scholarly journals Comprehensive analysis of abnormal expression, prognostic value and oncogenic role of the hub gene FN1 in pancreatic ductal adenocarcinoma via bioinformatic analysis and in vitro experiments

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e12141
Author(s):  
Xiaohua Lei ◽  
Guodong Chen ◽  
Jiangtao Li ◽  
Wu Wen ◽  
Jian Gong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Bioinformatic Analysis ◽  
Ductal Adenocarcinoma ◽  
Therapeutic Effects ◽  
Hub Genes ◽  
Poor Overall Survival ◽  
Geo Dataset

Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most commonly diagnosed cancers with a poor prognosis worldwide. Although the treatment of PDAC has made great progress in recent years, the therapeutic effects are still unsatisfactory. Methods. In this study, we identified differentially expressed genes (DEGs) between PDAC and normal pancreatic tissues based on four Gene Expression Omnibus (GEO) datasets (GSE15471, GSE16515, GSE28735 and GSE71729). A protein–protein interaction (PPI) network was established to evaluate the relationship between the DEGs and to screen hub genes. The expression levels of the hub genes were further validated through the Gene Expression Profiling Interactive Analysis (GEPIA), ONCOMINE and Human Protein Atlas (HPA) databases, as well as the validation GEO dataset GSE62452. Additionally, the prognostic values of the hub genes were evaluated by Kaplan–Meier plotter and the validation GEO dataset GSE62452. Finally, the mechanistic roles of the most remarkable hub genes in PDAC were examined through in vitro experiments. Results We identified the following nine hub genes by performing an integrated bioinformatics analysis: COL1A1, COL1A2, FN1, ITGA2, KRT19, LCN2, MMP9, MUC1 and VCAN. All of the hub genes were significantly upregulated in PDAC tissues compared with normal pancreatic tissues. Two hub genes (FN1 and ITGA2) were associated with poor overall survival (OS) rates in PDAC patients. Finally, in vitro experiments indicated that FN1 plays vital roles in PDAC cell proliferation, colony formation, apoptosis and the cell cycle. Conclusions In summary, we identified two hub genes that are associated with the expression and prognosis of PDAC. The oncogenic role of FN1 in PDAC was first illustrated by performing an integrated bioinformatic analysis and in vitro experiments. Our results provide a fundamental contribution for further research aimed finding novel therapeutic targets for overcoming PDAC.

scholarly journals Identification of the hub gene BUB1B in hepatocellular carcinoma via bioinformatic analysis and in vitro experiments

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e10943
Author(s):  
Jie Fu ◽  
Xiao Zhang ◽  
Likun Yan ◽  
Yaoli Shao ◽  
Xinxu Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Genetic Alterations ◽  
Therapeutic Effects ◽  
In Vitro Experiments ◽  
Hub Genes ◽  
Post Surgery ◽  
Mitochondrial Functions

Background Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers and the fourth leading cause of cancer-related deaths in the world. Although the treatment of HCC has made great progress in recent years, the therapeutic effects on HCC are still unsatisfactory due to difficulty in early diagnosis, chemoresistance and high recurrence rate post-surgery. Methods In this study, we identified differentially expressed genes (DEGs) based on four Gene Expression Omnibus (GEO) datasets (GSE45267, GSE98383, GSE101685 and GSE112790) between HCC and normal hepatic tissues. A protein–protein interaction (PPI) network was established to identify the central nodes associated with HCC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of the central nodes were conducted to find the hub genes. The expression levels of the hub genes were validated based on the ONCOMINE and Gene Expression Profiling Interactive Analysis (GEPIA) databases. Additionally, the genetic alterations of the hub genes were evaluated by cBioPortal. The role of the hub genes on the overall survival (OS) and relapse survival (RFS) of HCC patients was evaluated by Kaplan-Meier plotter. At last, the mechanistic role of the hub genes was illustrated by in vitro experiments. Results We found the following seven hub genes: BUB1B, CCNB1, CCNB2, CDC20, CDK1, MAD2L1 and RRM2 using integrated bioinformatics analysis. All of the hub genes were significantly upregulated in HCC tissues. And the seven hub genes were associated with the OS and RFS of HCC patients. Finally, in vitro experiments indicated that BUB1B played roles in HCC cell proliferation, migration, invasion, apoptosis and cell cycle by partially affecting mitochondrial functions. Conclusions In summary, we identified seven hub genes that were associated with the expression and prognosis of HCC. The mechanistic oncogenic role of BUB1B in HCC was first illustrated. BUB1B might play an important role in HCC and could be potential therapeutic targets for HCC.

scholarly journals KIF4A Regulates the Progression of Pancreatic Ductal Adenocarcinoma through Proliferation and Invasion

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Jing Chen ◽  
Cui-Cui Zhao ◽  
Fei-Ran Chen ◽  
Guo-Wei Feng ◽  
Fei Luo ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Disease Free Survival ◽  
High Expression ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion

Background. Pancreatic cancer is a malignant tumor of the digestive tract, which is difficult to diagnose and treat due to bad early diagnosis. We aimed to explore the role of kinesin superfamily 4A (KIF4A) in pancreatic ductal adenocarcinoma (PDAC). Methods. We first used the bioinformatic website to screen the data of pancreatic cancer in TCGA, and KIF4A protein was detected among the 86 specimens of patients in our hospital combined with clinic-pathological characteristics and survival analysis. KIF4A loss-expression cell lines were established by RNA interference (RNAi). In addition, we performed in vitro cell assays to detect the changes in cell proliferation, migration, and invasion. The proteins involved in the proliferation and metastasis of cancer cells were also detected by western blot. The above results could be proved in vivo. Further, the correlation between KIF4A and CDC5L was analyzed by TCGA and IHC data. Results. We first found a high expression of KIF4A in pancreatic cancer, suggesting a role of KIF4A in the development of pancreatic cancer. KIF4A was found to be differentially expressed ( P < 0.05 ) among the 86 specimens of patients in our hospital and was significantly associated with PDAC TNM stages and tumor size. High KIF4A expression also significantly worsened overall survival (OS) and disease-free survival rate (DFS) ( P < 0.05 , respectively). In addition, cell proliferation, migration, and invasion were inhibited by the KIF4A-shRNA group compared with the control ( P < 0.05 , respectively). In the end, knockdown of KIF4A could inhibit tumor development and metastasis in vivo. Further, the positive correlation between KIF4A and CDC5L existed, and KIF4A might promote pancreatic cancer proliferation by affecting CDC5L expression. Conclusion. In conclusion, the high expression level of KIF4A in PDAC was closely related to poor clinical and pathological status, lymphatic metastasis, and vascular invasion. KIF4A might be involved in promoting the development of PDAC in vitro and in vivo, which might be a new therapeutic target of PDAC.

scholarly journals Integrated Bioinformatics Analysis of Gene Expression Profiles for Potential Biomarker Identification Towards Early Therapeutic Intervention in Pancreatitis and Pancreatic Ductal Adenocarcinoma

2021 ◽  
Author(s):  
Manoj M Wagle ◽  
Ananya Rao Kedige ◽  
Shama P Kabekkodu ◽  
Sandeep Mallya
Keyword(s):  
Gene Expression ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Bioinformatics Analysis ◽  
Ductal Adenocarcinoma ◽  
Rapid Progression ◽  
Hub Genes ◽  
Altered Expression ◽  
Biochemical Pathways ◽  
Potential Biomarker ◽  
Key Genes

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a malignancy associated with rapid progression and an abysmal prognosis. It has been reported that chronic pancreatitis can increase the risk of developing PDAC by 16-fold. Our study aims to identify the key genes and biochemical pathways mediating pancreatitis and PDAC. The gene expression datasets were retrieved from the EMBL-EBI ArrayExpress and NCBI GEO database. A total of 172 samples of normal pancreatic tissue, 68 samples of pancreatitis, and 306 samples of PDAC were used in this study. The differentially expressed genes (DEGs) identified were used to perform downstream analysis for ontology, interaction, and associated pathways. Furthermore, hub gene expression was validated using the GEPIA2 tool and survival analysis using the Kaplan-Meier (KM) plotter. The potential druggability of the hub genes identified was determined using the Drug-Gene Interaction Database (DGIdb). Our study identified a total of 45 genes found to have altered expression levels in both PDAC and pancreatitis. Over-representation analysis revealed that protein digestion and absorption pathway, ECM-receptor interaction pathway, PI3k-Akt signaling pathway, and proteoglycans in cancer pathways as significantly enriched. Module analysis revealed 15 hub genes with 92 edges, of which 14 were found to be in the druggable genome category. Through bioinformatics analysis, we identified key genes and biochemical pathways disrupted in pancreatitis and PDAC. The results can provide new insights into targeted therapy and intervening therapeutically at an earlier stage can be used as an effective strategy to decrease the incidence and severity of PDAC.

scholarly journals Identify key genes and pathways in pancreatic ductal adenocarcinoma via bioinformatics analysis

2020 ◽  
Author(s):  
Huatian Luo ◽  
Da-qiu Chen ◽  
Jing-jing Pan ◽  
Zhang-wei Wu ◽  
Can Yang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Bioinformatics Analysis ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Gene Expression Omnibus ◽  
Ductal Adenocarcinoma ◽  
Hub Genes ◽  
Expression Levels

Abstract Background: Pancreatic cancer has many pathologic types, among which pancreatic ductal adenocarcinoma (PDAC) is the most common one. Bioinformatics has become a very common tool for the selection of potentially pathogenic genes. Methods: Three data sets containing the gene expression profiles of PDAC were downloaded from the gene expression omnibus (GEO) database. The limma package of R language was utilized to explore the differentially expressed genes (DEGs). To analyze functions and signaling pathways, the Database Visualization and Integrated Discovery (DAVID) was used. To visualize the protein-protein interaction (PPI) of the DEGs ,Cytoscape was performed under the utilization of Search Tool for the Retrieval of Interacting Genes (STRING). With the usage of the plug-in cytoHubba in cytoscape software, the hub genes were found out. To verify the expression levels of hub genes, Gene Expression Profiling Interactive Analysis (GEPIA) was performed. Last but not least, UALCAN analysis online tool was implemented to analyze the overall survival. Results: The 376 DEGs were highly enriched in biological processes including signal transduction, apoptotic process and several pathways, mainly associated with Protein digestion and absorption and Pancreatic secretion pathway. The expression levels of nucleolar and spindle associated protein 1 (NUSAP1) and SHC binding and spindle associated 1 (SHCBP1) were discovered highly expressed in pancreatic ductal adenocarcinoma tissues. NUSAP1 and SHCBP1 had a high correlation with prognosis. Conclusions: The findings of this bioinformatics analysis indicate that NUSAP1 and SHCBP1 may be key factors in the prognosis and treatment of pancreatic cancer.

scholarly journals Identification of Key Prognostic Biomarker and Its Correlation with Immune Infiltrates in Pancreatic Ductal Adenocarcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Hong Luan ◽  
Chuang Zhang ◽  
Tuo Zhang ◽  
Ye He ◽  
Yanna Su ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Poor Prognosis ◽  
Immune Therapy ◽  
The Cancer Genome Atlas ◽  
Ductal Adenocarcinoma ◽  
Immune Checkpoints ◽  
Hub Genes ◽  
Immune Infiltration ◽  
The Relationship

Pancreatic ductal adenocarcinoma (PDAC) is an extremely malignant tumor. The immune profile of PDAC and the immunologic milieu of its tumor microenvironment (TME) are unique; however, the mechanism of how the TME engineers the carcinogenesis of PDAC is not fully understood. This study is aimed at better understanding the relationship between the immune infiltration of the TME and gene expression and identifying potential prognostic and immunotherapeutic biomarkers for PDAC. Analysis of data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases identified differentially expressed genes (DEGs), including 159 upregulated and 53 downregulated genes. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes enrichment were performed and showed that the DEGs were mainly enriched for the PI3K-Akt signaling pathway and extracellular matrix organization. We used the cytoHubba plugin of Cytoscape to screen out the most significant ten hub genes by four different models (Degree, MCC, DMNC, and MNC). The expression and clinical relevance of these ten hub genes were validated using Gene Expression Profiling Interactive Analysis (GEPIA) and the Human Protein Atlas, respectively. High expression of nine of the hub genes was positively correlated with poor prognosis. Finally, the relationship between these hub genes and tumor immunity was analyzed using the Tumor Immune Estimation Resource. We found that the expression of SPARC, COL6A3, and FBN1 correlated positively with infiltration levels of six immune cells in the tumors. In addition, these three genes had a strong coexpression relationship with the immune checkpoints. In conclusion, our results suggest that nine upregulated biomarkers are related to poor prognosis in PDAC and may serve as potential prognostic biomarkers for PDAC therapy. Furthermore, SPARC, COL6A3, and FBN1 play an important role in tumor-related immune infiltration and may be ideal targets for immune therapy against PDAC.

scholarly journals Regulator of calcineurin 1 gene isoform 4 in pancreatic ductal adenocarcinoma regulates the progression of tumor cells

Oncogene ◽  
2021 ◽  
Author(s):  
Mengyi Lao ◽  
Xiaozhen Zhang ◽  
Tao Ma ◽  
Jian Xu ◽  
Hanshen Yang ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Tumor Cells ◽  
Vital Role ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Metastasis Model ◽  
Inducible Protein

AbstractTherapeutic strategies to treat pancreatic ductal adenocarcinoma (PDAC) remain unsatisfying and limited. Therefore, it is imperative to fully determine the mechanisms underlying PDAC progression. In the present study, we report a novel role of regulator of calcineurin 1, isoform 4 (RCAN1.4) in regulating PDAC progression. We demonstrated that RCAN1.4 expression was decreased significantly in PDAC tissues compared with that in para-cancerous tissues, and correlated with poor prognosis of patients with pancreatic cancer. In vitro, stable high expression of RCAN1.4 could suppress the metastasis and proliferation and angiogenesis of pancreatic tumor cells. In addition, interferon alpha inducible protein 27 (IFI27) was identified as having a functional role in RCAN1.4-mediated PDAC migration and invasion, while VEGFA play a vital role in RCAN1.4-mediated PDAC angiogenesis. Analysis of mice with subcutaneously/orthotopic implanted xenograft tumors and liver metastasis model confirmed that RCAN1.4 could modulate the growth, metastasis, and angiogenesis of tumors via IFI27/VEGFA in vivo. In conclusion, our results suggested that RCAN1.4 suppresses the growth, metastasis, and angiogenesis of PDAC, functioning partly via IFI27 and VEGFA. Importantly, our results provided possible diagnostic criteria and therapeutic targets for PDAC.

scholarly journals Role of microRNAs in response to cadmium chloride in pancreatic ductal adenocarcinoma

2021 ◽  
Author(s):  
Maria Mortoglou ◽  
Aleksandra Buha Djordjevic ◽  
Vladimir Djordjevic ◽  
Hunter Collins ◽  
Lauren York ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Cadmium Chloride ◽  
Epithelial Mesenchymal Transition ◽  
Environmental Pollutants ◽  
Environmental Pollutant ◽  
Ductal Adenocarcinoma ◽  
Mesenchymal Transition ◽  
Advanced Stages

AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the most fatal and aggressive malignancies with a 5-year survival rate less than 9%. Early detection is particularly difficult due to the lack of symptoms even in advanced stages. microRNAs (miRs/miRNAs) are small (~ 18–24 nucleotides), endogenous, non-coding RNAs, which are involved in the pathogenesis of several malignancies including PDAC. Alterations of miR expressions can lead to apoptosis, angiogenesis, and metastasis. The role of environmental pollutants such as cadmium (Cd) in PDAC has been suggested but not fully understood. This study underlines the role of miRs (miR-221, miR-155, miR-126) in response to cadmium chloride (CdCl2) in vitro. Lethal concentration (LC50) values for CdCl2 resulted in a toxicity series of AsPC-1 > HPNE > BxPC-3 > Panc-1 = Panc-10.5. Following the treatment with CdCl2, miR-221 and miR-155 were significantly overexpressed, whereas miR-126 was downregulated. An increase in epithelial–mesenchymal transition (EMT) via the dysregulation of mesenchymal markers such as Wnt-11, E-cadherin, Snail, and Zeb1 was also observed. Hence, this study has provided evidence to suggest that the environmental pollutant Cd can have a significant role in the development of PDAC, suggesting a significant correlation between miRs and Cd exposure during PDAC progression. Further studies are needed to investigate the precise role of miRs in PDAC progression as well as the role of Cd and other environmental pollutants.

scholarly journals Network analyses of circular RNAs expression profiles and their hub genes in pancreatic ductal adenocarcinoma

2019 ◽  
Author(s):  
Yanyan Tang ◽  
Ping Zhang
Keyword(s):  
Gene Expression ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Signaling Pathway ◽  
Pathway Analysis ◽  
Kegg Pathway ◽  
Expression Profiles ◽  
Ductal Adenocarcinoma ◽  
Ppi Network ◽  
Hub Genes ◽  
Kegg Pathway Analysis

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumor in digestive system. CircRNAs involve in lots of biological processes through interacting with miRNAs and their targeted mRNA. We obtained the circRNA gene expression profiles from Gene Expression Omnibus (GEO) and identified differentially expressed genes (DEGs) between PDAC samples and paracancerous tissues. Bioinformatics analyses, including GO analysis, KEGG pathway analysis and PPI network analysis, were conducted for further investigation. We also constructed circRNA‑microRNA-mRNA co-expression network. A total 291 differentially expressed circRNAs were screened out. The GO enrichment analysis revealed that up-regulated DEGs were mainly involved metabolic process, biological regulation, and gene expression, and down-regulated DEGs were involved in cell communication, single-organism process, and signal transduction. The KEGG pathway analysis, the upregulated circRNAs were enriched cGMP-PKG signaling pathway, and HTLV-I infection, while the downregulated circRNAs were enriched in protein processing in endoplasmic reticulum, insulin signaling pathway, regulation of actin cytoskeleton, etc. Four genes were identified from PPI network as both hub genes and module genes, and their circRNA‑miRNA-mRNA regulatory network also be constructed. Our study indicated possible involvement of dysregulated circRNAs in the development of PDAC and promoted our understanding of the underlying molecular mechanisms.

scholarly journals Reciprocal regulation of pancreatic ductal adenocarcinoma growth and molecular subtype by HNF4α and SIX1/4

2019 ◽  
Author(s):  
Soledad A. Camolotto ◽  
Veronika K. Belova ◽  
Luke Torre-Healy ◽  
Jeffery M. Vahrenkamp ◽  
Kristofer C. Berrett ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Molecular Subtype ◽  
Ductal Adenocarcinoma ◽  
Reciprocal Regulation ◽  
Expression Of Genes ◽  
Response To Chemotherapy ◽  
Expression Program

AbstractPancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a five-year survival of less than 5%. Transcriptomic analysis has identified two clinically relevant molecular subtypes of PDAC: Classical and Basal-like. The Classical subtype is characterized by a more favorable prognosis and better response to chemotherapy than the Basal-like subtype. The Classical subtype also expresses higher levels of lineage specifiers that regulate endodermal differentiation, including the nuclear receptor HNF4α. Using in vitro and in vivo PDAC models, we show that HNF4α restrains tumor growth and drives tumor cells toward an epithelial identity. Gene expression analysis from murine models and human tumors shows that HNF4α activates expression of genes associated with the Classical subtype. Although HNF4α loss is not sufficient for complete conversion to the Basal-like subtype gene expression profile, HNF4α directly represses SIX4 and SIX1, mesodermal lineage specifiers expressed in the Basal-like subtype. Finally, HNF4α-negative PDAC cells rely on expression of SIX4 and SIX1 for proliferation in vitro and in vivo. Overall, our data show that HNF4α regulates the growth and molecular subtype of PDAC by multiple mechanisms, including activation of the Classical gene expression program and repression of SIX4 and SIX1, which may represent novel dependencies of the Basal-like subtype.

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