scholarly journals ISG20L2 as a Novel Prognostic Biomarker Facilitates the Progression of Pancreatic Cancer Via Glycolysis

2021 ◽  
Author(s):  
Jianming Wei ◽  
Xibo Gao ◽  
Bingbing Ren ◽  
Daqing Sun ◽  
Tong Liu
Keyword(s):  
Pancreatic Cancer ◽  
Immune Cell ◽  
Xenograft Model ◽  
Gene Set Enrichment Analysis ◽  
Pathway Gene ◽  
Increased Risk ◽  
And Migration ◽  
Vesicle Cycle

Abstract Background: Longstanding type 2 diabetes mellitus (T2DM) is an increased risk of pancreatic cancer (PC) in western populations, and PC is also a cause of T2DM. However, the association of glucose metabolism between T2DM and PC remains unclear. Methods: Differentially expressed genes (DEGs) were identified by bioinformatic analysis from Gene Expression Omnibus (GEO) datasets GSE20966 and GSE16515, respectively. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, Gene Set Enrichment Analysis (GSEA), the Kaplan-Meier (KM) Plotter and Tumor Immune Estimation Resource (TIMER) database were applied. Pancreatic cancer cell lines and primary PDAC samples were used. Cell culture, immunohistochemistry (IHC), siRNA transfection, Western blot, RT-PCR, and migration assay, animal xenograft model studies and statistical analysis were performed in this study. Results: We identified 64 DEGs in GSE20966 of T2DM, and 296 DEGs were identified in GSE16515 of pancreatic cancer, respectively. T2DM-DEGs were mainly enriched in synaptic vesicle cycle, protein export. KEGG pathways in pancreatic cancer included spliceosome, RNA transport. Here, ISG20L2 was identified as only a co-expressed gene between T2DM and PDAC. We found that the expression of ISG20L2 was associated with tumor immune cell infiltration. ISG20L2 was significantly upregulated in PDAC and associated with prognosis of PDAC patients. Moreover, ISG20L2 expression was regulated by GLUT1 , HK2 , LDHA , PKM1 and PKM2 related with glycolysis in PDAC. ISG20L2 promoted PDAC cell proliferation and migration both in vitro and in vivo. Conclusion: This study showed that ISG20L2 promoted the progression and ISG20L2 may be a potential therapeutic strategy in PDAC.

scholarly journals ISG20L2 as a Novel Prognostic Biomarker Facilitates the Progression of Pancreatic Cancer via Glycolysis

2021 ◽  
Author(s):  
Jianming Wei ◽  
Xibo Gao ◽  
Bingbing Ren ◽  
Daqing Sun ◽  
Tong Liu
Keyword(s):  
Pancreatic Cancer ◽  
Immune Cell ◽  
Xenograft Model ◽  
Gene Set Enrichment Analysis ◽  
Pathway Gene ◽  
Increased Risk ◽  
And Migration ◽  
Vesicle Cycle

Abstract Background: Longstanding type 2 diabetes mellitus (T2DM) is an increased risk of pancreatic cancer (PC) in western populations, and PC is also a cause of T2DM. However, the association of glucose metabolism between T2DM and PC remains unclear. Methods: Differentially expressed genes (DEGs) were identified by bioinformatic analysis from Gene Expression Omnibus (GEO) datasets GSE20966 and GSE16515, respectively. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, Gene Set Enrichment Analysis (GSEA), the Kaplan-Meier (KM) Plotter and Tumor Immune Estimation Resource (TIMER) database were applied. Pancreatic cancer cell lines and primary PDAC samples were used. Cell culture, immunohistochemistry (IHC), siRNA transfection, Western blot, RT-PCR, and migration assay, animal xenograft model studies and statistical analysis were performed in this study. Results: We identified 64 DEGs in GSE20966 of T2DM, and 296 DEGs were identified in GSE16515 of pancreatic cancer, respectively. T2DM-DEGs were mainly enriched in synaptic vesicle cycle, protein export. KEGG pathways in pancreatic cancer included spliceosome, RNA transport. Here, ISG20L2 was identified as only a co-expressed gene between T2DM and PDAC. We found that the expression of ISG20L2 was associated with tumor immune cell infiltration. ISG20L2 was significantly upregulated in PDAC and associated with prognosis of PDAC patients. Moreover, ISG20L2 expression was regulated by GLUT1, HK2, LDHA, PKM1 and PKM2 related with glycolysis in PDAC. ISG20L2 promoted PDAC cell proliferation and migration both in vitro and in vivo. Conclusion: This study showed that ISG20L2 promoted the progression and ISG20L2 may be a potential therapeutic strategy in PDAC.

scholarly journals NR5A2 transcriptional activation by BRD4 promotes pancreatic cancer progression by upregulating GDF15

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Feng Guo ◽  
Yingke Zhou ◽  
Hui Guo ◽  
Dianyun Ren ◽  
Xin Jin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Transcriptional Activation ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells ◽  
Gene Sets ◽  
And Migration

AbstractNR5A2 is a transcription factor regulating the expression of various oncogenes. However, the role of NR5A2 and the specific regulatory mechanism of NR5A2 in pancreatic ductal adenocarcinoma (PDAC) are not thoroughly studied. In our study, Western blotting, real-time PCR, and immunohistochemistry were conducted to assess the expression levels of different molecules. Wound-healing, MTS, colony formation, and transwell assays were employed to evaluate the malignant potential of pancreatic cancer cells. We demonstrated that NR5A2 acted as a negative prognostic biomarker in PDAC. NR5A2 silencing inhibited the proliferation and migration abilities of pancreatic cancer cells in vitro and in vivo. While NR5A2 overexpression markedly promoted both events in vitro. We further identified that NR5A2 was transcriptionally upregulated by BRD4 in pancreatic cancer cells and this was confirmed by Chromatin immunoprecipitation (ChIP) and ChIP-qPCR. Besides, transcriptome RNA sequencing (RNA-Seq) was performed to explore the cancer-promoting effects of NR5A2, we found that GDF15 is a component of multiple down-regulated tumor-promoting gene sets after NR5A2 was silenced. Next, we showed that NR5A2 enhanced the malignancy of pancreatic cancer cells by inducing the transcription of GDF15. Collectively, our findings suggest that NR5A2 expression is induced by BRD4. In turn, NR5A2 activates the transcription of GDF15, promoting pancreatic cancer progression. Therefore, NR5A2 and GDF15 could be promising therapeutic targets in pancreatic cancer.

scholarly journals Positive feedback between lncRNA FLVCR1-AS1 and KLF10 may inhibit pancreatic cancer progression via the PTEN/AKT pathway

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Jiewei Lin ◽  
Shuyu Zhai ◽  
Siyi Zou ◽  
Zhiwei Xu ◽  
Jun Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Positive Feedback ◽  
Molecular Mechanisms ◽  
Tumor Tissues ◽  
And Migration

Abstract Background FLVCR1-AS1 is a key regulator of cancer progression. However, the biological functions and underlying molecular mechanisms of pancreatic cancer (PC) remain unknown. Methods FLVCR1-AS1 expression levels in 77 PC tissues and matched non-tumor tissues were analyzed by qRT-PCR. Moreover, the role of FLVCR1-AS1 in PC cell proliferation, cell cycle, and migration was verified via functional in vitro and in vivo experiments. Further, the potential competitive endogenous RNA (ceRNA) network between FLVCR1-AS1 and KLF10, as well as FLVCR1-AS1 transcription levels, were investigated. Results FLVCR1-AS1 expression was low in both PC tissues and PC cell lines, and FLVCR1-AS1 downregulation was associated with a worse prognosis in patients with PC. Functional experiments demonstrated that FLVCR1-AS1 overexpression significantly suppressed PC cell proliferation, cell cycle, and migration both in vitro and in vivo. Mechanistic investigations revealed that FLVCR1-AS1 acts as a ceRNA to sequester miR-513c-5p or miR-514b-5p from the sponging KLF10 mRNA, thereby relieving their suppressive effects on KLF10 expression. Additionally, FLVCR1-AS1 was shown to be a direct transcriptional target of KLF10. Conclusions Our research suggests that FLVCR1-AS1 plays a tumor-suppressive role in PC by inhibiting proliferation, cell cycle, and migration through a positive feedback loop with KLF10, thereby providing a novel therapeutic strategy for PC treatment.

scholarly journals STK3 Suppresses Ovarian Cancer Progression by Activating NF-κB Signaling to Recruit CD8+ T-Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Xiangyu Wang ◽  
Fengmian Wang ◽  
Zhi-Gang Zhang ◽  
Xiao-Mei Yang ◽  
Rong Zhang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
T Cells ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Gene Set Enrichment Analysis ◽  
Ovarian Cancer Cells ◽  
And Migration

Serine/threonine protein kinase-3 (STK3) is a critical molecule of the Hippo pathway but little is known about its biological functions in the ovarian cancer development. We demonstrated the roles of STK3 in ovarian cancer. Existing databases were used to study the expression profile of STK3. STK3 was significantly downregulated in OC patients, and the low STK3 expression was correlated with a poor prognosis. In vitro cell proliferation, apoptosis, and migration assays, and in vivo subcutaneous xenograft tumor models were used to determine the roles of STK3. The overexpression of STK3 significantly inhibited cell proliferation, apoptosis, and migration of ovarian cancer cells in vitro and tumor growth in vivo. Bisulfite sequencing PCR analysis was performed to validate the methylation of STK3 in ovarian cancer. RNA sequencing and gene set enrichment analysis (GSEA) were used to compare the transcriptome changes in the STK3 overexpression ovarian cancer and control cells. The signaling pathway was analyzed by western blotting. STK3 promoted the migration of CD8+ T-cells by activating nuclear transcription factor κB (NF-κB) signaling. STK3 is a potential predictor of OC. It plays an important role in suppressing tumor growth of ovarian cancer and in chemotaxis of CD8+ T-cells.

scholarly journals Dual Effects ofβ3Integrin Subunit Expression on Human Pancreatic Cancer Models

2010 ◽  
Vol 33 (5-6) ◽  
pp. 191-205 ◽  
Author(s):  
S. Marchán ◽  
S. Pérez-Torras ◽  
A. Vidal ◽  
J. Adan ◽  
F. Mitjans ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Rho Gtpases ◽  
Cell Attachment ◽  
Human Pancreatic Cancer ◽  
Cell Growth And Migration ◽  
Subunit Expression ◽  
And Migration

Background: Pancreatic cancer, the fifth leading cause of adult cancer death in Western countries, lacks early detection, and displays significant dissemination ability. Accumulating evidence shows that integrin-mediated cell attachment to the extracellular matrix induces phenotypes and signaling pathways that regulate tumor cell growth and migration.Methods: In view of these findings, we examined the role ofβ3in pancreatic cancer by generating two stableβ3-expressing pancreatic human cell lines and characterizing their behavior in vitro and in vivo.Results: Transduction ofβ3selectively augmented the functional membraneαvβ3integrin levels, as evident from the enhanced adhesion and migration abilities related to active Rho GTPases. No effects on in vitro anchorage-dependent growth, but higher anoikis were detected inβ3-overexpressing cells. Moreover, tumors expressingβ3displayed reduced growth. Interestingly, treatment of mice with anαv-blocking antibody inhibited the growth ofβ3-expressing tumors to a higher extent.Conclusion: Our results collectively support the hypothesis thatαvβ3integrin has dual actions depending on the cell environment, and provide additional evidence on the role of integrins in pancreatic cancer, which should eventually aid in improving prediction of the effects of therapies addressed to modulate integrin activities in these tumors.

scholarly journals The endothelial basement membrane acts as a checkpoint for entry of pathogenic T cells into the brain

2020 ◽  
Vol 217 (7) ◽  
Author(s):  
Xueli Zhang ◽  
Ying Wang ◽  
Jian Song ◽  
Hanna Gerwien ◽  
Omar Chuquisana ◽  
...  
Keyword(s):  
T Cells ◽  
Basement Membrane ◽  
Immune Cell ◽  
Cell Phenotype ◽  
T Cell Infiltration ◽  
And Migration ◽  
Endothelial Basement Membrane ◽  
Laminin 411

The endothelial cell basement membrane (BM) is a barrier to migrating leukocytes and a rich source of signaling molecules that can influence extravasating cells. Using mice lacking the major endothelial BM components, laminin 411 or 511, in murine experimental autoimmune encephalomyelitis (EAE), we show here that loss of endothelial laminin 511 results in enhanced disease severity due to increased T cell infiltration and altered polarization and pathogenicity of infiltrating T cells. In vitro adhesion and migration assays reveal higher binding to laminin 511 than laminin 411 but faster migration across laminin 411. In vivo and in vitro analyses suggest that integrin α6β1- and αvβ1-mediated binding to laminin 511–high sites not only holds T cells at such sites but also limits their differentiation to pathogenic Th17 cells. This highlights the importance of the interface between the endothelial monolayer and the underlying BM for modulation of immune cell phenotype.

Impaired T-cell priming in vivo resulting from dysfunction of WASp-deficient dendritic cells

Blood ◽  
2007 ◽  
Vol 110 (13) ◽  
pp. 4278-4284 ◽  
Author(s):  
Gerben Bouma ◽  
Siobhan Burns ◽  
Adrian J. Thrasher
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Immune Cell ◽  
Wild Type ◽  
Cytoskeletal Dynamics ◽  
T Cell Priming ◽  
And Migration ◽  
Priming Activity

The Wiskott-Aldrich syndrome (WAS) is characterized by defective cytoskeletal dynamics affecting multiple immune cell lineages, and leading to immunodeficiency and autoimmunity. The contribution of dendritic cell (DC) dysfunction to the immune dysregulation has not been defined, although both immature and mature WAS knockout (KO) DCs exhibit significant abnormalities of chemotaxis and migration. To exclude environmental confounders as a result of WAS protein (WASp) deficiency, we studied migration and priming activity of WAS KO DCs in vivo after adoptive transfer into wild-type recipient mice. Homing to draining lymph nodes was reduced and WAS KO DCs failed to localize efficiently in T-cell areas. Priming of both CD4+ and CD8+ T lymphocytes by WAS KO DCs preloaded with antigen was significantly decreased. At low doses of antigen, activation of preprimed wild-type CD4+ T lymphocytes by WAS KO DCs in vitro was also abrogated, suggesting that there is a threshold-dependent impairment even if successful DC–T cell colocalization is achieved. Our data indicate that intrinsic DC dysfunction due to WASp deficiency directly impairs the T-cell priming response in vivo, most likely as a result of inefficient migration, but also possibly influenced by suboptimal DC-mediated cognate interaction.

scholarly journals Single-Domain Antibodies for Targeting, Detection, and In Vivo Imaging of Human CD4+ Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Bjoern Traenkle ◽  
Philipp D. Kaiser ◽  
Stefania Pezzana ◽  
Jennifer Richardson ◽  
Marius Gramlich ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Cell ◽  
Inflammatory Diseases ◽  
Xenograft Model ◽  
Single Domain ◽  
Positron Emission ◽  
Depth Analysis ◽  
Single Domain Antibodies

The advancement of new immunotherapies necessitates appropriate probes to monitor the presence and distribution of distinct immune cell populations. Considering the key role of CD4+ cells in regulating immunological processes, we generated novel single-domain antibodies [nanobodies (Nbs)] that specifically recognize human CD4. After in-depth analysis of their binding properties, recognized epitopes, and effects on T-cell proliferation, activation, and cytokine release, we selected CD4-specific Nbs that did not interfere with crucial T-cell processes in vitro and converted them into immune tracers for noninvasive molecular imaging. By optical imaging, we demonstrated the ability of a high-affinity CD4-Nb to specifically visualize CD4+ cells in vivo using a xenograft model. Furthermore, quantitative high-resolution immune positron emission tomography (immunoPET)/MR of a human CD4 knock-in mouse model showed rapid accumulation of 64Cu-radiolabeled CD4-Nb1 in CD4+ T cell-rich tissues. We propose that the CD4-Nbs presented here could serve as versatile probes for stratifying patients and monitoring individual immune responses during personalized immunotherapy in both cancer and inflammatory diseases.

scholarly journals Nicotine Induces IL-8 Secretion from Pancreatic Cancer Stroma and Worsens Cancer-Induced Cachexia

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 329
Author(s):  
Patrick W. Underwood ◽  
Dong Yu Zhang ◽  
Miles E. Cameron ◽  
Michael H. Gerber ◽  
Daniel Delitto ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Cancer Patient ◽  
Xenograft Model ◽  
Pancreatic Cancer Patient ◽  
Nicotine Treatment ◽  
Pancreatic Cancer Cells ◽  
Cancer Tumor

Smoking is highly associated with pancreatic cancer. Nicotine, the addictive component of tobacco, is involved in pancreatic cancer tumorigenesis, metastasis, and chemoresistance. This work aimed to describe the role of nicotine within the pancreatic cancer tumor microenvironment. Nicotine treatment was used in vitro to assess its effect on tumor-associated stromal cells and pancreatic cancer cells. Nicotine treatment was then used in a pancreatic cancer patient-derived xenograft model to study the effects in vivo. Nicotine induced secretion of interleukin 8 (IL-8) by tumor-associated stroma cells in an extracellular signal-regulated kinase (ERK)-dependent fashion. The secreted IL-8 and nicotine acted on the pancreatic cancer cell, resulting in upregulation of IL-8 receptor. Nicotine treatment of mice bearing pancreatic cancer patient-derived xenografts had significantly increased tumor mass, increased tumor-free weight loss, and decreased muscle mass. These represent important pathways through which nicotine acts within the tumor microenvironment and worsens pancreatic cancer-induced cachexia, potentially representing future therapeutic targets.

scholarly journals Long noncoding RNA LINC01111 suppresses pancreatic cancer aggressiveness by regulating DUSP1 expression via microRNA-3924

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Shutao Pan ◽  
Ming Shen ◽  
Min Zhou ◽  
Xiuhui Shi ◽  
Ruizhi He ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Cell Invasion ◽  
Molecular Mechanisms ◽  
Invasion And Migration ◽  
Cancer Aggressiveness ◽  
And Migration

AbstractDysfunction in long noncoding RNAs (lncRNAs) is reported to participate in the initiation and progression of human cancer; however, the biological functions and molecular mechanisms through which lncRNAs affect pancreatic cancer (PC) are largely unknown. Here, we report a novel lncRNA, LINC01111, that is clearly downregulated in PC tissues and plasma of PC patients and acts as a tumor suppressor. We found that the LINC01111 level was negatively correlated with the TNM stage but positively correlated with the survival of PC patients. The overexpression of LINC01111 significantly inhibited cell proliferation, the cell cycle, and cell invasion and migration in vitro, as well as tumorigenesis and metastasis in vivo. Conversely, the knockdown of LINC01111 enhanced cell proliferation, the cell cycle, and cell invasion and migration in vitro, as well as tumorigenesis and metastasis in vivo. Furthermore, we found that high expression levels of LINC01111 upregulated DUSP1 levels by sequestering miR-3924, resulting in the blockage of SAPK phosphorylation and the inactivation of the SAPK/JNK signaling pathway in PC cells and thus inhibiting PC aggressiveness. Overall, these data reveal that LINC01111 is a potential diagnostic biomarker for PC patients, and the newly identified LINC01111/miR-3924/DUSP1 axis can modulate PC initiation and development.

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