TGFβ Drives Metabolic Perturbations during Epithelial Mesenchymal Transition in Pancreatic Cancer: TGFβ Induced EMT in PDAC

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy wherein a majority of patients present metastatic disease at diagnosis. Although the role of epithelial to mesenchymal transition (EMT), mediated by transforming growth factor beta (TGFβ), in imparting an aggressive phenotype to PDAC is well documented, the underlying biochemical pathway perturbations driving this behaviour have not been elucidated. We used high-resolution mass spectrometry (HRMS) based molecular phenotyping approach in order to delineate metabolic changes concomitant to TGFβ-induced EMT in pancreatic cancer cells. Strikingly, we observed robust changes in amino acid and energy metabolism that may contribute to tumor invasion and metastasis. Somewhat unexpectedly, TGFβ treatment resulted in an increase in intracellular levels of retinoic acid (RA) that in turn resulted in increased levels of extracellular matrix (ECM) proteins including fibronectin (FN) and collagen (COL1). These findings were further validated in plasma samples obtained from patients with resectable pancreatic cancer. Taken together, these observations provide novel insights into small molecule dysregulation that triggers a molecular cascade resulting in increased EMT-like changes in pancreatic cancer cells, a paradigm that can be potentially targeted for better clinical outcomes.

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CCL18 promotes epithelial-mesenchymal transition, invasion and migration of pancreatic cancer cells in pancreatic ductal adenocarcinoma

International Journal of Oncology ◽

10.3892/ijo.2014.2794 ◽

2014 ◽

Vol 46 (3) ◽

pp. 1109-1120 ◽

Cited By ~ 40

Author(s):

FANBIN MENG ◽

WAN LI ◽

CHANGLING LI ◽

ZHIGANG GAO ◽

KEJIAN GUO ◽

...

Keyword(s):

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Ductal Adenocarcinoma ◽

Mesenchymal Transition ◽

Invasion And Migration ◽

Pancreatic Cancer Cells ◽

And Migration

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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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MEG8 long noncoding RNA contributes to epigenetic progression of the epithelial-mesenchymal transition of lung and pancreatic cancer cells

Journal of Biological Chemistry ◽

10.1074/jbc.ra118.004006 ◽

2018 ◽

Vol 293 (47) ◽

pp. 18016-18030 ◽

Cited By ~ 22

Author(s):

Minoru Terashima ◽

Akihiko Ishimura ◽

Sasithorn Wanna-udom ◽

Takeshi Suzuki

Keyword(s):

Lung Cancer ◽

Pancreatic Cancer ◽

Cancer Cells ◽

Noncoding Rna ◽

Transforming Growth Factor ◽

Epithelial Mesenchymal Transition ◽

Morphological Changes ◽

Human Lung Cancer ◽

Mesenchymal Transition ◽

Pancreatic Cancer Cells

Long noncoding RNAs (lncRNAs) are important regulatory molecules in various biological and pathological processes, including cancer development. We have previously shown that the MEG3 lncRNA plays an essential role in transforming growth factor-β (TGF-β)–induced epithelial-mesenchymal transition (EMT) of human lung cancer cells. In this study, we investigated the function of another lncRNA, MEG8, which shares the DLK1–DIO3 locus with MEG3, in the regulation of EMT. MEG8 lncRNA expression was immediately induced during TGF-β–mediated EMT of A549 and LC2/ad lung cancer and Panc1 pancreatic cancer cell lines. MEG8 overexpression specifically suppressed the expression of microRNA-34a and microRNA-203 genes, resulting in up-regulation of SNAIL family transcriptional repressor 1 (SNAI1) and SNAI2 transcription factors, which repressed expression of cadherin 1 (CDH1)/E-cadherin. Mechanistic investigations revealed that MEG8 associates with enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) protein and induces its recruitment to the regulatory regions of the two microRNA genes for histone H3 methylation and transcriptional repression. Interestingly, expression of both MEG8 and MEG3, but not each individually, could induce EMT-related cell morphological changes and increased cell motility in the absence of TGF-β by activating the gene expression program required for EMT. MEG8 knockdown indicated that endogenous MEG8 lncRNA is indispensable for TGF-β–induced EMT in A549 lung cancer and Panc1 pancreatic cancer cells. Our findings indicate that MEG8 lncRNA significantly contributes to epigenetic EMT induction and increase our understanding of the lncRNA-mediated regulatory mechanisms involved in malignant progression of cancer.

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The metastasis suppressor, NDRG1, attenuates oncogenic TGF-β and NF-κB signaling to enhance membrane E-cadherin expression in pancreatic cancer cells

Carcinogenesis ◽

10.1093/carcin/bgy178 ◽

2018 ◽

Vol 40 (6) ◽

pp. 805-818 ◽

Cited By ~ 14

Author(s):

Sharleen V Menezes ◽

Leyla Fouani ◽

Michael L H Huang ◽

Bekesho Geleta ◽

Sanaz Maleki ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Membrane ◽

Cancer Cells ◽

Transforming Growth Factor ◽

Xenograft Model ◽

Tumor Xenograft ◽

Metastasis Suppressor ◽

Mesenchymal Transition ◽

Pancreatic Cancer Cells ◽

E Cadherin

AbstractThe metastasis suppressor, N-myc downstream-regulated gene-1 (NDRG1), plays multifaceted roles in inhibiting oncogenic signaling and can suppress the epithelial mesenchymal transition (EMT), a key step in metastasis. In this investigation, NDRG1 inhibited the oncogenic effects of transforming growth factor-β (TGF-β) in PANC-1 pancreatic cancer cells, promoting expression and co-localization of E-cadherin and β-catenin at the cell membrane. A similar effect of NDRG1 at supporting E-cadherin and β-catenin co-localization at the cell membrane was also demonstrated for HT-29 colon and CFPAC-1 pancreatic cancer cells. The increase in E-cadherin in PANC-1 cells in response to NDRG1 was mediated by the reduction of three transcriptional repressors of E-cadherin, namely SNAIL, SLUG and ZEB1. To dissect the mechanisms how NDRG1 inhibits nuclear SNAIL, SLUG and ZEB1, we assessed involvement of the nuclear factor-κB (NF-κB) pathway, as its aberrant activation contributes to the EMT. Interestingly, NDRG1 comprehensively inhibited oncogenic NF-κB signaling at multiple sites in this pathway, suppressing NEMO, Iĸĸα and IĸBα expression, as well as reducing the activating phosphorylation of Iĸĸα/β and IĸBα. NDRG1 also reduced the levels, nuclear co-localization and DNA-binding activity of NF-κB p65. Further, Iĸĸα, which integrates NF-κB and TGF-β signaling to upregulate ZEB1, SNAIL and SLUG, was identified as an NDRG1 target. Considering this, therapies targeting NDRG1 could be a new strategy to inhibit metastasis, and as such, we examined novel anticancer agents, namely di-2-pyridylketone thiosemicarbazones, which upregulate NDRG1. These agents downregulated SNAIL, SLUG and ZEB1 in vitro and in vivo using a PANC-1 tumor xenograft model, demonstrating their marked potential.

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