Oncomine Database Research Articles

Elevated expression of the MYB proto-oncogene like 2 (MYBL2)-encoding gene as a prognostic and predictive biomarker in human cancers.

Recently, MYBL2 is frequently found to be overexpressed and associated with poor patient outcome in breast cancer, colorectal cancer, bladder carcinoma, hepatocellular carcinoma, neuroblastoma and acute myeloid leukemia. In view of the fact that there is an association between MYBL2 expression and the clinicopathological features of human cancers, most studies reported so far are limited in their sample size, tissue type and discrete outcomes. Furthermore, we need to verify which additional cancer entities are also affected by MYBL2 deregulation and which patients could specifically benefit from using MYBL2 as a biomarker or therapeutic target. We characterized the up-regulated expression level of MYBL2 in a large variety of human cancer via TCGA and oncomine database. Subsequently, we verified the elevated MYBL2 expression effect on clinical outcome using various databases. Then, we investigate the potential pathway in which MYBL2 may participate in and find 4 TFs (transcript factors) that may regulate MYBL2 expression using bioinformatic methods. At last, we confirmed elevated MYBL2 expression can be useful as a biomarker and potential therapeutic target of poor patient prognosis in a large variety of human cancers. Additionally, we find E2F1, E2F2, E2F7 and ZNF659 could interact with MYBL2 promotor directly or indirectly, indicating the four TFs may be the upstream regulator of MYBL2. TP53 mutation or TP53 signaling altered may lead to elevated MYBL2 expression. Our findings indicate that elevated MYBL2 expression represents a prognostic biomarker for a large number of cancers. What's more, patients with both P53 mutation and elevated MTBL2 expression showed a worse survival in PRAD and BRCA.

The expression of HOXC10 is correlated with tumor-infiltrating immune cells in basal-like breast cancer and serves as a prognostic biomarker.

BackgroundHomeobox gene C10 (HOXC10) plays a vital role in the occurrence and development of several cancers, but its effects and underlying mechanism in the prognosis of different subtypes of breast cancer remain unclear.MethodsFirst, we evaluated and compared the expression levels of HOXC10 cancer to normal tissues in the Oncomine and Tumor Immune Estimation Resource (TIMER) databases. Second, the correlation between HOXC10 and the survival of patients with different types of cancer, including breast cancer, was analyzed in the PrognoScan, Gene Expression Profiling Interactive Analysis (GEPIA), and Kaplan-Meier plotter databases. Finally, the relationship between HOXC10 and immune-infiltration levels or gene marker sets of immune cells in basal-like breast cancer (BLBC) was investigated in the TIMER and GEPIA databases.ResultsThe expression of HOXC10 was elevated in breast cancer tissues. High HOXC10 expression indicated a poor prognosis for breast cancer patients, and expression affected the survival time of lymph-node positive or grade III breast cancer patients. In BLBC, the median overall survival (OS) of patients with high HOXC10 expression was significantly shorter than that of patients with low HOXC10 expression. HOXC10 was positively correlated with the immune infiltration of macrophages in BLBC. Breast cancer patients with low HOXC10 expression in different enriched immune-cell subgroups had a favorable prognosis.ConclusionsThe level of HOXC10 expression increased significantly in breast cancer, and elevated HOXC10 was positively correlated with immune-cell infiltration and poor prognosis in BLBC. These findings shed light on the important role of HOXC10 in breast cancer. HOXC10 should be recognized as a prognostic biomarker for determining prognosis and immune infiltration in BLBC patients.

Gelsolin Can Be a Prognostic Biomarker and Correlated with Immune Infiltrates in Gastric Cancer.

BackgroundGelsolin (GSN) is the most widely expressed actin-severing protein in humans, which could regulate cell morphology, differentiation, movement and apoptosis. This study aims to explore the GSN as a prognostic biomarker of stomach adenocarcinoma (STAD).MethodsIn this study, we used several online databases to comprehensively analyze the role of GSN in STAD. Oncomine and HPA databases were used to explore the GSN expression in various cancer, especially in gastric cancer. Then, UALCAN database was used to evaluate the relationship between GSN expression and promoter methylation in clinical characteristics. Finally, we used TIMER to analyze the correlation between GSN expression and immune infiltrates in gastric cancer.ResultsGSN was down-regulated in gastric cancer, and decreased expression of GSN was related to worse survival. The GSN expression was significantly related to tumor purity in STAD and significantly correlated with infiltrating level of various immune cells, especially the dendritic cells.ConclusionOur study proposes that GSN can be served as the biomarker of disease and neoantigen for STAD treatment, which can improve the deficiency of disease-specific targeted therapies currently exist.

CEMIP as a potential biomarker and therapeutic target for breast cancer patients.

Purpose: We aimed to evaluate whether CEMIP plays any role in the survival outcome of breast cancer (BC) patients, as well as to explore the regulatory mechanism of CEMIP in BC.Methods: We evaluated the expression and prognostic effect of CEMIP in BC patients using the Oncomine, GEPIA, UALCAN, and Kaplan-Meier plotter databases. Additionally, we detected CEMIP mRNA and protein levels in BC and normal tissues via PCR and western blotting analyses. Through immunochemistry analysis, we quantified CEMIP expression in 233 samples from BC patients. We then analyzed the link between the survival outcomes and CEMIP expression based on these clinical samples. Furthermore, we explored the immune-related molecules regulated by CEMIP and its coexpressed genes using the STRING database.Results: CEMIP expression was higher in BC tissues than in normal tissues. Patients with high CEMIP mRNA levels had a worse survival outcome. Similarly, patients expressing CEMIP had significantly shorter overall survival and disease-free survival than those not expressing the protein (P < 0.01). Some lymphocytes, immune inhibitors, immune stimulators, MHC molecules, chemokines, and chemokine receptors can be regulated by CEMIP, and CEMIP and its coexpressed genes can participate in the hyaluronan biosynthetic process, hyaluronan catabolic process, and other related biological processes in the progression of BC.Conclusion: Compared to normal tissues, BC tissues had higher number of CEMIP transcripts. CEMIP expression was associated with an adverse prognosis. CEMIP and its coexpressed genes can participate in the progression of BC. Therefore, CEMIP may be a potential biomarker for the treatment of BC patients.

Lower Manic Fringe Expression as an Independent Prognostic Biomarker and Correlated with Immune Suppression of Tumor Microenvironment in Lung Adenocarcinoma

Non-small cell lung cancer is the leading cause of cancer-associated mortality worldwide and lung adenocarcinoma is its most common type. The fringe protein family can modulate the Notch receptors to regulate pathways and affect a variety of physiological processes, such as embryo development and tumor formation. To investigate the influence of manic fringe expression on the prognosis of lung adenocarcinoma patients and evaluate its correlation with immune suppression of tumor microenvironment is the objective of the study. Wilcoxon rank test and logistic regression were used to analyze the relationship between manic fringe expression and clinical characteristics of patients with lung adenocarcinoma. The influence of manic fringe expression on the prognosis of lung adenocarcinoma patients was analyzed using Kaplan- Meier plotter analysis and Cox regression, and a receiver operating characteristic curve and nomogram were constructed. Single sample gene set enrichment analysis was used to analyze the correlation between manic fringe expression and immune infiltration. The expression of manic fringe in lung adenocarcinoma was verified using the Oncomine and tumor immune estimation resource database. Manic fringe expression in lung adenocarcinoma patients was significantly lower than that in normal lung tissues. Kaplan-Meier plotter analysis revealed that the overall survival and disease-specific survival of lung adenocarcinoma patients with low manic fringe expression were shorter (p<0.05) than those of patients with high expression. Multivariate Cox analysis further confirmed that high manic fringe expression was an independent predictor of longer overall survival in patients with lung adenocarcinoma. Furthermore, the other clinicopathological features, such as tumour and lymph nodes classification and residual tumor R classification, were correlated with worse prognosis. Single sample gene set enrichment analysis showed that manic fringe expression was correlated with infiltration of interdigitating dendritic cells and tumor cells. Manic fringe may be used as an independent prognostic biomarker and is associated with immune infiltration in lung adenocarcinoma.

Overexpressed GNAZ predicts poor outcome and promotes G0/G1 cell cycle progression in hepatocellular carcinoma.

We aimed to investigate the role of G protein subunit alpha Z(GNAZ) in the progression and prognosis of patients with hepatocellular carcinoma (HCC). Oncomine, GEO, TCGA, GEPIA2, Kaplan-Meier Plotter, TIMER2, Metascape, CCLE, LinkedOmics, and UALCAN databases were used to analyze the differential expression of GNAZ in HCC and normal liver tissues, relationship between GNAZ expression and prognosis of patients with HCC, and expression of GNAZ in common human HCC cell lines. Western blotting was performed to analyze GNAZ expression, while the Cell Counting Kit 8 assay was used to determine cell proliferation, and flow cytometry was used to evaluate the cell cycle and apoptosis. Wound healing and transwell invasion assays were used to investigate cell metastasis and invasion. Using Oncomine, Gene Expression Omnibus (GEO), and GEPIA2 databases, GNAZ was found to be overexpressed in HCC tissues compared with that in adjacent normal liver tissues, and western blotting analysis showed GNAZ overexpression in seven patients with HCC who underwent surgical resection of HCC and para-cancerous tissues (p<0.01). Survival analysis revealed that high GNAZ expression was negatively associated with overall survival (OS), recurrence-free survival, progression-free survival, and disease-specific survival in patients with HCC (p<0.05). GNAZ overexpression was associated with worse 4- month, 6- month, 12- month, 24- month, 36- month, 48- month, and 60-month OS, as well as with different clinicopathological characteristics of patients with HCC, including hepatitis virus infection state; alcohol consumption state; male; female; Asian; microvascular invasion, Stage I-II, Stage II-III, and Stage III-IV; and grade II (Cox regression, p<0.05). KEGG/GO biological process enrichment indicated that the genes similar to GNAZ in HCC were mainly enriched in the cell cycle, cell cycle phase transition, DNA replication checkpoint, and regulation of G0 to G1 transition. siRNA-GNAZ significantly reduced the viability of JHH-2 and SNU-761 cells from 12 to 96h; increased the percentage of cells in the G0/G1 phase and decreased that of cells in the S and G2/M phases (p<0.05); and markedly downregulated the expression of cyclin D, cyclin E, and CDK2 protein. siRNA-GNAZ also significantly increased the percentage of JHH-2 and SNU-761 cell apoptosis at late stages, while the number of surviving cells decreased (p<0.05), and upregulated the expression of apoptosis-related proteins Bax and caspase 3 protein. Furthermore, siRNA-GNAZ remarkably reduced the healing of scratch wounds in JHH-2 and SNU-761 cells and the number of invasive cells compared with that in the control group (p<0.001). Our study demonstrated that GNAZ plays a pivotal role as a potential oncogene and predicts poor prognosis in patients with HCC. It promotes tumor proliferation via cell cycle arrest, apoptosis, migration, and invasion. Thus, GNAZ may be a potential candidate biomarker providing useful insight into hepatocarcinogenesis and aggressiveness.

Identification of Biomarkers Associated with Hepatocellular Carcinoma Stem Cell Characteristics Based on Co-Expression Network Analysis of Transcriptome Data and Stemness Index.

Mounting evidence has revealed the key role of cancer stem cells in hepatocellular carcinoma (HCC) metastasis and therapy resistance, yet the genes maintaining HCC stem cell features remain to be explored. This study aimed to identify and validate the key biomarkers associated with HCC stemness. mRNA expression-based stemness index (mRNAsi) was calculating using one-class logistic regression algorithm. RNA-sequencing data and clinical information of HCC samples were downloaded from the cancer genome atlas (TCGA) and merged with the corresponding mRNAsi. We investigated the correlation between mRNAsi and HCC clinical characteristics, including tumor grades, pathologic stages, vascular invasion, and survival outcomes. Significant genes associated HCC stemness features were screened through weighted gene co-expression network analysis (WGCNA) and were functionally annotated using enrichment analysis. Protein-protein interaction network was constructed among significant genes and the key biomarkers were finally identified based on the maximal clique centrality (MCC) method. The expression of key biomarkers and its correlation with HCC clinical outcomes were validated using oncomine and gene expression omnibus (GEO) database. mR-NAsi was significantly higher in HCC tissues and gradually increased according to tumor grades and pathologic stages. Patients with vascular invasion or poor survival exhibited higher mRNAsi. Forty-four highly-correlated significant gens were screened through WGCNA and functionally related to cell cycle, cellular senescence, p53 signaling pathway, DNA replication, and mismatch repair. Four different GEO datasets confirmed that the expression levels of these 44 genes were notably higher in HCC tissues. We finally identified 15 key biomarkers (KIF4A, TTK, CCNB1, CDC20, NCAPG, CCNB2, CDC45, UBE2C, CENPA, AURKB, RRM2, CDCA8, BIRC5, TPX2, and KIF2C) through MCC method. The expression of these biomarkers was up-regulated in multiple types of cancers and showed a gradually increasing trend with HCC tumor grades. Furthermore, high expression levels of these biomarkers were also correlated with HCC metastasis, recurrence, sorafenib resistance, and poor overall survival. We identified 15 key biomarkers associated with HCC stemness features and these genes might serve as promising therapeutic targets for HCC.

HBO1 induces histone acetylation and is important for non-small cell lung cancer cell growth

We examined the expression and the potential biological function of HBO1 in non-small cell lung cancer (NSCLC). TCGA and Oncomine databases showed that HBO1 transcripts were elevated in NSCLC. Furthermore, in local NSCLC tumor tissues HBO1 expression was higher than that in matched adjacent lung tissues. In primary and immortalized NSCLC cells, HBO1 shRNA robustly inhibited cell viability, proliferation and migration. Moreover, HBO1 knockout by CRISPR/Cas9 induced significant anti-tumor activity in NSCLC cells. Conversely, ectopic HBO1 overexpression in primary NSCLC cells increased proliferation and migration. H3-H4 histone acetylation and expression of several potential oncogenic genes (CCR2, MYLK, VEGFR2 and OCIAD2) were significantly decreased in NSCLC cells with HBO1 silencing or knockout. They were however increased after HBO1 overexpression. Intratumoral injection of HBO1 shRNA-expressing adeno-associated virus hindered the growth of A549 cell xenografts and primary NSCLC cell xenografts in nude mice. H3-H4 histone acetylation as well as expression of HBO1 and HBO1-dependent genes were decreased in HBO1-silenced NSCLC xenograft tissues. An HBO1 inhibitor WM-3835 potently inhibited NSCLC cell growth. Together, HBO1 overexpression promotes NSCLC cell growth.

Expression and significance of SOX B1 genes in glioblastoma multiforme patients.

The overall survival of glioblastoma multiforme (GBM) patients remains poor. To improve patient outcomes, effective diagnostic and prognostic biomarkers for GBM are needed. In this study, we first applied bioinformatic analyses to identify biomarkers for GBM, focusing on SOX (sex‐determining region on the Y chromosome (SRY)‐related high mobility group (HMG) box) B1 family members. The ONCOMINE, GEPIA, LinkedOmics and CCLE databases were used to assess mRNA expression levels of the SOX B1 family members in different cancers and normal tissue. Further bioinformatic analysis was performed using the ONCOMINE database in combination with the LinkedOmics data set to identify the prognostic value of SOX B1 family members for GBM. We found mRNA expression levels of all tested SOX B1 genes were significantly increased in GBM. In the LinkedOmics database, increased expression of SOX3 indicated a better overall survival. In GEPIA databases, increased expression of all SOX B1 family members suggested an improved overall survival, but none of them were statistically different. Then, Transwell assays and wound healing were employed to evaluate the motility and invasive captivity of U251 cells when silencing SOX2 and SOX3. We found exogenous inhibition of SOX2 appeared to reduce the migration and invasion of U251 cells in vitro. Collectively, our research suggested that SOX2 might serve as a cancer‐promoting gene to identify high‐risk GBM patients, and SOX3 had the potential to be a prognostic biomarker for GBM patients.

Identification and validation of PGLS as a metabolic target for early screening and prognostic monitoring of gastric cancer.

BackgroundGastric cancer is the third leading cause of cancer‐related death in the world. The purpose of the present study is to investigate the expression and prognostic significance of 6‐phosphogluconolactonase (PGLS) in gastric cancer.MethodsThe protein extracted from a panel of four pairs of gastric cancer tissues and adjacent tissues, labeled with iTRAQ (8‐plex) reagents, and followed by LC‐ESI‐MS/MS. The expressions of proteins were further validated by immunohistochemistry analysis. The expression levels of mRNA were analyzed and validated in the Oncomine database. The correlations of PGLS with prognostic outcomes were evaluated with Kaplan‐Meier plotter database.ResultsThe present study found that PGLS was significantly up‐regulated in gastric cancer by using iTRAQ‐based proteomics and immunohistochemistry analysis. The sensitivity of PGLS in gastric cancer was 72.9%. The high expression of PGLS was significantly correlated with TNM staging in gastric cancer (p = 0.02). The overexpression of PGLS predicts worse overall survival (OS) and post‐progression survival (PPS) for gastric cancer (OS, HR = 1.48, p = 2.1e‐05; PPS, HR = 1.35, p = 0.015). Specifically, the high PGLS expression predicts poor OS, PPS in male gastric cancer patients, in patients with lymph node metastasis and in patients with Her‐2 (‐).ConclusionsThese findings suggested that PGLS was aberrantly expressed in gastric cancer and predicts poor overall survival, post‐progression survival for gastric cancer patients. The present study collectively supported that PGLS is an important target for early determining and follow‐up monitoring for gastric cancer.

Identification of HMMR as a prognostic biomarker for patients with lung adenocarcinoma via integrated bioinformatics analysis

BackgroundLung adenocarcinoma (LUAD) is the most prevalent tumor in lung carcinoma cases and threatens human life seriously worldwide. Here we attempt to identify a prognostic biomarker and potential therapeutic target for LUAD patients.MethodsDifferentially expressed genes (DEGs) shared by GSE18842, GSE75037, GSE101929 and GSE19188 profiles were determined and used for protein-protein interaction analysis, enrichment analysis and clinical correlation analysis to search for the core gene, whose expression was further validated in multiple databases and LUAD cells (A549 and PC-9) by quantitative real-time PCR (qRT-PCR) and western blot analyses. Its prognostic value was estimated using the Kaplan-Meier method, meta-analysis and Cox regression analysis based on the Cancer Genome Atlas (TCGA) dataset and co-expression analysis was conducted using the Oncomine database. Gene Set Enrichment Analysis (GSEA) was performed to illuminate the potential functions of the core gene.ResultsA total of 115 shared DEGs were found, of which 24 DEGs were identified as candidate hub genes with potential functions associated with cell cycle and FOXM1 transcription factor network. Among these candidates, HMMR was identified as the core gene, which was highly expressed in LUAD as verified by multiple datasets and cell samples. Besides, high HMMR expression was found to independently predict poor survival in patients with LUAD. Co-expression analysis showed that HMMR was closely related to FOXM1 and was mainly involved in cell cycle as suggested by GSEA.ConclusionHMMR might be served as an independent prognostic biomarker for LUAD patients, which needs further validation in subsequent studies.

Mutation of Hashimoto's Thyroiditis and Papillary Thyroid Carcinoma Related Genes and the Screening of Candidate Genes.

Clinical studies have shown similarities in the genetic background and biological functional characteristics between Hashimoto’s thyroiditis (HT) and papillary thyroid carcinoma (PTC), and that HT may increase risks of PTC. Here, we set to determine the gene expression specificity of HT and PTC by screening related genes or co-expressed genes and exploring their genetic correlation. Referencing the Oncomine database, HT-related genes were discovered to be expressed in many different types of thyroid cancer, such as TSHR that is highly expressed in thyroid cancer. An in-depth genetic analysis and verification of 35 cancer and paracancerous tissue pairs from patients with thyroid cancer, and 35 tissues and blood cells pairs from patients with Hashimoto’s thyroiditis was conducted. Gene chip technology research showed that TSHR, BACH2, FOXE1, RNASET2, CTLA4, PTPN22, IL2RA and other HT-related genes were all expressed in PTC, in which TSHR was significantly over-expressed in PTC patients sensitive to radioactive iodine therapy, while BACH2 was significantly under-expressed in these patients. The biologically significant candidate Tag SNP highlighted from HT-related genes was screened by the high-throughput detection method. Somatic mutations in patients with HT and PTC were detected by target region capture technique, and 75 mutations were found in patients with HT and PTC. The upstream regulatory factors of the different genes shared by HT and PTC were analyzed based on Ingenuity Pathway Analysis (IPA), and it was found that HIF-1α and PD-L1 could be used as important upstream regulatory signal molecules. These results provide a basis for screening key diagnostic genes of PTC by highlighting the relationship between some HT-related genes and their polymorphisms in the pathogenesis of PTC.

Berberine enhances gemcitabine‑induced cytotoxicity in bladder cancer by downregulating Rad51 expression through inactivating the PI3K/Akt pathway.

Although gemcitabine (GEM) has been used to treat bladder cancer (BC) for a number of years, severe adverse events or drug resistance frequently develops. A series of drugs have been proved to sensitize patients to GEM and reduce the side effects. The aim of the present study was to evaluate the potential effects of berberine (BER) on GEM‑induced cytotoxicity in BC and to explore the possible underlying mechanisms. T24 and 5637 human BC cell lines were treated with GEM and/or BER before cell proliferation, apoptosis and migration were studied. Oncomine databases and Gene Expression Profiling Interactive Analysis (GEPIA) were used to retrieve RAD51 recombinase (Rad51) mRNA expression. Overexpression plasmid or specific Rad51 small interfering RNA were used to examine the role of Rad51 in drug‑treated BC cells. BC model mice were administered with GEM and/or BER before changes in tumor volume, size and Ki67 expression were assessed. BER enhanced GEM‑induced cytotoxicity, apoptosis and inhibition of migration, whilst attenuating the GEM‑induced upregulation of phosphorylated Akt and Rad51 expression. According to Oncomine and GEPIA analyses, Rad51 was found to be significantly upregulated in BC tissues compared with that in normal tissues, where there was a weak positive correlation between Rad51 and Akt1 expression. Knockdown of Rad51 enhanced GEM‑induced cytotoxicity, whilst overexpression of Rad51 reversed the suppressed cell viability induced by BER and GEM. Inactivation of the PI3K/Akt pathway by LY294002 or BER enhanced GEM‑induced cytotoxicity and downregulated Rad51 expression, whilst overexpression of constitutively active Akt restored Rad51 expression and cell viability that was previously decreased by BER and GEM. BER additively inhibited tumor growth and Ki67 expression when combined with GEM invivo. These results suggest that BER can enhance GEM‑induced cytotoxicity in BC by downregulating Rad51 expression through inactivating the PI3K/Akt pathway, which may represent a novel therapeutic target for BC 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.

Keratin 17 upregulation promotes cell metastasis and angiogenesis in colon adenocarcinoma

ABSTRACT Colon adenocarcinoma (COAD), having high malignancy and poor prognosis, is the main pathological type of colon cancer. Previous studies show that Keratin 17 (KRT17) plays an important role in the development of many malignant tumors. However, its role and the molecular mechanism underlying COAD remain unclear. Using TCGA and ONCOMINE databases, as well as immunohistochemistry, we found that the expression of KRT17 was higher in COAD tissues as compared to that in the adjacent normal tissues. Cell- and animal-based experiments showed that overexpression of KRT17 promoted the invasion and metastasis of colon cancer cells while knocking down KRT17 reversed these processes both in vitro and in vivo. In addition, we also showed that KRT17 promoted the formation of new blood vessels. Mechanistically, KRT17 could regulate the WNT/β-catenin signaling pathway, and APC may be involved in this process by interacting with KRT17. In summary, these findings suggested that high expression of KRT17 could promote cell metastasis and angiogenesis of colon cancer cells by regulating the WNT/β-catenin signaling pathway. Thus, KRT17 could be a potential therapeutic target for COAD treatment.

Comprehensive Analysis of Myoferlin in Human Pancreatic Cancer via Bioinformatics.

Pancreatic cancer is the fourth leading cause of cancer-related death and urgently needs biomarkers for clinical diagnosis and prognosis. It has been reported that myoferlin (MYOF) is implicated in the regulation of proliferation, invasion, and migration of tumor cells in many cancers including pancreatic cancer. To confirm the prognostic value of MYOF in pancreatic cancer, a comprehensive cancer versus healthy people analysis was conducted using public data. MYOF mRNA expression levels were compared in many kinds of cancers including pancreatic cancer via the Oncomine and Gene Expression Profiling Interactive Analysis (GEPIA) databases. The results have shown that MYOF mRNA expression levels were upregulated in most types of cancers, especially in pancreatic cancer, compared with healthy people's tissues. Data from the Cancer Cell Line Encyclopedia (CCLE) and European Bioinformatics Institute (EMBL-EML) database also revealed that MYOF mRNA is highly expressed in most cancer cells, particularly in pancreatic cancer cell lines. Furthermore, the prognostic value of MYOF was evaluated using GEPIA and Long-term Outcome and Gene Expression Profiling Database of pan-cancers (LOGpc) database. Higher expression of MYOF was associated with poorer overall survival, especially in the lower stage and lower grade. Coexpressed genes, possible regulators, and the correlation between MYOF expressions were analyzed via the GEPIA and LinkedOmics database. Nineteen coexpressed genes were identified, and most of these genes were related to cancer. The Tumor Immune Estimation Resource (TIMER) database was used to analyze the correlation between MYOF and immune response. Notably, we found that MYOF might have a potential novel immune regulatory role in tumor immunity. These results support that MYOF is a candidate prognostic biomarker for pancreatic cancer, which calls for further genomics research of pancreatic cancer and deeply functional studies on MYOF.

A novel NRF2/ARE inhibitor gossypol induces cytotoxicity and sensitizes chemotherapy responses in chemo-refractory cancer cells.

NRF2/ARE signaling pathway is a principal regulator of cellular redox homoeostasis. The stress-induced transcription factor, NRF2, can shield cells from the oxidative damages via binding to the consensus antioxidant-responsive element (ARE) and driving several cyto-protective genes expression. Increasing evidence indicated that aberrant activation of NRF2 in malignant cells may support their survival through various pathways to detoxify chemotherapy drugs, attenuate drug-induced oxidative stress, or induce drug efflux, all of which are crucial in developing drug resistance. Accordingly, NRF2 is a potential drug target for improving the effectiveness of chemotherapy and to reverse drug resistance in cancer cells. A stable ARE-driven reporter human head and neck squamous cell carcinoma (HNSCC) cell line, HSC3-ARE9, was established and utilized to screen novel NRF2 inhibitors from a compound library. The cotton plant derived phenolic aldehyde-gossypol was selected for further analyses. The effects of gossypol in cancer cells were determined by western blotting, RT-qPCR, clonogenic assay, and cell viability assays. The gossypol-responsive gene expression levels were assessed in the Oncomine database. The effects of gossypol on conferring chemo-sensitization were evaluated in etoposide-resistant and cisplatin-resistant cancer cells. Our study is the first to identify that gossypol is effective to reduce both basal and NRF2 activator tert-butylhydroquinone (t-BHQ)-induced ARE-luciferase activity. Gossypol diminishes NRF2 protein stability and thereby leads to the suppression of NRF2/ARE pathway, which resulted in decreasing the expression levels of NRF2 downstream genes in both time- and dose-dependent manners. Inhibition of NRF2 by gossypol significantly decreases cell viabilities in human cancer cells. In addition, we find that gossypol re-sensitizes topoisomerase II poison treatment in etoposide-resistant cancer cells via suppression of NRF2/ABCC1 axis. Moreover, gossypol suppresses NRF2-mediated G6PD expression thereby leads to induce synthetic lethality with cisplatin not only in parental cancer cells but also in cisplatin-resistant cancer cells. These findings suggest that gossypol is a novel NRF2/ARE inhibitor, and can be a potential adjuvant chemotherapeutic agent for treatment of chemo-refractory tumor.

Role of the CBX Molecular Family in Lung Adenocarcinoma Tumorigenesis and Immune Infiltration.

Background: The members of the Chromobox (CBX) family are important epigenetic regulatory molecules with critical biological roles in many tumors. However, no study has analyzed or verified their role in lung adenocarcinoma (LUAD). Methods: UALCAN and Oncomine databases were used to analyze CBX expression in LUAD, and the cBioPortal database was used to analyze CBX genetic variations. The Kaplan-Meier plotter and UALCAN databases were used to identify molecules with prognostic value. Gene Ontology pathway, receiver operating characteristic curves, and tumor-infiltrating immune cell analyses were used to clarify the biological function of the CBX hub molecules. Paired tumor samples and lung adenocarcinoma cell lines were collected for molecular functional assays to validate the results of the bioinformatics analysis. Results: CBX3/5 may have a cancer-promoting effect and its expression is associated with a poor patient prognosis, while CBX7 shows an opposite trend. CBX3/5/7 can regulate signaling pathways, regulate tumor immune cell infiltration, and has diagnostic value. Molecular biology experiments show that CBX3/5 is highly expressed in LUAD patients; in vitro it promotes the proliferation and migration of the LUAD cell line and can regulate the expression of the corresponding cytokines. CBX7 has opposite effects. Conclusion: Our bioinformatics analysis and subsequent experimental verification confirmed the CBX family members acted as hub signaling molecules in LUAD. The results provide new potential targets for the diagnosis and treatment of this cancer.

Overexpression of SKA3 correlates with poor prognosis in female early breast cancer.

BackgroundSpindle and kinetochore associated complex subunit 3 (SKA3) plays an important role in tumorigenesis and the progression of various tumors. But the relationship between SKA3 and early breast cancer remains unclear. The study aimed to explore the prognostic significance of SKA3 in breast cancer.MethodsIn the study, SKA3 expression was initially assessed using the Oncomine database and The Cancer Genome Atlas database (TCGA). Then, we presented validation results for RT-qPCR (quantitative reverse transcription PCR) and ELISA (enzyme-linked immunosorbent assay). The relationship between clinical characteristics and SKA3 expression was assessed by Chi-square test and Fisher’s exact test. Kaplan–Meier method and Cox regression analysis were conducted to evaluate the prognostic value of SKA3. Gene set enrichment analysis (GSEA) was performed to screen biological pathways using the TCGA dataset. Besides, single sample gene set enrichment analysis (ssGSEA) was utilized to identify immune infiltration cells about SKA3.ResultsSKA3 mRNA was expressed at high levels in breast cancer tissues compared with normal tissues. Chi-square test and Fisher’s exact test showed SKA3 expression was related to age, tumor (T) classification, node (N) classification, tumor-node-metastasis (TNM) stage, estrogen receptor (ER), progesterone receptor (PR), molecular subtype, and race. RT-qPCR results showed that SKA3 expression was overexpressed in ER, PR status, and molecular subtype in Chinese people. Kaplan–Meier curves implicated that high SKA3 expression was related to a poor prognosis in female early breast cancer patients. Cox regression models showed that high SKA3 expression could be used as an independent risk factor for female early breast cancer. Four signaling pathways were enriched in the high SKA3 expression group, including mTORC1 signaling pathway, MYC targets v1, mitotic spindle, estrogen response early. Besides, the SKA3 expression level was associate with infiltrating levels of activated CD4 T cells and eosinophils in breast cancer.ConclusionHigh SKA3 expression correlates with poor prognosis and immune infiltrates in breast cancer. SKA3 may become a biomarker for the prognosis of breast cancer.

Use the Chinese herbal compound regulatory network to verify the relationship between the Jun, Chen, Zuo, and Shi of Xiaochaihu Decoction in treating hepatitis

PurposeTo verify the relationship between the monarch(Jun), minister(Chen), assistant(Zuo), and guide(Shi) of Xiaochaihu Decoction in treating hepatitis through the regulation network of traditional Chinese Pharmacy compound. MethodsFirst, We use the data in the TCMSP database to obtain the effective ingredients and targets of Xiaochaihu Decoction, and screen the effective ingredients. Then, the genes related to hepatitis diseases obtain from the five databases, and the intersection genes with the target genes Xiaochaihu Decoction were screened. Third, We draw the "traditional Chinese Pharmacy - compound - target (gene)" network diagram of Xiaochaihu Decoction and hepatitis, then we get the network core of the network. Fourth, We perform GO enrichment analysis and KEGG enrichment analysis on the intersection genes. Fifth, We use molecular docking technology to verify the interaction between crucial targets and compounds. Finally, get data from the Oncomine database for Meta-analysis. We have verified the gene expression and protein expression determination of AKT, IKKs, IκBα through PCR and WB experiments. ResultsWe screened and obtained the drug target information of Xiaochaihu Decoction, and we finally obtained a total of 163 active ingredients and 6854 hepatitis-related genes. There are 193 genes common to drug targets and hepatitis. We obtained 18 core genes from the Chinese herbal compound regulatory network diagram. The results of Meta-analysis and molecular docking are both ideal. It proved that Xiaochaihu Decoction has an inhibitory effect on the TNF signaling pathway and the gene expression of AKT, IKKs, and IκBα. The Jun (Monarch) Chen (Minister) medicine plays an essential guiding role in Xiaochaihu Decoction. ConclusionsThe results obtained through the Chinese herbal compound regulatory network analysis can scientifically explain the relationship between the Jun (Monarch), Chen (Minister), Zuo (Assistant), and Shi (Guide) of Xiaochaihu Decoction.