Identification of FEZ2 as a potential oncogene in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the common malignant tumors with high lethal rate and poor prognosis. Dysregulation of many genes have been reported to be involved in the occurrence and development of PDAC. However, as a highly conserved gene in eukaryotes, the role of Fasciculation and Elongation protein Zeta 2 (FEZ2) in pancreatic cancer progression is not clear. In this study, we identified the oncogenic effect of FEZ2 on PDAC. By mining of The Cancer Genome Atlas (TCGA) database, we found that FEZ2 was upregulated in PDAC tissues and FEZ2 expression was negatively regulated by its methylation. Moreover, high expression and low methylation of FEZ2 correlated with poor prognosis in PDAC patients. Besides, we found that FEZ2 could promote PDAC cells proliferation, migration and 5-FU resistance in vitro. Furthermore, Gene pathway enrichment analysis demonstrated a positive correlation between Wnt signaling activation and FEZ2 expression in PDAC patients. Western blot showed that FEZ2 knockdown significantly suppressed β-catenin expression. Collectively, our finding revealed that FEZ2 functioned as a potential oncogene on PDAC progression and migration, and the expression of FEZ2 had guidance value for the treatment and chemotherapy program of PDAC patients.

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Upregulation of KLK8 Predicts Poor Prognosis in Pancreatic Cancer

10.21203/rs.3.rs-95055/v1 ◽

2020 ◽

Author(s):

Qing Hua ◽

Tianjiao Li ◽

Yixuan Liu ◽

Xuefang Shen ◽

Xiaoyan Zhu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Progression ◽

Poor Prognosis ◽

Disease Free Survival ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Human Pancreatic Cancer ◽

Ductal Adenocarcinoma ◽

Pancreatic Cancer Cells

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is a growing cause of cancer-related mortality worldwide. Kallikrein-related peptidase 8 (KLK8) has potential clinical values in many cancers. However, the clinicopathological significances of KLK8 in PDAC remain unknown. Methods: The relationship of KLK8 to clinicopathological features of PDAC was investigated based on public databases. KLK8 expression was examined in human PDAC tissues. Cell proliferation and apoptosis were evaluated in KLK8-overexpressed human pancreatic cancer cell lines Mia-paca-2 and Panc-1. The related signaling pathways of KLK8 involved in pancreatic cancer progression were analyzed by gene set enrichment analysis (GSEA) and further verified in in vitro studies. Results: KLK8 was up-regulated in tumor tissues in the TCGA-PAAD cohort, and was an independent prognostic factor for both overall survival and disease-free survival of PDAC. KLK8 mRNA and protein expressions were increased in PDAC tissues compared with para-cancerous pancreas. KLK8 overexpression exerted pro-proliferation and anti-apoptotic functions in Mia-paca-2 and Panc-1 cells. GSEA analysis showed that KLK8 was positively associated with PI3K-Akt-mTOR and Notch pathways. KLK8-induced pro-proliferation and anti-apoptotic effects in Mia-paca-2 and Panc-1 cells were attenuated by inhibitors for PI3K, Akt, and mTOR, but not by inhibitor for Notch.Conclusion: KLK8 overexpression exerts pro-proliferation and anti-apoptotic functions in pancreatic cancer cells via PI3K/Akt/mTOR pathway. Upregulated KLK8 in PDAC predicts poor prognosis and may be a potential therapeutic target for PDAC.

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Plasma Metabolome Profiling Identifies Metabolic Subtypes of Pancreatic Ductal Adenocarcinoma

Cells ◽

10.3390/cells10071821 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1821

Author(s):

Ujjwal Mukund Mahajan ◽

Ahmed Alnatsha ◽

Qi Li ◽

Bettina Oehrle ◽

Frank-Ulrich Weiss ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Enrichment Analysis ◽

Response Prediction ◽

Ductal Adenocarcinoma ◽

Pathway Enrichment Analysis ◽

Metabolome Analysis ◽

Dismal Prognosis ◽

Chemotherapeutic Response ◽

Plasma Metabolome ◽

Metabolome Profiling

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Developing biomarkers for early detection and chemotherapeutic response prediction is crucial to improve the dismal prognosis of PDAC patients. However, molecular cancer signatures based on transcriptome analysis do not reflect intratumoral heterogeneity. To explore a more accurate stratification of PDAC phenotypes in an easily accessible matrix, plasma metabolome analysis using MxP® Global Profiling and MxP® Lipidomics was performed in 361 PDAC patients. We identified three metabolic PDAC subtypes associated with distinct complex lipid patterns. Subtype 1 was associated with reduced ceramide levels and a strong enrichment of triacylglycerols. Subtype 2 demonstrated increased abundance of ceramides, sphingomyelin and other complex sphingolipids, whereas subtype 3 showed decreased levels of sphingolipid metabolites in plasma. Pathway enrichment analysis revealed that sphingolipid-related pathways differ most among subtypes. Weighted correlation network analysis (WGCNA) implied PDAC subtypes differed in their metabolic programs. Interestingly, a reduced expression among related pathway genes in tumor tissue was associated with the lowest survival rate. However, our metabolic PDAC subtypes did not show any correlation to the described molecular PDAC subtypes. Our findings pave the way for further studies investigating sphingolipids metabolisms in PDAC.

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GLRX3, a novel cancer stem cell-related secretory biomarker of pancreatic ductal adenocarcinoma

BMC Cancer ◽

10.1186/s12885-021-08898-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jung Hyun Jo ◽

Sun A Kim ◽

Jeong Hoon Lee ◽

Yu Rang Park ◽

Chanyang Kim ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Cancer Progression ◽

Biomarker Discovery ◽

Disease Free Survival ◽

Tumor Formation ◽

Ductal Adenocarcinoma ◽

Curative Surgery ◽

In Vitro Proliferation

Abstract Background Cancer stem cells (CSCs) are implicated in carcinogenesis, cancer progression, and recurrence. Several biomarkers have been described for pancreatic ductal adenocarcinoma (PDAC) CSCs; however, their function and mechanism remain unclear. Method In this study, secretome analysis was performed in pancreatic CSC-enriched spheres and control adherent cells for biomarker discovery. Glutaredoxin3 (GLRX3), a novel candidate upregulated in spheres, was evaluated for its function and clinical implication. Results PDAC CSC populations, cell lines, patient tissues, and blood samples demonstrated GLRX3 overexpression. In contrast, GLRX3 silencing decreased the in vitro proliferation, migration, clonogenicity, and sphere formation of cells. GLRX3 knockdown also reduced tumor formation and growth in vivo. GLRX3 was found to regulate Met/PI3K/AKT signaling and stemness-related molecules. ELISA results indicated GLRX3 overexpression in the serum of patients with PDAC compared to that in healthy controls. The sensitivity and specificity of GLRX3 for PDAC diagnosis were 80.0 and 100%, respectively. When GLRX3 and CA19–9 were combined, sensitivity was significantly increased to 98.3% compared to that with GLRX3 or CA19–9 alone. High GLRX3 expression was also associated with poor disease-free survival in patients receiving curative surgery. Conclusion Overall, these results indicate GLRX3 as a novel diagnostic marker and therapeutic target for PDAC targeting CSCs.

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Immortalization-Upregulated Protein Promotes Pancreatic Cancer Progression By Regulating NPM1/FHL1-Mediated Cell-Cycle-Checkpoint Protein Activity

10.21203/rs.3.rs-1077168/v1 ◽

2021 ◽

Author(s):

Qiankun Luo ◽

Yanfeng Pan ◽

Qiang Fu ◽

Xu Zhang ◽

Shuai Zhou ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Cell Cycle Arrest ◽

Cancer Progression ◽

Cell Cycle Checkpoint ◽

The Cancer Genome Atlas ◽

Ductal Adenocarcinoma ◽

Cycle Arrest ◽

Cycle Checkpoint

Abstract Immortalization-upregulated protein (IMUP) plays a vital role in cell proliferation and tumor progression. However, its role in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we select IMUP as an alternative gene based on GeneChip analysis of clinical PDAC tissues and transcriptome data from The Cancer Genome Atlas. IMUP expression is upregulated in PDAC tumor tissues. Moreover, high IMUP expression correlates with poor prognosis, while IMUP depletion inhibits PDAC cell proliferation and colony formation capacity in vitro, and decreases xenograft tumor growth in vivo. IMUP downregulation leads to cell-cycle arrest in the S phase. IMUP Knockdown increases the expression of four-and-a-half LIM domain protein 1 (FHL1), which regulates the phosphorylation of cell division cycle 25A (CDC25A) by cycle checkpoint kinase 1 (CHK1) and promotes cytoplasmic distribution of CDC25A by interaction with 14-3-3ξ. Furthermore, FHL1 knockdown restores the effects induced by IMUP depletion. liquid chromatography tandem mass spectrometry and immunoprecipitation analysis further show that IMUP interacts directly with nucleophosmin (NPM1) and enhances its stability. DNA methylation sequencing shows that FHL1 promoter methylation decreases when IMUP is downregulated. Overexpression of NPM1 can increase the methylation level of FHL1, thereby decreasing its expression. Our study provides a novel perspective on IMUP/NPM1/FHL1-mediated cell-cycle arrest by regulating CDC25A phosphorylation in PDAC. These findings may provide a new therapeutic target for PDAC.

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

Disease Markers ◽

10.1155/2020/8825997 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12 ◽

Cited By ~ 1

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.

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Identification and validation of a miRNA-based prognostic signature for cervical cancer through an integrated bioinformatics approach

Scientific Reports ◽

10.1038/s41598-020-79337-4 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Yumei Qi ◽

Yo-Liang Lai ◽

Pei-Chun Shen ◽

Fang-Hsin Chen ◽

Li-Jie Lin ◽

...

Keyword(s):

Cervical Cancer ◽

Poor Prognosis ◽

Expression Profiles ◽

Survival Rates ◽

Enrichment Analysis ◽

Functional Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Functional Enrichment ◽

Additive Effects

AbstractCervical cancer is the fourth most common cancer in women worldwide. Increasing evidence has shown that miRNAs are related to the progression of cervical cancer. However, the mechanisms that affect the prognosis of cancer are still largely unknown. In the present study, we sought to identify miRNAs associated with poor prognosis of patient with cervical cancer, as well as the possible mechanisms regulated by them. The miRNA expression profiles and relevant clinical information of patients with cervical cancer were obtained from The Cancer Genome Atlas (TCGA). The selection of prognostic miRNAs was carried out through an integrated bioinformatics approach. The most effective miRNAs with synergistic and additive effects were selected for validation through in vitro experiments. Three miRNAs (miR-216b-5p, miR-585-5p, and miR-7641) were identified as exhibiting good performance in predicting poor prognosis through additive effects analysis. The functional enrichment analysis suggested that not only pathways traditionally involved in cancer but also immune system pathways might be important in regulating the outcome of the disease. Our findings demonstrated that a synergistic combination of three miRNAs may be associated, through their regulation of specific pathways, with very poor survival rates for patients with cervical cancer.

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A System Pharmacology Model for Decoding the Synergistic Mechanisms of Compound Kushen Injection in Treating Breast Cancer

Frontiers in Pharmacology ◽

10.3389/fphar.2021.723147 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yi Li ◽

Kexin Wang ◽

Yupeng Chen ◽

Jieqi Cai ◽

Xuemei Qin ◽

...

Keyword(s):

Breast Cancer ◽

Signaling Pathway ◽

Malignant Tumors ◽

Differentially Expressed Gene ◽

Enrichment Analysis ◽

Pathway Enrichment Analysis ◽

Active Components ◽

System Pharmacology ◽

Compound Kushen Injection

Breast cancer (BC) is one of the most common malignant tumors among women worldwide and can be treated using various methods; however, side effects of these treatments cannot be ignored. Increasing evidence indicates that compound kushen injection (CKI) can be used to treat BC. However, traditional Chinese medicine (TCM) is characterized by “multi-components” and “multi-targets”, which make it challenging to clarify the potential therapeutic mechanisms of CKI on BC. Herein, we designed a novel system pharmacology strategy using differentially expressed gene analysis, pharmacokinetics synthesis screening, target identification, network analysis, and docking validation to construct the synergy contribution degree (SCD) and therapeutic response index (TRI) model to capture the critical components responding to synergistic mechanisms of CKI in BC. Through our designed mathematical models, we defined 24 components as a high contribution group of synergistic components (HCGSC) from 113 potentially active components of CKI based on ADME parameters. Pathway enrichment analysis of HCGSC targets indicated that Rhizoma Heterosmilacis and Radix Sophorae Flavescentis could synergistically target the PI3K-Akt signaling pathway and the cAMP signaling pathway to treat BC. Additionally, TRI analysis showed that the average affinity of HCGSC and targets involved in the key pathways reached -6.47 kcal/mmol, while in vitro experiments proved that two of the three high TRI-scored components in the HCGSC showed significant inhibitory effects on breast cancer cell proliferation and migration. These results demonstrate the accuracy and reliability of the proposed strategy.

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PADI1 contributes to epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma through activating ERK1/2-p38 signaling pathway

10.21203/rs.3.rs-304683/v1 ◽

2021 ◽

Author(s):

Tengfei Ji ◽

Keqiang Ma ◽

Liang Chen ◽

Tiansheng Cao

Keyword(s):

Cell Migration ◽

Pancreatic Ductal Adenocarcinoma ◽

Signaling Pathway ◽

Epithelial Mesenchymal Transition ◽

The Cancer Genome Atlas ◽

Ductal Adenocarcinoma ◽

Migration And Invasion ◽

Survival Prognosis ◽

Mesenchymal Transition

Abstract Background Peptidylarginine deiminase 1 (PADI1) may be relative with the progression of epithelial-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PAAD). We aim to explore the role of PADI1 in PAAD. Methods The expression pattern of PADI1 in PAAD tissues and normal tissues was analyzed using The Cancer Genome Atlas (TCGA) dataset. PADI1 was knocked down in CFPAN-1 and HPAC cells, while overexpressed in PANC-1 and Bxpc-3 cells by RNA interference. Wound healing assay was performed to analyze relative cell migration distance. Cell migration and invasion were assessed by Transwell assay. Related protein expression levels were measured by western blot and immunofluorescence. Results Bioinformatics analysis showed that PADI1 was overexpressed in PAAD tissues and associated with worse survival prognosis. Knockdown of PADI1 suppressed the cell migration, invasion and activated ERK1/2-p38 signaling pathway in CFPAN-1 and HPAC cells. Overexpression of PADI1 obtained the opposite results in PANC-1 and Bxpc-3 cells. Moreover, treatment with MEK1/2 inhibitor significantly recovered the effects of PADI1 knockdown on cell migration, invasion, EMT process and p-ERK1/2 and p38 expression in CFPAN-1 and HPAC cells. Conclusions Our data suggested that PADI1 may function as an oncogene in regulating metastasis in vitro in PAAD.

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MicroRNA-374a Inhibits Aggressive Tumor Biological Behavior in Bladder Carcinoma by Suppressing Wnt/β-Catenin Signaling

Cellular Physiology and Biochemistry ◽

10.1159/000491911 ◽

2018 ◽

Vol 48 (2) ◽

pp. 815-826 ◽

Cited By ~ 5

Author(s):

Xiaoliang Chen ◽

Chunshu Jia ◽

Chunyi Jia ◽

Xingyi Jin ◽

Xinquan Gu

Keyword(s):

Bladder Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Poor Prognosis ◽

Nuclear Translocation ◽

Malignant Tumors ◽

Expression Patterns ◽

The Cancer Genome Atlas ◽

Biological Behavior ◽

Bladder Cancer Cells

Background/Aims: microRNA (miR)-374a plays a crucial role in cancer progression by promoting the metastasis and proliferation of various types of malignant tumors. Because its role in bladder cancer is unknown, we investigated whether miR-374a affects the progression of bladder cancer and studied the underlying mechanism. Methods: The Cancer Genome Atlas was used to analyze the clinical relevance of miR-374a. Quantitative PCR, western blotting, and luciferase and immunofluorescence assays were used to detect the expression patterns, downstream targets, and function of miR-374a in bladder cancer cells. Apoptosis was evaluated by flow cytometry after cisplatin treatment. Results: Via in silico analysis, low levels of miR-374a were associated with poor prognosis in bladder cancer patients with distant metastasis. WNT5A was a direct target of miR-374a in two bladder cancer cell lines. miR-374a mimic abrogated the metastatic potential and invasiveness of bladder cancer cells via WNT5A downregulation in both T24 and TCCSUP human bladder cancer cells; the opposite was observed with miR-374a inhibitor. In addition, miR-374a treatment reduced the phosphorylation and nuclear translocation of β-catenin. Cisplatin treatment significantly increased the apoptosis rate. Expression levels of cancer stemness-related proteins were reduced in miR-374a mimic-pretreated cells. Conclusion: Lower expression of miR-374a is associated with poor prognosis and miR-374a improves tumor biological behavior in bladder cancer cells, suggesting that miR-374a might be a novel small-molecule therapeutic target.

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Integrated transcriptome meta-analysis of pancreatic ductal adenocarcinoma and matched adjacent pancreatic tissues

PeerJ ◽

10.7717/peerj.10141 ◽

2020 ◽

Vol 8 ◽

pp. e10141

Author(s):

Sevcan Atay

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Interaction Analysis ◽

Meta Analysis ◽

Prognostic Significance ◽

Enrichment Analysis ◽

Prognostic Biomarkers ◽

Ductal Adenocarcinoma ◽

Receptor Interaction ◽

Pathway Enrichment Analysis ◽

Adjacent Tissue

A comprehensive meta-analysis of publicly available gene expression microarray data obtained from human-derived pancreatic ductal adenocarcinoma (PDAC) tissues and their histologically matched adjacent tissue samples was performed to provide diagnostic and prognostic biomarkers, and molecular targets for PDAC. An integrative meta-analysis of four submissions (GSE62452, GSE15471, GSE62165, and GSE56560) containing 105 eligible tumor-adjacent tissue pairs revealed 344 differentially over-expressed and 168 repressed genes in PDAC compared to the adjacent-to-tumor samples. The validation analysis using TCGA combined GTEx data confirmed 98.24% of the identified up-regulated and 73.88% of the down-regulated protein-coding genes in PDAC. Pathway enrichment analysis showed that “ECM-receptor interaction”, “PI3K-Akt signaling pathway”, and “focal adhesion” are the most enriched KEGG pathways in PDAC. Protein-protein interaction analysis identified FN1, TIMP1, and MSLN as the most highly ranked hub genes among the DEGs. Transcription factor enrichment analysis revealed that TCF7, CTNNB1, SMAD3, and JUN are significantly activated in PDAC, while SMAD7 is inhibited. The prognostic significance of the identified and validated differentially expressed genes in PDAC was evaluated via survival analysis of TCGA Pan-Cancer pancreatic ductal adenocarcinoma data. The identified candidate prognostic biomarkers were then validated in four external validation datasets (GSE21501, GSE50827, GSE57495, and GSE71729) to further improve reliability. A total of 28 up-regulated genes were found to be significantly correlated with worse overall survival in patients with PDAC. Twenty-one of the identified prognostic genes (ITGB6, LAMC2, KRT7, SERPINB5, IGF2BP3, IL1RN, MPZL2, SFTA2, MET, LAMA3, ARNTL2, SLC2A1, LAMB3, COL17A1, EPSTI1, IL1RAP, AK4, ANXA2, S100A16, KRT19, and GPRC5A) were also found to be significantly correlated with the pathological stages of the disease. The results of this study provided promising prognostic biomarkers that have the potential to differentiate PDAC from both healthy and adjacent-to-tumor pancreatic tissues. Several novel dysregulated genes merit further study as potentially promising candidates for the development of more effective treatment strategies for PDAC.

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