Laminin‑332 mediates proliferation, apoptosis, invasion, migration and epithelial‑to‑mesenchymal transition in pancreatic ductal adenocarcinoma

Huang, Caiqun

doi:10.3892/mmr.2020.11649

Cited by 30 publications

(24 citation statements)

References 39 publications

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“…Particularly, laminin proteins appear to be ubiquitously distributed within the stroma, creating a discontinuous basement membrane [77]. Among the laminin, laminin 5 (consisting of subunits α3, β3, and γ2) has been shown to mediate proliferation, apoptosis, invasion, migration and epithelialto-mesenchymal transition in vitro [78,79] and it is negatively associated with patients' survival [80]. It interacts with cells through focal adhesion and hemidesmosomes formed via the interaction with α3β1 integrin and α6β4 integrin.…”

Section: Fibrosis and Ecm Remodeling Affect Pancreatic Microenvironmentmentioning

confidence: 99%

The Extracellular Matrix in Pancreatic Cancer: Description of a Complex Network and Promising Therapeutic Options

Ferrara¹,

Pignatelli²,

Cossutta

et al. 2021

Cancers

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The stroma is a relevant player in driving and supporting the progression of pancreatic ductal adenocarcinoma (PDAC), and a large body of evidence highlights its role in hindering the efficacy of current therapies. In fact, the dense extracellular matrix (ECM) characterizing this tumor acts as a natural physical barrier, impairing drug penetration. Consequently, all of the approaches combining stroma-targeting and anticancer therapy constitute an appealing option for improving drug penetration. Several strategies have been adopted in order to target the PDAC stroma, such as the depletion of ECM components and the targeting of cancer-associated fibroblasts (CAFs), which are responsible for the increased matrix deposition in cancer. Additionally, the leaky and collapsing blood vessels characterizing the tumor might be normalized, thus restoring blood perfusion and allowing drug penetration. Even though many stroma-targeting strategies have reported disappointing results in clinical trials, the ECM offers a wide range of potential therapeutic targets that are now being investigated. The dense ECM might be bypassed by implementing nanoparticle-based systems or by using mesenchymal stem cells as drug carriers. The present review aims to provide an overview of the principal mechanisms involved in the ECM remodeling and of new promising therapeutic strategies for PDAC.

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Section: Fibrosis and Ecm Remodeling Affect Pancreatic Microenvironmentmentioning

confidence: 99%

The Extracellular Matrix in Pancreatic Cancer: Description of a Complex Network and Promising Therapeutic Options

Ferrara¹,

Pignatelli²,

Cossutta

et al. 2021

Cancers

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show abstract

“…Previously, we reported that extracellular Ser restriction decreased total glutathione content and led to the generation of H 2 O 2 and induction of inflammation-related gene expression in mouse embryonic fibroblasts deficient in Phgdh [ 5 ]. Recent studies also demonstrated that Phgdh deletion elicited an inflammation-like response through the production of cytokines via an increase in reactive oxygen species in chondrocytes [ 41 ], while orally administered Ser was able to protect LPS-induced intestinal inflammation via p53-mediated glutathione synthesis [ 42 ]. Hence, it is presumed that a decrease in the glutathione content and/or a dysregulation of the mitochondrial electron transport system lead to oxidative stress in the liver of LKO mice, which may trigger inflammation-like responses in the liver of LKO mice.…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte-Specific Phgdh-Deficient Mice Culminate in Mild Obesity, Insulin Resistance, and Enhanced Vulnerability to Protein Starvation

et al. 2021

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L-Serine (Ser) is synthesized de novo from 3-phosphoglycerate via the phosphorylated pathway committed by phosphoglycerate dehydrogenase (Phgdh). A previous study reported that feeding a protein-free diet increased the enzymatic activity of Phgdh in the liver and enhanced Ser synthesis in the rat liver. However, the nutritional and physiological functions of Ser synthesis in the liver remain unclear. To clarify the physiological significance of de novo Ser synthesis in the liver, we generated liver hepatocyte-specific Phgdh KO (LKO) mice using an albumin-Cre driver. The LKO mice exhibited a significant gain in body weight compared to Floxed controls at 23 weeks of age and impaired systemic glucose metabolism, which was accompanied by diminished insulin/IGF signaling. Although LKO mice had no apparent defects in steatosis, the molecular signatures of inflammation and stress responses were evident in the liver of LKO mice. Moreover, LKO mice were more vulnerable to protein starvation than the Floxed mice. These observations demonstrate that Phgdh-dependent de novo Ser synthesis in liver hepatocytes contributes to the maintenance of systemic glucose tolerance, suppression of inflammatory response, and resistance to protein starvation.

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“…Inhibition of the kinase resulted in lower laminin expression. Furthermore, recent studies on pancreatic ductal adenocarcinoma cells revealed that knockdown of individual LAM genes resulted in different cell activity (proliferation/migration/EMT) ( 13 ). It is known that soluble factors, such as TGF-β, EGF and PGGF play a role ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

“…LN-332 has the highest affinity for α6β4 integrin, which stabilizes the binding of cells to the basement membrane through hemidesmosomes ( 12 ). Moreover, LN-332 promotes cell polarization, proliferation, and apoptosis ( 13 ). A soluble form of LN-332 causes activation of protein kinase C (PKC), phosphatidyl inositol 3-kinase (PI3K), and mitogen-activated protein kinase (MEK) signaling pathways ( 14 ).…”

Section: Introductionmentioning

confidence: 99%

Gene Expression in Amnion-Derived Cells Cultured on Recombinant Laminin 332—A Preliminary Study

et al. 2021

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Human amniotic cells (hAC) exhibit characteristics of undifferentiated cells and immunomodulatory properties. Recognition of the relationship between amniotic cells and components of the extracellular matrix is an important condition for their ex vivo preparation and further successful clinical application in regenerative medicine and transplantology. Laminin 332 (LN-332), as a natural component of the basement membrane of amniotic epithelial cells and a ligand for integrin receptors, may strongly influence the phenotype and fate of amniotic cells. We investigated the impact of recombinant LN-332 on hAC viability and expression of markers for pluripotency, early differentiation, adhesion, and immunomodulatory properties. During 14 days of culture, hAC were quantified and qualified by light microscopy, immunohistochemistry, immunocytochemistry, and flow cytometry. Gene expression was assessed with real-time polymerase chain reaction (RT-PCR) arrays and compared with differentiated cells originated from the three germ layers. LN-332 caused an over 2-fold increase in the total number of hAC, accompanied by a 75% reduction of SSEA-4-positive cells and an increase in HLA-ABC-positive cells. In particular, we observed that the presence of laminin 332 in the medium of a short-time culture modifies the effect of culture duration on hAC, enhancing time-dependent inhibition of expression of certain genes, including pluripotency and differentiation markers, laminin 332 subunits (which may be part of self-regulation of LN-332 synthesis by amniotic cells), and integrins. The changes observed in hAC were more distinct with respect to differentiated mesenchymal cells, resulting in more comparable phenotypes than those represented by differentiated endo- and ectodermal cells. We concluded that laminin 332 present in the culture medium influences to a certain extent proliferation, adhesion, and differentiation of amniotic cells in culture.

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Laminin‑332 mediates proliferation, apoptosis, invasion, migration and epithelial‑to‑mesenchymal transition in pancreatic ductal adenocarcinoma

Cited by 30 publications

References 39 publications

The Extracellular Matrix in Pancreatic Cancer: Description of a Complex Network and Promising Therapeutic Options

The Extracellular Matrix in Pancreatic Cancer: Description of a Complex Network and Promising Therapeutic Options

Hepatocyte-Specific Phgdh-Deficient Mice Culminate in Mild Obesity, Insulin Resistance, and Enhanced Vulnerability to Protein Starvation

Gene Expression in Amnion-Derived Cells Cultured on Recombinant Laminin 332—A Preliminary Study

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