NEDD9 may regulate hepatocellular carcinoma cell metastasis by promoting epithelial-mesenchymal-transition and stemness via repressing Smad7

Wang, Zhipeng; Shen, Min; Lü, Peng; Xiao, Li; Zhu, Shaojun; Yue, Shu-Qiang

doi:10.18632/oncotarget.13852

Cited by 25 publications

(19 citation statements)

References 34 publications

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“…During mechanotransduction, the Wnt-independent activation of β-catenin is also initiated by FAK upregulation[46] to increase MMP2 and MMP9 activity, thereby contributing to tumorigenesis[47]. FAK signaling pathway also regulates cancer malignancy by modulating ALDH[48] and CD133[49]. In this study, intrascaffold-cultured MG63 cells were predominantly affected by ECM stiffness, which may be regulated through the integrin-mediated FA signaling pathway (Fig.…”

Section: Discussionmentioning

confidence: 99%

Untangling the response of bone tumor cells and bone forming cells to matrix stiffness and adhesion ligand density by means of hydrogels

Jiang

Zhao

et al. 2019

Biomaterials

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How cancer cells and their anchorage-dependent normal counterparts respond to the adhesion ligand density and stiffness of the same extracellular matrix (ECM) is still not very clear. Here we investigated the effects of ECM adhesion ligand density and stiffness on bone tumor cells (osteosarcoma cells) and bone forming cells (osteoblasts) by using poly (ethylene glycol) diacrylate (PEGDA) and methacrylated gelatin (GelMA) hydrogels. By independently changing the PEGDA and GelMA content in the hydrogels, we achieved crosslinked hydrogel matrix with independently tunable stiffness (1.6, 6 and 25 kPa for 5%, 10%, 15% PEDGA, respectively) and adhesion ligand density (low, medium and high for 0.05%, 0.2%, 0.5% GelMA respectively). By using a series of biochemical and cell biological characterizations as well as in vivo studies, we confirmed that osteosarcoma and osteoblastic cells responded differently to the stiffness and adhesion ligand density within 3D ECM. When cultured within the 3D PEGDA/GelMA hydrogel matrix, osteosarcoma cells are highly dependent on the matrix stiffness via regulating the integrin-mediated focal adhesion (FA) pathway, whereas osteoblasts are highly sensitive to the matrix adhesion ligand density through regulating the integrin-mediated adherens junction (AJ) pathway. However, when seeded on the 2D surface of the hydrogels, osteosarcoma cells behaved differently and became sensitive to the matrix adhesion ligand density because they were “forced” to attach to the substrate, similar to anchorage-dependent osteoblasts. This study might provide new insights into rational design of scaffolds for generating in vitro tumor models to test anticancer therapeutics and for regenerating tissue to repair defects.

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Section: Discussionmentioning

confidence: 99%

Untangling the response of bone tumor cells and bone forming cells to matrix stiffness and adhesion ligand density by means of hydrogels

Jiang

Zhao

et al. 2019

Biomaterials

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“…It was shown previously that the elongated mesenchymal movement of cells is driven by activation of Rac1 through DOCK3/NEDD9 complex . In addition, NEDD9 signaling activated by EMT effectors has been implicated in tumor progression and metastasis in several cancers . Overexpression of NEDD9 in DU145 increased Rac1 levels and resulted in increased migratory activity of cells, which was suppressed by PA treatment.…”

Section: Discussionmentioning

confidence: 89%

“…25 In addition, NEDD9 signaling activated by EMT effectors has been implicated in tumor progression and metastasis in several cancers. [26][27] Overexpression of NEDD9 in DU145 increased Rac1 levels and resulted in increased migratory activity of cells, which was Theoretically, eliminating tumor cells that have undergone mesenchymal transition by inhibiting their growth in combination with conventional therapeutic strategies that target the epithelial population may be an appropriate way to address the dynamic partial EMT state and tumor heterogeneity. To this end, a number of smallmolecule inhibitors are being studied in preclinical settings.…”

Section: Discussionmentioning

confidence: 99%

Targeting epithelial to mesenchymal transition in prostate cancer by a novel compound, plectranthoic acid, isolated from Ficus microcarpa

Akhtar

Syed

Lall

et al. 2018

Molecular Carcinogenesis

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Epithelial-to-mesenchymal transition (EMT) plays a crucial role in prostate cancer (PCa) metastasis. This has led to a surge in the efforts for identification of safer and more effective compounds which can modulate EMT and consequently inhibiting migration and invasion of PCa cells. We reported previously that Plectranthoic acid (PA), a natural compound isolated from the extracts of Ficus microcarpa, has the capability to induce cell cycle arrest and apoptosis in PCa cells. Here, we determined the effects of PA on EMT, migration, and invasion of PCa cells. Inhibition of EMT induced by different mitogens was effectively inhibited by PA treatment with subsequent decrease in migration of PCa cells. Employing a PCa cell culture model of TGF-β-induced EMT, we showed that PA has the ability to reverse EMT. PA treatment was associated with induction of epithelial markers and decrease in the expression of mesenchymal markers in PCa cells. Proteomic analysis identified Rac1 as the major cadherin signaling protein modulated with PA treatment. In silico studies indicated that PA docked to the CH domain of NEDD9 protein with an estimated free binding energy of -7.34 Kcal/moL. Our studies revealed significant inhibition of Rac1/NEDD9 pathway in PA treated cells thereby providing a molecular basis of the inhibitory effect of PA on PCa cell migration and invasion. In conclusion, our data suggest that PA should be investigated further as an adjuvant treatment in human PCa cells, given its potential as an anti-invasive agent.

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“…In broader view point, actively involved in the process of cell growth, mortality and escaping apoptosis in tumor development. 22 In tumor metastatic pathway, cellular coordination during invasion, migration signalling network mediated by NEDD9 to invade from primary site by formation of neovessels for circulation and surviavlity, secondary tumor establishment to form metastatic colonies at secondary tissue. 23 Several in-vitro, in-vivo validation revealed that, NEDD9 is the key component in the pathway of tumorigenesis and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Differential genotypical expression of a NEDD9 in normal and tumor tissues: a possible pharmacological target

Kumar¹,

Krishna

Prabahkar

2018

Int J Basic Clin Pharmacol

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Background: Neural precursor cell expressed developmentally down regulated-9 (NEDD9) is a E, D, D scaffolding metastatic marker protein in multiple cancer types. Generally, the expression occurs during the embryonic development and depletes in adults. Expression of NEDD9 in adults leads to the progression of tumor which is sufficient for the cellular invasion. Elevated behavior of the gene mediates metastatic movement which includes protease dependent neovessel formation, invasion and migration of tumor cells from the site of origin to the distant tissues.Methods: The current study involves the screening and elucidation of differential expression of NEDD9 in normal and tumor subtypes with various tissues of mice by immunohistochemistry.Results: The validating approaches in the study, low expression of NEDD9 was observed in the normal tissues and predominance in the tumor subsets.Conclusions: The experimental analysis proven that NEDD9 expression is merely associated with tumor progression and the molecular mechanism of NEDD9 is restricted in the establishment of metastatic cascade. NEDD9 association in tumor prognosis which helps in the emergence of diagnostic and therapeutic approaches.

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NEDD9 may regulate hepatocellular carcinoma cell metastasis by promoting epithelial-mesenchymal-transition and stemness via repressing Smad7

Cited by 25 publications

References 34 publications

Untangling the response of bone tumor cells and bone forming cells to matrix stiffness and adhesion ligand density by means of hydrogels

Untangling the response of bone tumor cells and bone forming cells to matrix stiffness and adhesion ligand density by means of hydrogels

Targeting epithelial to mesenchymal transition in prostate cancer by a novel compound, plectranthoic acid, isolated from Ficus microcarpa

Differential genotypical expression of a NEDD9 in normal and tumor tissues: a possible pharmacological target

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