Transcriptomic and CRISPR/Cas9 technologies reveal FOXA2 as a tumor suppressor gene in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with low survival rates and limited therapeutic options. Thus elucidation of signaling pathways involved in PDAC pathogenesis is essential for identifying novel potential therapeutic gene targets. Here, we used a systems approach to elucidate those pathways by integrating gene and microRNA profiling analyses together with CRISPR/Cas9 technology to identify novel transcription factors involved in PDAC pathogenesis. FOXA2 transcription factor was found to be significantly downregulated in PDAC relative to control pancreatic tissues. Functional experiments revealed that FOXA2 has a tumor suppressor function through inhibition of pancreatic cancer cell growth, migration, invasion, and colony formation. In situ hybridization analysis revealed miR-199a to be significantly upregulated in pancreatic cancer. Bioinformatics and luciferase analyses showed that miR-199a negatively but directly regulates FOXA2 expression through binding in its 3′-untranslated region (UTR). Evaluation of the functional importance of miR-199a on pancreatic cancer revealed that miR-199a acts as an inhibitor of FOXA2 expression, inducing an increase in pancreatic cancer cell proliferation, migration, and invasion. Additionally, gene ontology and network analyses in PANC-1 cells treated with a small interfering RNA (siRNA) against FOXA2 revealed an enrichment for cell invasion mechanisms through PLAUR and ERK activation. FOXA2 deletion (FOXA2Δ) by using two CRISPR/Cas9 vectors in PANC-1 cells induced tumor growth in vivo resulting in upregulation of PLAUR and ERK pathways in FOXA2Δ xenograft tumors. We have identified FOXA2 as a novel tumor suppressor in pancreatic cancer and it is regulated directly by miR-199a, thereby enhancing our understanding of how microRNAs interplay with the transcription factors to affect pancreatic oncogenesis.

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Corn silk crude polysaccharide exerts anti-pancreatic cancer activity by blocking the EGFR/PI3K/AKT/CREB signaling pathway

Food & Function ◽

10.1039/d0fo00403k ◽

2020 ◽

Vol 11 (8) ◽

pp. 6961-6970

Author(s):

Hong Tao ◽

Xia Chen ◽

Zhenyun Du ◽

Kan Ding

Keyword(s):

Pancreatic Cancer ◽

Cancer Cell ◽

Pancreatic Cancer Cell ◽

Migration And Invasion ◽

Cancer Cell Proliferation ◽

Cancer Cell Migration ◽

Corn Silk ◽

Crude Polysaccharide

S1, a crude polysaccharide from corn silk, may significantly inhibit pancreatic cancer cell proliferation in vitro and in vivo. It can induce apoptosis, arrest the cell cycle in S phase and impede pancreatic cancer cell migration and invasion.

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TRIM29 as a Novel Biomarker in Pancreatic Adenocarcinoma

Disease Markers ◽

10.1155/2014/317817 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 11

Author(s):

Hongli Sun ◽

Xianwei Dai ◽

Bing Han

Keyword(s):

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Cancer Cell ◽

Pancreatic Cancer Cell ◽

Multivariate Logistic Regression Analysis ◽

Immunohistochemical Analysis ◽

Ductal Adenocarcinoma ◽

Migration And Invasion ◽

Tripartite Motif

Background and Aim. Tripartite motif-containing 29 (TRIM29) is structurally a member of the tripartite motif family of proteins and is involved in diverse human cancers. However, its role in pancreatic cancer remains unclear.Methods. The expression pattern of TRIM29 in pancreatic ductal adenocarcinoma was assessed by immunocytochemistry. Multivariate logistic regression analysis was used to investigate the association between TRIM29 and clinical characteristics.In vitroanalyses by scratch wound healing assay and invasion assays were performed using the pancreatic cancer cell lines.Results. Immunohistochemical analysis showed TRIM29 expression in pancreatic cancer tissues was significantly higher (n=186)than that in matched adjacent nontumor tissues. TRIM29 protein expression was significantly correlated with lymph node metastasis(P=0.019). Patients with positive TRIM29 expression showed both shorter overall survival and shorter recurrence-free survival than those with negative TRIM29 expression. Multivariate analysis revealed that TRIM29 was an independent factor for pancreatic cancer over survival (HR=2.180, 95% CI: 1.324–4.198,P=0.011).In vitro,TRIM29 knockdown resulted in inhibition of pancreatic cancer cell proliferation, migration, and invasion.Conclusions. Our results indicate that TRIM29 promotes tumor progression and may be a novel prognostic marker for pancreatic ductal adenocarcinoma.

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Deferasirox, an oral iron chelator, with gemcitabine synergistically inhibits pancreatic cancer cell growth in vitro and in vivo

Oncotarget ◽

10.18632/oncotarget.25421 ◽

2018 ◽

Vol 9 (47) ◽

pp. 28434-28444 ◽

Cited By ~ 11

Author(s):

Shuhei Shinoda ◽

Seiji Kaino ◽

Shogo Amano ◽

Hirofumi Harima ◽

Toshihiko Matsumoto ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Growth ◽

Cancer Cell ◽

Pancreatic Cancer Cell ◽

Iron Chelator ◽

Oral Iron ◽

Cancer Cell Growth ◽

Oral Iron Chelator

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

BioMed Research International ◽

10.1155/2021/8249293 ◽

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.

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Regulatory Network Analysis Reveals Prognosis-Related CircRNAs in Pancreatic Cancer Cells

10.21203/rs.3.rs-122183/v1 ◽

2020 ◽

Author(s):

Heying Zhang ◽

Juan Zeng ◽

Yuexian Li ◽

Cheng Sun ◽

Yang Zhou ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Suppressor ◽

Cell Lines ◽

Differentially Expressed Genes ◽

Cancer Cell ◽

Regulatory Network ◽

Pancreatic Cancer Cell ◽

Kegg Pathway ◽

Regulatory Factors ◽

Pancreatic Cancers

Abstract Objective: To construct a key prognosis-related regulatory network and to identify the epigenomic alterations of RNAs that have crucial functions in cancer pathogenesis.Methods: RNA expression profiles of miRNAs, mRNAs and circRNAs were extracted from the NCBI GEO and EBI ArrayExpress databases. The identification of differentially expressed genes was performed by R language. Databases such as starBase and TCGA were used for annotation, visualization, and integrated discovery. GO and KEGG pathway enrichment analyses were performed by DAVID 6.8. The key prognosis-related regulatory network was constructed with Cytoscape software. The involved circRNAs were verified by quantitative real-time PCR (qRT-PCR) in five pancreatic cancer cell lines. Proliferation ability was assessed by the CCK-8 assay, apoptosis was detected by flow cytometry, and migratory and invasive abilities were assessed by Transwell assays.Results: In total, 798 differentially expressed genes, consisting of 85 circRNAs, 19 miRNAs and 694 mRNAs, were obtained. A miRNA interaction network was predicted and used to construct a prognosis-related regulatory network. GO annotation and KEGG pathway analysis revealed important biological processes and pathways in pancreatic cancers. The key regulatory factors in the network were miR-146b-5p and miR-152. Eight circRNAs included in the network were verified, and hsa_circ_0006502 was downregulated in the five tested pancreatic cancer cell lines and functioned as a tumor suppressor, as predicted.Conclusion: In conclusion, a key prognosis-related regulatory network in pancreatic cancers was constructed through bioinformatics analysis of public RNA databases, and miR-146b-5p and miR-152 were the key regulatory factors. Hsa_circ_0006502 was identified as a tumor suppressor that interacted closely with miR-146b-5p and might serve as a potential therapeutic agent.

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Keratin 17 Suppresses Cell Proliferation and Epithelial-Mesenchymal Transition in Pancreatic Cancer

Frontiers in Medicine ◽

10.3389/fmed.2020.572494 ◽

2020 ◽

Vol 7 ◽

Author(s):

Yong Zeng ◽

Min Zou ◽

Yan Liu ◽

Keting Que ◽

Yunbing Wang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Cancer Cell ◽

Cell Cycle Progression ◽

Pancreatic Cancer Cell ◽

Epithelial Mesenchymal Transition ◽

Migration And Invasion ◽

Cancer Cell Proliferation ◽

Cycle Progression ◽

Mesenchymal Transition

Keratin 17 (K17), a member of type I acidic epithelial keratin family, has been reported to be upregulated in many malignant tumors and to be involved in promoting the development of tumors. However, the precise role of K17 in progression of pancreatic cancer is still unknown. In this study, we found that K17 expression was highly expressed in pancreatic cancer tissues and cell lines and that upregulated expression was associated with the pathological grade and poor prognosis. K17 expression served as an independent predictor of pancreatic cancer survival. Meanwhile, we showed that knocking down K17 induced pancreatic cancer cell proliferation, colony formation and tumor growth in xenografts in mice. However, K17 upregulation inhibited pancreatic cancer cell proliferation and colony formation. Further mechanistic study revealed that K17 knockdown promoted cell cycle progression by upregulating CyclinD1 expression and repressed cell apoptosis. However, K17 upregulation suppressed cell cycle progression by decreasing CyclinD1 expression, and induced apoptosis by increasing the levels of cleaved Caspase3. In addition, K17 knockdown promoted pancreatic cancer cell migration and invasion, but K17 upregulation suppressed cell migration and invasion. Moreover, knocking down K17 promoted epithelial-mesenchymal transition (EMT) in pancreatic cancer cell by inhibiting E-cadherin expression and inducing Vimentin expression, and the effects of K17 upregulation were opposite to that of K17downregulation. Taken together, our findings suggest that K17 functions as a potential tumor suppressor, even though it is upregulated in pancreatic cancer.

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