Modulation of the Leptin Receptor Mediates Tumor Growth and Migration of Pancreatic Cancer Cells

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

Cell Death Discovery ◽

10.1038/s41420-021-00462-8 ◽

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.

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The NAD+-dependent Histone Deacetylase SIRT6 Promotes Cytokine Production and Migration in Pancreatic Cancer Cells by Regulating Ca2+Responses

Journal of Biological Chemistry ◽

10.1074/jbc.m112.405837 ◽

2012 ◽

Vol 287 (49) ◽

pp. 40924-40937 ◽

Cited By ~ 87

Author(s):

Inga Bauer ◽

Alessia Grozio ◽

Denise Lasigliè ◽

Giovanna Basile ◽

Laura Sturla ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Histone Deacetylase ◽

Cytokine Production ◽

Pancreatic Cancer Cells ◽

And Migration

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LncRNA-PVT1 promotes pancreatic cancer cells proliferation and migration through acting as a molecular sponge to regulate miR-448

Journal of Cellular Physiology ◽

10.1002/jcp.26072 ◽

2017 ◽

Vol 233 (5) ◽

pp. 4044-4055 ◽

Cited By ~ 62

Author(s):

Liang Zhao ◽

Hongru Kong ◽

Hongwei Sun ◽

Zongjing Chen ◽

Bicheng Chen ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Pancreatic Cancer Cells ◽

And Migration ◽

Proliferation And Migration

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Long Noncoding RNA CERS6-AS1 Accelerates the Proliferation and Migration of Pancreatic Cancer Cells by Sequestering MicroRNA-15a-5p and MicroRNA-6838-5p and Modulating HMGA1

Pancreas ◽

10.1097/mpa.0000000000001806 ◽

2021 ◽

Vol 50 (4) ◽

pp. 617-624

Author(s):

Rongxi Shen ◽

Xinbo Wang ◽

Sizhen Wang ◽

Daojun Zhu ◽

Min Li

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Pancreatic Cancer Cells ◽

And Migration ◽

Proliferation And Migration

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Hypoxia inducible factor (HIF)-1α directly activates leptin receptor (Ob-R) in pancreatic cancer cells

Cancer Letters ◽

10.1016/j.canlet.2014.08.001 ◽

2014 ◽

Vol 354 (1) ◽

pp. 172-180 ◽

Cited By ~ 26

Author(s):

He Ren ◽

Lingling Jia ◽

Tiansuo Zhao ◽

Huan Zhang ◽

Jing Chen ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Leptin Receptor ◽

Hypoxia Inducible Factor ◽

Pancreatic Cancer Cells

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LAMC2 modulates the acidity of microenvironments to promote invasion and migration of pancreatic cancer cells via regulating AKT-dependent NHE1 activity

Experimental Cell Research ◽

10.1016/j.yexcr.2020.111984 ◽

2020 ◽

Vol 391 (1) ◽

pp. 111984 ◽

Cited By ~ 1

Author(s):

Hui Wang ◽

Jun Cai ◽

Shaoxia Du ◽

Wei Wei ◽

Xiaohong Shen

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Invasion And Migration ◽

Pancreatic Cancer Cells ◽

Nhe1 Activity ◽

And Migration

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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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