuf2 is highly expressed in GC and is related to the prognosis of patients with GC. And there is a significant negative correlation between the Nuf2 transcription level and high immune cell infiltration. Notably, the expression of Nuf2 in GC patients with Her2 negative rather than positive is related to poor OS, FP and PPS, indicating the potential to target Nuf2 gene in GC patients with Her2 negative.We suggested that Nuf2 could be used as a diagnostic gene as a biomarker of the occurrence and prognosis of GC.

Pan-Cancer and Single-Cell Analysis Reveals CENPL as a Cancer Prognosis and Immune Infiltration-Related Biomarker.

BackgroundCentromere protein L (CENPL) is an important member of the centromere protein (CENP) family. However, the correlation between CENPL expression and cancer development and immune infiltration has rarely been studied. Here, we studied the role of CENPL in pan-cancer and further verified the results in lung adenocarcinoma (LUAD) through in vitro experiments.MethodsThe CENPL expression level was studied with TIMER 2.0 and Oncomine databases. The potential value of CENPL as a diagnostic and prognostic biomarker in pan-cancer was evaluated with the TCGA database and GEPIA. The CENPL mutation character was analyzed using the cBioPortal database. The LinkedOmics and CancerSEA databases were used to carry out the function analysis of CENPL. The role of CENPL in immune infiltration was studied using the TIMER and TISIDB websites. Moreover, the expression of CENPL was detected through RT-qPCR and Western blotting. Immunohistochemistry was used to evaluate the infiltration level of CD8+ T cells. Cell proliferation was detected by EdU and CCK8. A flow cytometer was used to analyze the influence of CENPL in cell cycle and apoptosis.ResultsCENPL was increased in most of the cancers. The upregulation and mutation of CENPL were associated with a poorer prognosis in many cancers. The results showed a significant positive correlation between CENPL and myeloid-derived suppressor cell (MDSC) infiltration and a negative correlation between CENPL and T-cell NK infiltration in most of the cancers. CENPL regulated cell proliferation and cell cycle, and was negatively correlated with the inflammation level of LUAD. The in vitro experiments suggested that CENPL was increased in LUAD tissue and cell lines. There was a negative correlation between CENPL expression and CD8+ T-cell infiltration. The knockdown of CENPL significantly suppressed the expression of CDK2 and CCNE2, and induced G0/G1 arrest and apoptosis of LUAD.ConclusionsCENPL may function as a potential biomarker and oncogene in pan-cancer, especially LUAD. Furthermore, CENPL was associated with immune cell infiltration in pan-cancer, providing a potential immune therapy target for tumor treatment.

CD155 promotes radioresistance and malignancy of esophageal cancer by regulating Hippo-YAP pathway

The expression of CD155 has been observed to increase in various human cancers, but its role in the development of esophageal cancer (EC) is unclear. Radiotherapy is one of the primary therapeutic options for EC. However, radioresistance is still a severe issue in EC treatment. In this study, Oncomine database mining, immunohistochemistry, and survival analysis showed that higher expression of CD155 in patients with EC than in healthy controls. In vitro and in vivo, we found for the first time that irradiation increased the expression of CD155 in EC cells. CD155 knockdown inhibited cell proliferation and migration and tumor formation, and significantly increased radiosensitivity in EC. The in vivo model with high CD155 expression significantly promoted the proliferation and migration of EC cells. Furthermore, increased CD155 expression was associated with poor prognosis in patients with EC. CD155 regulated the Hippo-Yap pathway, influencing cell proliferation and migration. Therefore, CD155 is essential for the proliferation, migration, and radioresistance of EC. CD155 inhibition may be a viable strategy for improving radiation treatment efficacy in individuals with EC.

Downregulation of LRRC19 Is Associated with Poor Prognosis in Colorectal Cancer

Objective Colorectal cancer (CRC) is globally one of the most often diagnosed cancers with high mortality rates. This study aimed to explore novel biomarkers for the diagnosis and prognosis of CRC. Methods We collected 4 datasets about CRC in GEO and sought differentially expressed genes (DEGs) with GEO2R. Leucine-rich repeat-containing protein 19 (LRRC19) expression was assessed through the Oncomine and TIMER database analyses, which was further confirmed by qRT-PCR of CRC samples. We used online survival analysis tools (GEPIA, PrognoScan, and Kaplan–Meier plotter) to examine the prognostic value of LRRC19 in CRC and other malignancies. GO and KEGG enrichment analyses were employed to explore the biological functions of LRRC19. Finally, we conducted network prediction by STRING and further validation on the GEPIA to discover other molecules that might interact with LRRC19. Results A total of 21 upregulated and 46 downregulated DEGs were identified from the 4 datasets. The TIMER and Oncomine online analyses showed lower mRNA of LRRC19 in CRC tissues compared with adjacent normal tissues, which was validated by qRT-PCR in CRC patient samples. The survival analysis through the GEPIA and PrognoScan websites revealed that low LRRC19 expression was significantly correlated with poor prognosis in CRC patients. The Kaplan–Meier plotter survival analysis indicated that low LRRC19 expression was significantly associated with the disease progression of patients with ovarian cancer, gastric cancer, breast cancer, and lung cancer. The enrichment analysis suggested that low expression of LRRC19 could be involved in the retinol metabolism and the zymogen granule membrane. Through STRING and GEPIA, it was found that LRRC19 is clearly associated with ZCCHC10, MOB3B, IMMP2L, and TRMT11. Conclusion LRRC19 mRNA was prominently decreased in human CRC tissues and was significantly associated with shorter survival in CRC patients. LRRC19 might serve as a possible target for early diagnosis and prognosis assessment in CRC.

Aberrant MEK5 signalling promotes clear cell renal cell carcinoma development via mTOR activation.

This study was designed to evaluate the role and expression of MEK5 signalling in clear cell renal cell carcinoma (ccRCC) and to determine the relevance of MEK5 and mTOR signalling in ccRCC. The expression of MEK5 was compared between ccRCC and normal tissues using the ONCOMINE and TCGA databases. MEK5 expression was evaluated in 14 human ccRCC samples. CCK8, wound-healing, and clone formation assays were performed to examine the cell proliferation, migration, and clone formation abilities of ccRCC cells treated with MEK5 and the inhibitor BIX02189. Furthermore, Western blotting was performed to verify the regulation and influence of MEK5 on the mTOR signalling pathway. Finally, a murine subcutaneous tumour model was constructed, and the effect and safety of BIX02189 were evaluated in vivo. The ONCOMINE and TCGA databases indicated that MEK5 expression in ccRCC was significantly higher than that in normal tissues, which was further confirmed in clinical specimens. MEK5 knockdown markedly inhibited ccRCC cell proliferation, colony formation, and migration, whereas MEK5 overexpression resulted in the opposite results. Western blotting revealed that overexpression of MEK5 could further activate the mTOR signalling pathway. Moreover, the MEK5 inhibitor BIX02189 significantly inhibited cell proliferation, arrested the cell cycle in the G0/G1 phase, induced apoptosis, and effectively inhibited cell migration and clone formation. BIX02189 also showed an excellent antitumor effect and a favourable safety profile in murine models. MEK5 expression was aberrantly increased in ccRCC, which activated the mTOR signalling pathway and regulated cell proliferation, cell cycle progression, migration, and clone formation in ccRCC. Targeted inhibition of MEK5 represents a promising new strategy in patients with ccRCC.

Prognostic and Immunological Value of GNB4 in Gastric Cancer by Analyzing TCGA Database.

Background Gastric cancer (GC) represents a universal malignant tumor of the digestive system. Stromal and immune cells belong to two main nontumor components exerting a vital function in the tumor microenvironment. Methods Based on TCGA database, this study downloaded clinical information and gene profiles of GC. The ESTIMATE algorithm was adopted for evaluating the score of immune-infiltrating cells. This work employed Sangerbox to explore the differentially denoted genes (DEGs) related to stromal, immunity, and prognosis. Besides, the STRING database was involved in order to detect the association among the proteins. The MCODE module of Cytoscape software was used to screen key genes. Oncomine and GEPIA databases were used, aiming to study the differences in key genes in healthy gastric mucosa and GC. At last, we adopted TISDIB and TIMER databases for analyzing the association of guanine nucleotide binding protein subunit-4 (GNB4) between gastric cancer and tumor immune cells. qRT-PCR was applied for exploring differential GNB4 expression between GC and normal gastric mucosa and investigating the relation of GNB4 with tumor-infiltrating lymphocytes (TILs). Results Patients undergoing a great stromal score exhibited worse prognostic outcome, and cases having a low immune score had better prognosis. Overall, altogether 656 genes were upregulated with 5 genes being downregulated, which were matrix immune-related differential genes. Furthermore, 18 genes were screened as hub genes on the basis of the univariate Cox risk model of TCGA database (82 differential genes predicted poor GC survival). Oncomine and GEPIA databases revealed that GNB4 expression in gastric cancer was obviously higher in comparison with that in normal gastric mucosa. The GSEA, TISDIB, and TIMER databases revealed that GNB4 is involved in various tumor signal pathways and immune and metabolic processes. qRT-PCR demonstrated that GNB4 expression in gastric cancer was notably higher in comparison with that in normal gastric mucosa, showing significant association with matrix TILs. Conclusion The selected key gene GNB4 is a potential biomarker to guide the immunotherapy of gastric cancer.

Thrombospondin-2 acts as a bridge between tumor extracellular matrix and immune infiltration in pancreatic and stomach adenocarcinomas: an integrative pan-cancer analysis

BackgroundThrombospondin-2 (THBS2) is a versatile glycoprotein that regulates numerous biological functions, including the apoptosis-proliferation balance in endothelial cells, and it has been linked to tumor angiogenesis. However, the exact role of THBS2 in human cancer remains unknown. This study aimed to determine THBS2 expression in a pan-cancer analysis and its association with pan-cancer prognosis and to further identify its possible roles in tumor immunity and the extracellular matrix (ECM).MethodsData on THBS2 expression in cancers and normal tissues were downloaded from the Genotype-Tissue Expression portal and UCSC Xena visual exploration tool and analyzed using the ONCOMINE database, Perl programming language, and Gene Expression Profiling and Interactive Analyses vision 2 webserver. In addition, survival prognosis was analyzed using the survival, survminer, limma, and forestplot packages in R v. 4.0.3.Immune and matrix components were also analyzed using R v. 4.0.3. Most importantly, we partially validated the role and mechanism of THBS2 in pancreatic and gastric cancers in vitro using PANC1 and BGC-823 cell lines.ResultsTHBS2 was significantly overexpressed in 17 of the 33 investigated cancers and linked to a poor prognosis in pan-cancer survival analysis. High THBS2 expression was an independent unfavorable prognostic factor in kidney renal papillary cell, mesothelioma, and stomach and pancreatic adenocarcinomas. Immune infiltration and THBS2 expression were also related. THBS2 expression has been linked to immune and stromal scores and immune checkpoint markers in various cancers. The protein–protein interaction network revealed that THBS2 is associated with multiple ECM and immune proteins. THBS2 knockdown decreased the expression of CD47 and matrix metallopeptidase 2 (MMP-2) as well as the proliferation, migration, and invasion of PANC1 and BGC-823 cells in vitro.ConclusionsOur findings suggested that THBS2 might promote cancer progression by remodeling the tumor microenvironment, affecting CD47-mediated signaling pathways, activating the pro-tumor functions of a disintegrin and metalloproteinase with thrombospondin motifs, and enhancing MMP-2 expression. Furthermore, it functions as a bridge between the ECM and immune infiltration in cancer and serves as a potential prognostic biomarker for several cancers, especially pancreatic and gastric adenocarcinomas.

Identification of significant prognostic risk markers for pancreatic ductal adenocarcinoma: a bioinformatic analysis.

This study aimed to identify novel prognostic biomarkers of pancreatic ductal adenocarcinoma (PDAC) using bioinformatics analyzes. Clinical information, microRNAs (miRNAs), and genes expression profile data from PDAC cases were downloaded from the Cancer Genome Atlas (TCGA) database. The potential prognostic risk miRNAs and genes were screened using the Elastic Net Cox proportional risk regression hazards (EN-COX) model. The receiver operating characteristic (ROC) curve and the Kaplan-Meier (KM) curve were used to identify miRNAs and genes of significant prognostic risk. Furthermore, significant prognostic risk miRNAs were functional enrichment analyses based on their target genes. Furthermore, the survival analyzes of the hub genes were validated through OncoLnc. Complete clinical records and expression data of 797 miRNAs and 19969 genes from 137 PDAC cases were obtained, of which 59 potential prognostic risk factors, including 54 genes and 5 miRNAs, were selected by EN-COX analyzes. A total of 17 significant prognostic risk markers were identified (all P<0.05), including 16 genes and 1 miRNA (miRNA-125a). The miRNA-125a target genes were found in the MiRWalk database and the function enrichment analyzes were performed in the the DAVID website. Furthermore, according to data from the Oncomine and Human Protein Atlas (HPA) databases, the mRNA and protein level of frizzled class receptor 8 (FZD8) were overexpressed in pancreatic cancer tissues compared to the corresponding noncancer normal tissues (P<0.001). However, both glutathione S-transferase mu 4 (GSTM4) and inducible T cell costimulator ligand (ICOSLG) were negatively regulated in tissues of pancreatic cancer tissues (P<0.001). Finally, survival analysis was used to validate these factors by the OncoLnc database, and the results revealed that overexpression of ICOSLG was associated with a better prognosis (P=0.025). This study showed that the expression levels of FZD8, GSTM4 and ICOSLG were significantly different between PDAC and non-tumor tissues, especially ICOSLG, which could be a prognostic indicator and therapeutic target for PDAC.

Lower Expression of TWEAK is Associated with Poor Survival and Dysregulate TIICs in Lung Adenocarcinoma.

Background Lung cancer remains the leading cause of cancer death worldwide, and the most subtype is lung adenocarcinoma (LUAD). Tumor-infiltrating immune cells (TIICs) greatly impact the prognosis of LUAD. Tumor necrosis factor–like weak inducer of apoptosis (TWEAK), signal via its receptor fibroblast growth factor-inducible 14 (Fn14), dysregulates immune cell recruitment within tumor environment, thus promoting the progression of autoimmune diseases and cancer. We aimed to explore its role in LUAD. Methods The expression level of TWEAK was explored in Tumor Immune Estimation Resource 2.0 (TIMER2.0) and Oncomine databases. The Tumor Immune Dysfunction and Exclusion (TIDE) and Lung Cancer Explorer (LCE) databases were applied to evaluate the survival in correlation to TWEAK expression. TIICs were assessed with TIMER2.0 and TIDE datasets. The expression of TWEAK protein was detected in LUAD cell lines and also in tissue samples from LUAD patients via western blotting or combination with immunochemistry. Results Our results showed that TWEAK was downregulated in LUAD tumors compared to normal tissues in TIMER2.0, Oncomine, cell lines, and clinical specimens. Poor survival was uncovered in lower TWEAK expression of LUAD patients in LCE (meta − HR = 0.84 [95% CI, 0.76-0.92]) and TCGA (Continuous Z = −1.97, p = 0.0486) and GSE13213@PRECOG (Continuous Z = −4.25, p = 2.12e − 5) in TIDE. Multiple tumor-infiltrating immune cells (TIICs) were found closely correlated with TWEAK expression in LUAD, especially hematopoietic stem cell (Rho = 0.505, p = 2.78e − 33), common lymphoid progenitor (Rho = −0.504, p = 3.79e − 33), and myeloid-derived suppressor cells (MDSCs) (Rho = −0.615, p = 1.36e − 52). Conclusion Lower level of TWEAK was linked with poor survival and aberrant recruitment and phenotype of TIICs in LUAD, which might motivate immune escape and weaken the effects of immunotherapy.

Paeoniflorin induces apoptosis and cycle arrest in B-cell acute lymphoblastic leukemia cells by inhibiting SENP1/c-Myc signaling pathway

The effect of paeoniflorin on apoptosis and cell cycle in human B-cell acute lymphoblastic leukemia(B-ALL) and its underlying mechanism were investigated in this study. Nalm-6 and SUP-B15 cells were cultured in vitro and divided into control group(0 μg·mL~(-1)) and experimental groups(200, 400, and 800 μg·mL~(-1) paeoniflorin). Cell counting kit-8(CCK-8) was used to measure the viability of Nalm-6 and SUP-B15 cells, and cell apoptosis and cell cycle distribution were analyzed by flow cytometry. Western blot was used to detect the protein levels of cleaved caspase-3, cleaved poly(ADP-ribose) polymerase(cleaved PARP), c-Myc, and small ubiquitin-like modifier-specific protease 1(SENP1). The mRNA levels of c-Myc and SENP1 in acute lymphoblastic leukemia(ALL) patients were analyzed based on the Oncomine database. AutoDock was used for molecular docking to analyze the interaction of paeoniflorin with c-Myc and SENP1 proteins. RESULTS:: showed that paeoniflorin inhibited the viability of Nalm-6 and SUP-B15 cells in concentration and time-dependent manners. Compared with the control group, paeoniflorin significantly up-regulated the expression of apoptosis-related proteins cleaved caspase-3 and cleaved PARP to induce apoptosis, evidently increased the proportion of G_2/M phase cells and induced G_2/M phase arrest, and obviously down-regulated the expression of c-Myc and SENP1 proteins in Nalm-6 and SUP-B15 cells. The mRNA levels of c-Myc and SENP1 in ALL patients were higher than those in the normal cell. Molecular docking demonstrated that paeoniflorin had good binding to c-Myc and SENP1 proteins. In summary, paeoniflorin inhibits the proliferation of Nalm-6 and SUP-B15 cells by inducing apoptosis and G_2/M phase arrest, which may be related to the down-regulation of c-Myc and SENP1 proteins.