Propofol Regulates ADAM8 in Pancreatic Cancer Cells by Targeting SP1

Abstract BackgroundPropofol is a commonly used anesthetic with controversial effects on cancer cells. A growing number of studies have demonstrated that low concentrations of propofol are associated with tumor suppression, but deeper insights into its underlying mechanism are needed. The study detailed herein focuses uponthe effect of propofol on pancreatic cells and the mechanism by which propofol down-regulated ADAM8 expression.MethodsTreatment pancreatic cell line Panc-1was performed with different concentrations of propofol. MTT assay and flow cytometry were used to assess cell proliferation and the cell cycle. A wound healing assay was used to evaluate the migration capacity of Panc-1 cells. Quantitative real-time PCR (qRT-PCR) and western blot were used to analyze specificity protein 1 (SP1) and a disintegrin and metalloproteinase 8 (ADAM8) expression. Luciferase assay was performed to determine the transcriptional activity of SP1.RNA interference (RNAi) was used to explore whether propofol regulated ADAM8 in Panc-1 cells by targeting SP1. ResultsPropofol significantly inhibited the proliferation, migration and invasion of pancreatic cancer cells and decreased the percentage of cells in S-phase. Furthermore, propofol failed to regulate ADAM8 expression in Panc-1 cells with SP1 knockdown. Luciferase assays demonstrated that propofol repressed the transcriptional activity of SP1, while ADAM8 was a direct target of SP1. ConclusionsThese results suggest that propofol affect biological behavior of pancreatic cancer cells through ADAM8 by targeting SP1.

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Long Non-coding RNA DLEU2L Targets miR-210-3p to Suppress Gemcitabine Resistance in Pancreatic Cancer Cells via BRCA2 Regulation

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.645365 ◽

2021 ◽

Vol 8 ◽

Author(s):

Fei Xu ◽

Heshui Wu ◽

Jiongxin Xiong ◽

Tao Peng

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Aerobic Glycolysis ◽

Critical Role ◽

Migration And Invasion ◽

Pancreatic Cell ◽

Clinical Issue ◽

Pancreatic Cancer Cells

Gemcitabine (GEM) resistance remains a challenging clinical issue to overcome in chemotherapy against pancreatic cancer. We previously demonstrated that miR-210 derived from pancreatic cancer stem cells enhanced the GEM-resistant properties of pancreatic cancer cells, thus identifying miR-210 as an oncogenic miRNA. Herein, we report the existence of an upstream effector that acts as a competing endogenous RNA (ceRNA) to miR-210. Bioinformatic screening was performed to identify lncRNAs with a binding relationship to miR-210. Overexpression and interference vectors were constructed to demonstrate the effect of ceRNA activity in pancreatic cell behavior, both in vitro and in vivo. DLEU2L (deleted in lymphocytic leukemia 2-like), which is expressed at low levels in pancreatic cancer tissues, was shown to exhibit a binding relationship with miR-210-3p. Overexpression of DLEU2L and silencing of miR-210-3p suppressed the proliferation, migration, and invasion of pancreatic cancer cells while promoting apoptosis. These effects occurred via the inhibition of the Warburg effect (aerobic glycolysis) and AKT/mTOR signaling. In addition, we showed that BRCA2 is a target gene of miR-210-3p, and the downregulation of miR-210-3p by DLEU2L effectively induced an upregulation of BRCA2 via the ceRNA mechanism. In vivo, DLEU2L overexpression and miR-210-3p interference suppressed pancreatic tumor progression, consistent with the results of in vitro studies. The findings of our study establish DLEU2L as a ceRNA to miR-210-3p and reveal the critical role of the DLEU2L/miR-210-3p crosstalk in targeting GEM resistance.

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MALAT1 Promotes Epithelial-Mesenchymal Transition of Pancreatic Cancer Cells Through miR-141-5p/ TGFBR1 / TGFBR2 Axis

10.21203/rs.3.rs-63556/v1 ◽

2020 ◽

Author(s):

Huimin Lu ◽

Mao Li ◽

Jun Ye ◽

Ling Zhang ◽

Shan Lu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Transforming Growth Factor Beta ◽

Noncoding Rna ◽

Transforming Growth Factor ◽

Specific Binding ◽

Luciferase Assay ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Pancreatic Cancer Cells

Abstract Background: Pancreatic cancer is one of the leading causes of cancer deaths, with high chance of metastasis associated with high mortality rates. Epithelial-to-mesenchymal transition (EMT) is one of the crucial steps in the initiation of metastasis, when cells begin to lose adhesion and gain invasive properties. Transforming growth factor beta (TGF-β) is known to promote EMT via binding to its receptors, TGFBR1 and TGFBR2, which are overexpressed in pancreatic cancer cells. Methods: The expression of MALAT1 was detected in pancreatic cancer tissues. The dual-luciferase assay was performed to validate the binding between MALAT1 and miR-141-5p. The western blot was performed to detect the expression of both TGFBR1 and TGFBR2.Results: The long noncoding RNA (lncRNA) MALAT1 is highly expressed in cancer cells and positively correlated with tumor growth and metastasis. Our study revealed that MALAT1 suppresses the expression of miR-141-5p by acting as a “miRNA sponge”. We validated the sequence-specific binding between MALAT1 and miR-141-5p by dual-luciferase experiment, and found that their expressions are negatively correlated in pancreatic cancer cells. Furthermore, miR-141-5p downregulates TGFBR1 and TGFBR2, and reduces cell migration and invasion that are caused by TGF-β-induced EMT. However, the overexpression of MALAT1 in pancreatic cancer cells suppresses the expression of miR-141-5p. Underexpression of miR-141-5p promotes the expression of TGFBR1 and TGFBR2, inducing EMT through the TGF-β pathway. Conclusions: The overexpression of MALAT1 is a key component in initiating metastasis in pancreatic cancer, by inhibiting the effect of miR-141-5p and promoting TGF-β-induced EMT.

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Targeted Fluorescence Imaging and Biological Effects of Peptide Conjugated Quantum Dots on Pancreatic Cancer Cells

Journal of Nanoscience and Nanotechnology ◽

10.1166/jnn.2020.16949 ◽

2020 ◽

Vol 20 (3) ◽

pp. 1351-1357 ◽

Cited By ~ 1

Author(s):

Xiudong Shi ◽

Chunzi Shi ◽

Wen Ye ◽

Lin Wang ◽

Yi Zhan ◽

...

Keyword(s):

Pancreatic Cancer ◽

Quantum Dots ◽

Cancer Cells ◽

Cell Biology ◽

Biological Effects ◽

Biological Behavior ◽

Phase Cell ◽

Migration And Invasion ◽

Fluorescence Signal ◽

Pancreatic Cancer Cells

Arginine-glycine-aspartic acid (RGD) peptide sequences exist in a variety of biological extracellular matrices and can specifically bind the cell-surface integrin αvβ3, which is overexpressed in cancer cells and plays important roles in tumor growth and invasion. Quantum dots (QDs) have been applied in the field of cell biology and can be physically conjugated to the surface of cancer cells for imaging. In this research, we developed QDs-RGD nanoparticles and investigated its application in pancreatic cancer cell imaging and its influence on the biological behavior of pancreatic cancer cells. The results of flow cytometric analysis showed that the αvβ3 receptor was markedly overexpressed on pancreatic cancer cells. In cellular uptake studies, the fluorescence signal of QDs-RGD nanoparticles in pancreatic cancer cells was higher than that of QDs without RGD conjugation, as determined by an inverted fluorescence microscope. Furthermore, the biological behavior of pancreatic cancer cells was affected by QDs-RGD nanoparticles, which inhibited proliferation, migration and invasion and induced G2-phase cell cycle arrest. With integrin αvβ3 as a target, QDs-RGD nanoparticles can generate high-quality images of pancreatic cancer cells and have immense potential for use in the targeted diagnosis and therapy of pancreatic cancer.

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LncRNA XIST enhanced TGF-β2 expression by targeting miR-141-3p to promote pancreatic cancer cells invasion

Bioscience Reports ◽

10.1042/bsr20190332 ◽

2019 ◽

Vol 39 (7) ◽

Cited By ~ 7

Author(s):

Jianmin Sun ◽

Yubao Zhang

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Underlying Mechanism ◽

Inhibitory Effect ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Pancreatic Cell ◽

Pancreatic Cancer Cells

Abstract The level of expression of long non-coding RNA (LncRNA) X-inactive specific transcript (XIST) is up-regulated in pancreatic cancer (PC). However, the role of XIST in PC and the underlying mechanism are still unknown. The present study aimed to elucidate how XIST participates in PC and its potential target, miR-141-3p. We detected the XIST expression in PC tissues and cells by qRT-PCR. Cell proliferation was measured using a CCK8 kit, and the migration and invasion of cells was measured by Transwell assay. Silencing XIST and miR-141-3p was performed with transfection by Lipofectamine kit. Binding assay was conducted by luciferase reporter assay. Protein expression was examined by Western blot. These results indicate that (i) XIST is highly expressed in tumor tissues while miR-141-3p is down-regulated. (ii) Silencing XIST inhibits the pancreatic cell proliferation, migration and invasion. (iii) MiR-141-3p inhibitor alleviates the inhibitory effect by siXIST in PC cell lines. (iv) MiR-141-3p directly interacts with XIST and also negatively regulates transforming growth factor-β 2 (TGF-β2) expression. (v) Overexpression of XIST attenuates the inhibition of TGF-β2 expression by miR-141-3p. The conclusion, is that XIST could promote proliferation, migration and invasion of PC cells via miR-141-5p/TGF-β2 axis.

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Mesothelin blockage by Amatuximab suppresses cell invasiveness, enhances gemcitabine sensitivity and regulates cancer cell stemness in mesothelin-positive pancreatic cancer cells

BMC Cancer ◽

10.1186/s12885-020-07722-3 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Fumihiko Matsuzawa ◽

Hirofumi Kamachi ◽

Tatsuzo Mizukami ◽

Takahiro Einama ◽

Futoshi Kawamata ◽

...

Keyword(s):

Pancreatic Cancer ◽

Mouse Model ◽

Cancer Cells ◽

Cancer Cell ◽

Morphological Changes ◽

Pancreatic Cancer Cells ◽

Cell Invasiveness ◽

And Migration ◽

Migration Capacity

Abstract Background Mesothelin is a 40-kDa glycoprotein that is highly overexpressed in various types of cancers, however molecular mechanism of mesothelin has not been well-known. Amatuximab is a chimeric monoclonal IgG1/k antibody targeting mesothelin. We recently demonstrated that the combine therapy of Amatuximab and gemcitabine was effective for peritonitis of pancreatic cancer in mouse model. Methods We discover the role and potential mechanism of mesothelin blockage by Amatuximab in human pancreatic cells both expressing high or low level of mesothelin in vitro experiment and peritonitis mouse model of pancreatic cancer. Results Mesothelin blockage by Amatuximab lead to suppression of invasiveness and migration capacity in AsPC-1 and Capan-2 (high mesothelin expression) and reduce levels of pMET expression. The combination of Amatuximab and gemcitabine suppressed proliferation of AsPC-1 and Capan-2 more strongly than gemcitabine alone. These phenomena were not observed in Panc-1 and MIA Paca-2 (Mesothelin low expression). We previously demonstrated that Amatuximab reduced the peritoneal mass in mouse AsPC-1 peritonitis model and induced sherbet-like cancer cell aggregates, which were vanished by gemcitabine. In this study, we showed that the cancer stem cell related molecule such as ALDH1, CD44, c-MET, as well as proliferation related molecules, were suppressed in sherbet-like aggregates, but once sherbet-like aggregates attached to peritoneum, they expressed these molecules strongly without the morphological changes. Conclusions Our work suggested that Amatuximab inhibits the adhesion of cancer cells to peritoneum and suppresses the stemness and viability of those, that lead to enhance the sensitivity for gemcitabine.

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Su1863 Tenascin C in Cancer Stroma Induces Migration and Invasion of Pancreatic Cancer Cells by Interaction With Fibronectin

Gastroenterology ◽

10.1016/s0016-5085(14)61753-4 ◽

2014 ◽

Vol 146 (5) ◽

pp. S-488

Author(s):

Hideyuki Yoshitomi ◽

Hiroaki Shimizu ◽

Masayuki Ohtsuka ◽

Atsushi Kato ◽

Katsunori Furukawa ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Migration And Invasion ◽

Tenascin C ◽

Cancer Stroma ◽

Pancreatic Cancer Cells

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Identification of phosphoenolpyruvate carboxykinase 1 as a potential therapeutic target for pancreatic cancer

Cell Death and Disease ◽

10.1038/s41419-021-04201-w ◽

2021 ◽

Vol 12 (10) ◽

Author(s):

Xiao-ren Zhu ◽

Shi-qing Peng ◽

Le Wang ◽

Xiao-yu Chen ◽

Chun-xia Feng ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Therapeutic Target ◽

Phosphoenolpyruvate Carboxykinase ◽

Human Pancreatic Cancer ◽

Migration And Invasion ◽

Potential Therapeutic Target ◽

Protein Levels ◽

Pancreatic Cancer Cells

AbstractPancreatic cancer is the third leading cause of cancer-related mortalities and is characterized by rapid disease progression. Identification of novel therapeutic targets for this devastating disease is important. Phosphoenolpyruvate carboxykinase 1 (PCK1) is the rate-limiting enzyme of gluconeogenesis. The current study tested the expression and potential functions of PCK1 in pancreatic cancer. We show that PCK1 mRNA and protein levels are significantly elevated in human pancreatic cancer tissues and cells. In established and primary pancreatic cancer cells, PCK1 silencing (by shRNA) or CRISPR/Cas9-induced PCK1 knockout potently inhibited cell growth, proliferation, migration and invasion, and induced robust apoptosis activation. Conversely, ectopic overexpression of PCK1 in pancreatic cancer cells accelerated cell proliferation and migration. RNA-seq analyzing of differentially expressed genes (DEGs) in PCK1-silenced pancreatic cancer cells implied that DEGs were enriched in the PI3K-Akt-mTOR cascade. In pancreatic cancer cells, Akt-mTOR activation was largely inhibited by PCK1 shRNA, but was augmented after ectopic PCK1 overexpression. In vivo, the growth of PCK1 shRNA-bearing PANC-1 xenografts was largely inhibited in nude mice. Akt-mTOR activation was suppressed in PCK1 shRNA-expressing PANC-1 xenograft tissues. Collectively, PCK1 is a potential therapeutic target for pancreatic cancer.

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LINC01121 Inhibits Cell Apoptosis While Facilitating Proliferation, Migration, and Invasion Though Negative Regulation of the Camp/PKA Signaling Pathway via GLP1R

Cellular Physiology and Biochemistry ◽

10.1159/000490167 ◽

2018 ◽

Vol 47 (3) ◽

pp. 1007-1024 ◽

Cited By ~ 6

Author(s):

Yi-Gang Qian ◽

Zhou Ye ◽

Hai-Yong Chen ◽

Zhen Lv ◽

Ai-Bin Zhang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Signaling Pathway ◽

Microarray Data ◽

Cell Apoptosis ◽

Migration And Invasion ◽

Protein Levels ◽

Pancreatic Cancer Cells ◽

Significant Difference

Background/Aims: Pancreatic cancer is an aggressive malignancy as a result of highly metastatic potential. The current study was carried out to alter the expression of LINC01121 in pancreatic cancer, with the aim of elucidating its effects on the biological processes of cell proliferation, migration, invasion, and apoptosis. We hypothesized that both the GLP1R gene and cAMP/PKA signaling pathway participate in the aforementioned process. Methods: Microarray data (GSE14245, GSE27890 and GSE16515) and annotating probe files linked to pancreatic cancer were downloaded through the GEO database. The Multi Experiment Matrix (MEM) site was used to predict the target gene of lncRNA. Both pancreatic cancer tissues (n = 56) and paracancerous tissues (n = 45) were collected from patients diagnosed with pancreatic cancer. Immunohistochemistry was applied to identify the positive expression rate of GLP1R protein. Isolated pancreatic cancer cells and PANC-1 cells were independently classified into the blank, negative control (NC), LINC01121 vector, siRNA-LINC01121, siRNA-GLP1R and siRNA-LINC01121 + siRNA-GLP1R groups. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis were applied to detect the expressions of LINC01121, GLP1R, cAMP, PKA, CREB, Bcl-2, Bad and PCNA. Cell proliferation, migration, invasion, cycle progression, and apoptosis were examined by MTT assay, scratch test, Transwell assay and flow cytometry analyses of Annexin V-FITC/PI staining. Results: Observations were made indicating that LINC01121 was highly expressed, while low expressions of GLP1R in pancreatic cancer were detected based on microarray data, which was largely in consistent with the data collected of LINC01121 and GLP1R within the tissues. The target prediction program and luciferase activity analysis was testament to the notion suggesting that GLP1R was indeed a target of LINC01121. In contrast to the blank and NC groups, the LINC01121 vector group exhibited increased expressions of LINC01121; decreased mRNA and protein levels of GLP1R, Bad, cAMP, and PKA; increased protein levels of CREB, Bcl-2, PCNA, p-PKA and p-CREB; increased cell proliferation, migration and invasion; and decreased cell apoptosis. There was no significant difference detected among the blank, NC, and siRNA-LINC01121 + siRNA-GLP1R groups, except that decreased LINC01121 expression was determined in the siRNA-LINC01121 + siRNA-GLP1R group. Parallel data were observed in the pancreatic cancer cells and PANC-1 cells. Conclusion: The current study presents evidence indicating that LINC01121 might inhibit apoptosis while acting to promote proliferation, migration, and invasion of pancreatic cancer cells, supplementing the stance held that LINC01121 functions as a tumor promoter by means of its involvement in the process of translational repression of the GLP1R and inhibition of the cAMP/PKA signaling pathway.

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