scholarly journals A 3D bioinspired highly porous polymeric scaffolding system forin vitrosimulation of pancreatic ductal adenocarcinoma

RSC Advances ◽  
2018 ◽  
Vol 8 (37) ◽  
pp. 20928-20940 ◽  
Author(s):  
Stella Totti ◽  
Mark C. Allenby ◽  
Susana Brito Dos Santos ◽  
Athanasios Mantalaris ◽  
Eirini G. Velliou
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Highly Porous

A 3D biomimetic model forin vitrostudies of pancreatic cancer.

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 Aspartate β-hydroxylase promotes pancreatic ductal adenocarcinoma metastasis through activation of SRC signaling pathway

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Kosuke Ogawa ◽  
Qiushi Lin ◽  
Le Li ◽  
Xuewei Bai ◽  
Xuesong Chen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Stem Cell Marker ◽  
Ductal Adenocarcinoma ◽  
Physical Interaction ◽  
Pancreatic Cancer Cells ◽  
Ecm Degradation ◽  
Invadopodia Formation ◽  
Pdx Models

Abstract Background Signaling pathways critical for embryonic development re-emerge in adult pancreas during tumorigenesis. Aspartate β-hydroxylase (ASPH) drives embryonic cell motility/invasion in pancreatic development/differentiation. We explored if dysregulated ASPH is critically involved in pancreatic cancer pathogenesis. Methods To demonstrate if/how ASPH mediates malignant phenotypes, proliferation, migration, 2-D/3-D invasion, pancreatosphere formation, immunofluorescence, Western blot, co-immunoprecipitation, invadopodia formation/maturation/function, qRT-PCR, immunohistochemistry (IHC), and self-developed in vitro metastasis assays were performed. Patient-derived xenograft (PDX) models of human pancreatic ductal adenocarcinoma (PDAC) were established to illustrate in vivo antitumor effects of the third-generation small molecule inhibitor specifically against ASPH’s β-hydroxylase activity. Prognostic values of ASPH network components were evaluated with Kaplan-Meier plots, log-rank tests, and Cox proportional hazards regression models. Results ASPH renders pancreatic cancer cells more aggressive phenotypes characterized by epithelial–mesenchymal transition (EMT), 2-D/3-D invasion, invadopodia formation/function as demonstrated by extracellular matrix (ECM) degradation, stemness (cancer stem cell marker upregulation and pancreatosphere formation), transendothelial migration (mimicking intravasation/extravasation), and sphere formation (mimicking metastatic colonization/outgrowth at distant sites). Mechanistically, ASPH activates SRC cascade through direct physical interaction with ADAM12/ADAM15 independent of FAK. The ASPH-SRC axis enables invadopodia construction and initiates MMP-mediated ECM degradation/remodeling as executors for invasiveness. Pharmacologic inhibition of invadopodia attenuates in vitro metastasis. ASPH fosters primary tumor development and pulmonary metastasis in PDX models of PDAC, which is blocked by a leading compound specifically against ASPH enzymatic activity. ASPH is silenced in normal pancreas, progressively upregulated from pre-malignant lesions to invasive/advanced stages of PDAC. Expression profiling of ASPH-SRC network components independently/jointly predicts clinical outcome of PDAC patients. Compared to a negative-low level, a moderate-very high level of ASPH, ADAM12, activated SRC, and MMPs correlated with curtailed overall survival (OS) of pancreatic cancer patients (log-rank test, ps < 0.001). The more unfavorable molecules patients carry, the more deleterious prognosis is destinated. Patients with 0–2 (n = 4), 3–5 (n = 8), 6–8 (n = 24), and 9–12 (n = 73) unfavorable expression scores of the 5 molecules had median survival time of 55.4, 15.9, 9.7, and 5.0 months, respectively (p < 0.001). Conclusion Targeting the ASPH-SRC axis, which is essential for propagating multi-step PDAC metastasis, may specifically/substantially retard development/progression and thus improve prognosis of PDAC.

scholarly journals DNA-Methylation-Caused Downregulation of miR-30 Contributes to the High Expression of XPO1 and the Aggressive Growth of Tumors in Pancreatic Ductal Adenocarcinoma

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1101 ◽  
Author(s):  
Asfar S. Azmi ◽  
Yiwei Li ◽  
Amro Aboukameel ◽  
Irfana Muqbil ◽  
Philip A. Philip ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cells ◽  
Nuclear Export ◽  
The United States ◽  
High Expression ◽  
Ductal Adenocarcinoma ◽  
Multiple Tumor ◽  
Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma is one of the most aggressive cancers, with high mortality in the United States. One of the important signal transduction proteins involved in the regulation of pancreatic cancer’s aggressive progression is the nuclear export protein (XPO1). High expression of XPO1 has been found in pancreatic, lung, breast and other cancers and lymphomas with a poor prognosis of patients with tumors and high proliferative activity of cancer cells. Because XPO1 exports multiple tumor suppressor proteins simultaneously from the nucleus, the inhibition of XPO1 may retain multiple tumor suppressors in the nucleus, resulting in the suppression of cell proliferation and the induction of apoptosis in tumors. In this study, we found that the high expression of XPO1 in pancreatic cancer cells could be, in part, due to the methylation of the miR-30 gene, leading to the low expression level of the miR-30 family. By co-transfection of the XPO1 3′-UTR-Luc target vector with miR-30 mimic, we found that XPO1 is a direct target of the miR-30 family. We also observed that the enforced expression of the miR-30 family inhibited the expression of XPO1, resulting in the suppression of pancreatic cancer growth both in vitro and in vivo. These findings could help to design a novel therapeutic strategy for the treatment of pancreatic cancer by introducing miR-30 into cancer cells.

scholarly journals DDX31: A Novel Functional Oncogene Promotes Migration and Proliferation of Pancreatic Cancer

2021 ◽  
Author(s):  
Yang Liu ◽  
Yongjie Xie ◽  
Jinsheng Ding ◽  
Liangliang Wu
Keyword(s):  
Pancreatic Cancer ◽  
Western Blot ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cells ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Ductal Adenocarcinoma ◽  
Rna Helicases ◽  
Pancreatic Cancer Cells

Abstract Purpose: Pancreatic cancer is one of the most malignant cancers with rapid disease progression. Pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90% in exocrine pancreatic cancer. DDX31 is one of the Asp-Glu-Ala-Asp (DEAD)-box RNA helicases (DDX) family member, which has never been reported in pancreatic ductal adenocarcinoma. Through comprehensive analysis of bioinformatics screening, clinical pathological data and experiment results verification, we found DDX31 may be a promising oncogene.Patients and methods: The potential correlation between DDX3 expression and clinical feature of PDAC was analyzed, which revealed that patients with high DDX31 expression may have a poor prognosis. Elevated expression levels of DDX31 in PDAC compared with adjacent normal tissues were determined by immunohistochemical and Western blot analyses. Western blot analysis of N-cadherin, Snail, transwell, and wound healing assays was carried out to evaluate the pro-metastasis effects of DDX31 in PDAC. In vitro experiments included colony formation assay. Edu labeling assay, CCK-8, western blot analysis of Ki67, PCNA, and an in vivo subcutaneous mouse model were used to analyze the role of DDX31 in PDAC proliferation.Results: In our research, integrated bioinformatics analysis of the TCGA and GEO databases was performed to identify the metastasis and proliferation-related differentially expressed genes (DEG). DDX31 predicts strong metastasis and proliferation capacity of PDAC, was finally screened. Then, the clinical data identified that highexpression-DDX31 was correlated with pancreatic tumor size, pathological grade, and lymph node metastasis. The in vitro and vivo experiments revealed that overexpression-DDX31 promoted the migration, proliferation and cell viability of pancreatic cancer cells, these functions of DDX31 had also been proved in the knockdown results. Moreover, the EMT related markers and proliferation markers were identified to be positively regulated by DDX31 in pancreatic cancer cells.Conclusion: Thus, our work uncovered that DDX31 promotes migration and proliferation in PDAC and might be a promising therapeutic target in pancreatic cancer.

scholarly journals Neurotensin is a Versatile Modulator of In Vitro Human Pancreatic Ductal Adenocarcinoma Cell (PDAC) Migration

2007 ◽  
Vol 29 (4) ◽  
pp. 315-326
Author(s):  
Tatjana Mijatovic ◽  
Philippe Gailly ◽  
Véronique Mathieu ◽  
Nancy De Nève ◽  
Paul Yeaton ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Rho Gtpases ◽  
Small Gtpase ◽  
Ductal Adenocarcinoma ◽  
Computer Assisted ◽  
Altered Expression ◽  
Adenocarcinoma Cells ◽  
Small Rho Gtpases

Background: While the neurotensin (NT) roles in pancreatic cancer growth are well documented, its effects on pancreatic cancer cell migration have not been described. Methods: The NT-induced effects on the migration process of human pancreatic ductal adenocarcinoma cells (PDACs) were characterized by means of various assays including computer-assisted video-microscopy, fluorescence microscopy, ELISA-based, small GTPase pull-down and phosphorylation assays. Results: The NT-induced modifications on in vitro PDACs migration largely depended on the extra-cellular matrix environment and cell propensity to migrate collectively or individually. While NT significantly reduced the level of migration of collectively migrating PDACs on vitronectin, it significantly increased the level of individually migrating PDACs. These effects were mainly mediated through the sortilin/NTR3 receptor. Neurotensin both induced altered expression of αV and β5 integrin subunits in PDACs cultured on vitronectin resulting in modified adhesion abilities, and caused modifications to the organization of the actin cytoskeleton through the NT-mediated activation of small Rho GTPases. While the NT effects on individually migrating PDACs were mediated at least through the EGFR/ERK signaling pathways, those on collectively migrating PDACs appeared highly dependent on the PI 3-kinase pathway. Conclusion: This study strongly suggests the involvement of neurotensin in the modulation of human PDAC migration.

scholarly journals Effect of Adenomatous Polyposis Coli Loss on Tumorigenic Potential in Pancreatic Ductal Adenocarcinoma

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1084 ◽  
Author(s):  
Jennifer M. Cole ◽  
Kaitlyn Simmons ◽  
Jenifer R. Prosperi
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cell Lines ◽  
Pancreatic Cancer Cell ◽  
Ductal Adenocarcinoma ◽  
Adenomatous Polyposis ◽  
Polyposis Coli ◽  
Pathway Activation ◽  
Functional Implications

Loss of the Adenomatous Polyposis Coli (APC) tumor suppressor in colorectal cancer elicits rapid signaling through the Wnt/β-catenin signaling pathway. In contrast to this well-established role of APC, recent studies from our laboratory demonstrated that APC functions through Wnt-independent pathways to mediate in vitro and in vivo models of breast tumorigenesis. Pancreatic ductal adenocarcinoma (PDAC) has an overall median survival of less than one year with a 5-year survival rate of 7.2%. APC is lost in a subset of pancreatic cancers, but the impact on Wnt signaling or tumor development is unclear. Given the lack of effective treatment strategies for pancreatic cancer, it is important to understand the functional implications of APC loss in pancreatic cancer cell lines. Therefore, the goal of this project is to study how APC loss affects Wnt pathway activation and in vitro tumor phenotypes. Using lentiviral shRNA, we successfully knocked down APC expression in six pancreatic cancer cell lines (AsPC-1, BxPC3, L3.6pl, HPAF-II, Hs 766T, MIA PaCa-2). No changes were observed in localization of β-catenin or reporter assays to assess β-catenin/TCF interaction. Despite this lack of Wnt/β-catenin pathway activation, the majority of APC knockdown cell lines exhibit an increase in cell proliferation. Cell migration assays showed that the BxPC-3 and L3.6pl cells were impacted by APC knockdown, showing faster wound healing in scratch wound assays. Interestingly, APC knockdown had no effect on gemcitabine treatment, which is the standard care for pancreatic cancer. It is important to understand the functional implications of APC loss in pancreatic cancer cells lines, which could be used as a target for therapeutics.

scholarly journals TRIM29 as a Novel Biomarker in Pancreatic Adenocarcinoma

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
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.

scholarly journals TMPRSS4 Promotes Cell Proliferation and Inhibits Apoptosis in Pancreatic Ductal Adenocarcinoma by Activating ERK1/2 Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Jianyou Gu ◽  
Wenjie Huang ◽  
Junfeng Zhang ◽  
Xianxing Wang ◽  
Tian Tao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Signaling Pathway ◽  
Cellular Proliferation ◽  
Function Analysis ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells

Transmembrane protease serine 4 (TMPRSS4) is upregulated in various kinds of human cancers, including pancreatic cancer. However, its biological function in pancreatic ductal adenocarcinoma (PDAC) remains unclear. In the current study, real-time qPCR, immunohistochemical staining, Western blotting, and database (Cancer Genome Atlas and Gene Expression) analysis revealed remarkable overexpression of TMPRSS4 in PDAC tissue as compared to non-tumor tissue. The TMPRSS4 overexpression was associated with poor prognosis of PDAC patients. Moreover, multivariate analysis revealed that TMPRSS4 serves as an independent risk factor in PDAC. We performed gain-and loss-of-function analysis and found that TMPRSS4 promotes cellular proliferation and inhibits apoptosis of PDAC cells both in vitro and in vivo. Furthermore, we showed that TMPRSS4 might promote cell proliferation and inhibit apoptosis through activating ERK1/2 signaling pathway in pancreatic cancer cells. These findings were validated by using ERK1/2 phosphorylation inhibitor SCH772984 both in vitro and in vivo. Taken together, this study suggests that TMPRSS4 is a proto-oncogene, which promotes initiation and progression of PDAC by controlling cell proliferation and apoptosis. Our findings indicate that TMPRSS4 could be a promising prognostic biomarker and a therapeutic target for the treatment of pancreatic cancer.

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