RNAi- AND ANTISENSE-TARGETED DOWN-REGULATION OF GASTRIN IN PANCREATIC CANCER CELLS INHIBITS TUMOR GROWTH AND METASTASIS

AbstractPancreatic cancer is a highly aggressive and lethal digestive system malignancy. Our previous studies revealed the correlation of high levels of lncRNA SOX2OT expression with patients’ poor survival outcomes, the promoting role of SOX2OT in proliferation and cycle progression of pancreatic cancer cells, and the in vivo binding of SOX2OT to RNA binding protein FUS, which destabilized the protein expression of FUS. However, the mechanism of SOX2OT binding and inhibiting FUS protein stability remains unclear. In this study, we performed RNA pull-down, cycloheximide-chase, and ubiquitination assays to determine the effect of SOX2OT on FUS ubiquitination, and explored the specific regulatory mechanism of SOX2OT–FUS axis in pancreatic cancer cell migration, invasion, in vivo tumor growth, and metastasis through RNA sequencing. We found that SOX2OT binds to FUS through its 5′ and 3′ regions, resulting in FUS ubiquitination and degradation. The SOX2OT–FUS regulatory axis promotes migration, invasion, tumor growth, and metastasis ability of pancreatic cancer cells. The in-depth elaboration of the SOX2OT–FUS regulatory axis in pancreatic cancer may clarify the mechanism of action of SOX2OT and provide new ideas for pancreatic cancer treatment.

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Faculty Opinions recommendation of An inhibitor of GSK3B and hdacs kills pancreatic cancer cells and slows pancreatic tumor growth and metastasis in mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.733866005.793569597 ◽

2020 ◽

Author(s):

Dahn Clemens

Keyword(s):

Pancreatic Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Pancreatic Tumor ◽

Pancreatic Cancer Cells ◽

Tumor Growth And Metastasis

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An Inhibitor of GSK3B and HDACs Kills Pancreatic Cancer Cells and Slows Pancreatic Tumor Growth and Metastasis in Mice

Gastroenterology ◽

10.1053/j.gastro.2018.08.028 ◽

2018 ◽

Vol 155 (6) ◽

pp. 1985-1998.e5 ◽

Cited By ~ 15

Author(s):

Mouad Edderkaoui ◽

Chintan Chheda ◽

Badr Soufi ◽

Fouzia Zayou ◽

Robert W. Hu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Pancreatic Tumor ◽

Pancreatic Cancer Cells ◽

Tumor Growth And Metastasis

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Use of decoy receptor 3 to block gemcitabine-induced apoptosis via binding with TRAIL in pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.238 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 238-238

Author(s):

Wei Wang ◽

Wenjie Lin ◽

Xin Zhuang ◽

Qingda Wang ◽

Jinbing Luo

Keyword(s):

Pancreatic Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Growth Delay ◽

Tumor Growth Delay ◽

Down Regulation ◽

In Vivo Experiment ◽

Pancreatic Cancer Cells ◽

Induced Apoptosis

238 Background: Most of human pancreatic cancer cell lines are resistant to chemotherapeutics-induced apoptosis including gemcitabine. This study is to address the role of decoy receptor3 (DcR3) in pancreatic cancer resistant to chemotherapeutics. Methods: siRNA targeted for DcR3 was used to down-regulate DcR3 expression in pancreatic cancer cells. On exploring for the pathway of DcR3 blocking Gemcitabine-induced apoptosis, up or down-regulated DcR3 level of pancreatic cancer cells were treated with Gemcitabine and apoptosis susceptibility was evaluated with apoptosis analysis. To investigate whether DcR3 is involved in TRAIL, FasL or LIGHT-mediated apoptosis, PARP and apoptotic cells staining were determined under different DcR3 level. Through ELISA-like binding analysis, immunoprecipitation and FACS, TRAIL binding with DcR3 was tested. In vivo experiment, it is to investigate whether down-regulation of DcR3 affects gemcitabine-induced apoptosis and tumor growth delay. Results: It demonstrates that DcR3 down-regulation sensitizes cells to gemcitabine-induced apoptosis and additional DcR3 level can impair gemcitabine-induced apoptosis in both of cells. It is proved that DcR3 blocks gemcitabine-induced apoptosis via binding with TRAIL which was thought not to bind with DcR3 previously. Furthermore, Regulation of DcR3 changes the amount of membrane-bound TRAIL which is correlated with gemcitabine-stimulation. In vivo experiment of AsPC-1 xenografts, stable down-regulation of DcR3 significantly enhances gemcitabine-induced apoptosis and tumor growth delay. Conclusions: DcR3 may play important role resistant to gemcitabine-induced apoptosis via binding with TRAIL in some of pancreatic cancer cells lines. Targeting DcR3 represents a promising strategy to enhance the anti-tumor activity of chemo-agent in pancreatic cancer, which has important clinical implications.

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Down-regulation of stathmin is required for TGF-β inducible early gene 1 induced growth inhibition of pancreatic cancer cells

Cancer Letters ◽

10.1016/j.canlet.2008.09.017 ◽

2009 ◽

Vol 274 (1) ◽

pp. 101-108 ◽

Cited By ~ 31

Author(s):

Lei Jiang ◽

Yangchao Chen ◽

Chu-yan Chan ◽

Xin Wang ◽

Lin Lin ◽

...

Keyword(s):

Pancreatic Cancer ◽

Growth Inhibition ◽

Cancer Cells ◽

Early Gene ◽

Down Regulation ◽

Pancreatic Cancer Cells

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Antitumor activity of curcumin is involved in down-regulation of YAP/TAZ expression in pancreatic cancer cells

Oncotarget ◽

10.18632/oncotarget.12596 ◽

2016 ◽

Vol 7 (48) ◽

pp. 79076-79088 ◽

Cited By ~ 24

Author(s):

Xiuxia Zhou ◽

Jingna Su ◽

Shaoyan Feng ◽

Lixia Wang ◽

Xuyuan Yin ◽

...

Keyword(s):

Pancreatic Cancer ◽

Antitumor Activity ◽

Cancer Cells ◽

Down Regulation ◽

Pancreatic Cancer Cells

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2-Triazenoazaindoles: A novel class of triazenes inducing transcriptional down-regulation of EGFR and HER-2 in human pancreatic cancer cells

International Journal of Oncology ◽

10.3892/ijo.2011.1272 ◽

2011 ◽

Vol 40 (4) ◽

pp. 914-922 ◽

Cited By ~ 3

Author(s):

JAN N. KREUTZER ◽

ALESSIA SALVADOR ◽

PATRIZIA DIANA ◽

GIROLAMO CIRRINCIONE ◽

DANIELA VEDALDI ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Human Pancreatic Cancer ◽

Down Regulation ◽

Pancreatic Cancer Cells ◽

Her 2

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TGF-βRII Knock-down in Pancreatic Cancer Cells Promotes Tumor Growth and Gemcitabine Resistance. Importance of STAT3 Phosphorylation on S727

Cancers ◽

10.3390/cancers10080254 ◽

2018 ◽

Vol 10 (8) ◽

pp. 254 ◽

Cited By ~ 5

Author(s):

Vincent Drubay ◽

Nicolas Skrypek ◽

Lucie Cordiez ◽

Romain Vasseur ◽

Céline Schulz ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Locally Advanced ◽

Western World ◽

Pancreatic Cancer Cells ◽

Stat3 Phosphorylation ◽

The Impact

Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers in the Western world because of a lack of early diagnostic markers and efficient therapeutics. At the time of diagnosis, more than 80% of patients have metastasis or locally advanced cancer and are therefore not eligible for surgical resection. Pancreatic cancer cells also harbour a high resistance to chemotherapeutic drugs such as gemcitabine that is one of the main palliative treatments for PDAC. Proteins involved in TGF-β signaling pathway (SMAD4 or TGF-βRII) are frequently mutated in PDAC (50–80%). TGF-β signalling pathway plays antagonistic roles during carcinogenesis by initially inhibiting epithelial growth and later promoting the progression of advanced tumors and thus emerged as both tumor suppressor and oncogenic pathways. In order to decipher the role of TGF-β in pancreatic carcinogenesis and chemoresistance, we generated CAPAN-1 and CAPAN-2 cell lines knocked down for TGF-βRII (first actor of TGF-β signaling). The impact on biological properties of these TGF-βRII-KD cells was studied both in vitro and in vivo. We show that TGF-βRII silencing alters tumor growth and migration as well as resistance to gemcitabine. TGF-βRII silencing also leads to S727 STAT3 and S63 c-Jun phosphorylation, decrease of MRP3 and increase of MRP4 ABC transporter expression and induction of a partial EMT phenotype. These markers associated with TGF-β signaling pathways may thus appear as potent therapeutic tools to better treat/manage pancreatic cancer.

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