Acquisition of EMT phenotype in the gefitinib-resistant cells of a head and neck squamous cell carcinoma cell line through Akt/GSK-3β/snail signalling pathway

Maseki, Shinichiro; Ijichi, Kei; Tanaka, Harunari; Fujii, Makiko; Hasegawa, Yasuhisa; Ogawa, Tetsuya; Murakami, Shingo; Kondo, Eisaku; Nakanishi, Hayao

doi:10.1038/bjc.2012.24

Cited by 101 publications

(71 citation statements)

References 29 publications

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“…AKT induces activation of GSK-3β, which in turn suppresses phosphorylation of Snail to induce EMT. Participation of Akt/GSK-3 β /Snail pathway in the acquisition of EMT phenotype has been reported previously [62]. In this study, FSS up-regulated both Snail and Slug, that may suppress the expression of E-cad and promote EMT.…”

Section: Discussionsupporting

confidence: 79%

Fluid shear stress induces epithelial-mesenchymal transition (EMT) in Hep-2 cells

et al. 2016

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Laryngeal squamous cell carcinoma (LSCC) is one of the most commonly diagnosed malignancies with high occurrence of tumor metastasis, which usually exposes to fluid shear stress (FSS) in lymphatic channel and blood vessel. Epithelial-mesenchymal transition (EMT) is an important mechanism that induces metastasis and invasion of tumors. We hypothesized that FSS induced a progression of EMT in laryngeal squamous carcinoma. Accordingly, the Hep-2 cells were exposed to 1.4 dyn/cm2 FSS for different durations. Our results showed that most of cells changed their morphology from polygon to elongated spindle with well-organized F-actin and abundant lamellipodia/filopodia in protrusions. After removing the FSS, cells gradually recovered their flat polygon morphology. FSS induced Hep-2 cells to enhance their migration capacity in a time-dependent manner. In addition, FSS down-regulated E-cadherin, and simultaneously up-regulated N-cadherin, translocated β-catenin into the nucleus. These results confirmed that FSS induced the EMT in Hep-2 cells, and revealed a reversible mesenchymal-epithelial transition (MET) process when FSS was removed. We further examined the time-expressions of signaling cascades, and demonstrated that FSS induces the EMT and enhances cell migration depending on integrin-ILK/PI3K-AKT-Snail signaling events. The current study suggests that FSS, an important biophysical factor in tumor microenvironment, is a potential determinant of cell behavior and function regulation.

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Section: Discussionsupporting

confidence: 79%

Fluid shear stress induces epithelial-mesenchymal transition (EMT) in Hep-2 cells

et al. 2016

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“…This observation is in accordance with studies of pancreatic and colon cancer cells [9,28] . Inhibition of Akt activity by the down-regulation of pAkt can decrease pGSK-3β levels, while activation of Akt might phosphorylate GSK-3β [31] . Meanwhile, using an Akt inhibitor leads to β-catenin repression, which is similar to observations made using Gal-3-siRNA.…”

Section: Discussionmentioning

confidence: 99%

Galectin-3 gene silencing inhibits migration and invasion of human tongue cancer cells in vitro via downregulating β-catenin

et al. 2012

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Aim: Galectin-3 (Gal-3) is a member of the carbohydrate-binding protein family that contributes to neoplastic transformation, tumor survival, angiogenesis, and metastasis. The aim of this study is to investigate the role of Gal-3 in human tongue cancer progression. Methods: Human tongue cancer cell lines (SCC-4 and CAL27) were transfected with a small-interfering RNA against Gal-3 (Gal-3-siRNA). The migration and invasion of the cells were examined using a scratch assay and BD BioCoat Matrigel Invasion Chamber, respectively. The mRNA and protein levels of β-catenin, Akt/pAkt, GSK-3β/pGSK-3β, MMP-9 in the cells were measured using RT-PCR and Western blotting, respectively. Results: Transient silencing of Gal-3 gene for 48 h significantly suppressed the migration and invasion of both SCC-4 and CAL27 cells. Silencing of Gal-3 gene significantly decreased the protein level of β-catenin, leaving the mRNA level of β-catenin unaffected. Furthermore, silencing Gal-3 gene significantly decreased the levels of phosphorylated Akt and GSK-3β, and suppressed the mRNA and protein levels of MMP-9 in the cells. Conclusion: Our data suggest that Gal-3 mediates the migration and invasion of tongue cancer cells in vitro via regulating the Wnt/ β-catenin signaling pathway and Akt phosphorylation.

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“…1 Enhanced genome instability with gross chromosomal abnormalities has been directly correlated with tumor recurrence and metastasis of NPC, 2,3 leading to high mortality and low five-year overall survival, which have not been improved in decades. 4 Understanding of the molecular mechanisms involved in the development of advanced head and neck cancers will help in clinical management and drug discovery. Genome-wide surveys and clinical association studies have identified two recurrent copy-number aberrations, 3p deletion (3p12.3-p14.2) and 3q amplification (3q26.2--26.32), with prognostic value for metastatic NPC.…”

Section: Introductionmentioning

confidence: 99%

LRIG1 modulates aggressiveness of head and neck cancers by regulating EGFR-MAPK-SPHK1 signaling and extracellular matrix remodeling

et al. 2013

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EGFR overexpression and chromosome 3p deletion are two frequent events in head and neck cancers. We previously mapped the smallest region of recurrent copy-number loss at 3p12.2-p14.1. LRIG1, a negative regulator of EGFR, was found at 3p14, and its copy-number loss correlated with poor clinical outcome. Inducible expression of LRIG1 in head and neck cancer TW01 cells, a line with low LRIG1 levels, suppressed cell proliferation in vitro and tumor growth in vivo. Gene expression profiling, quantitative RT-PCR, chromatin immunoprecipitation, and western blot analysis demonstrated that LRIG1 modulated extracellular matrix (ECM) remodeling and EGFR-MAPK-SPHK1 transduction pathway by suppressing expression of EGFR ligands/activators, MMPs and SPHK1. In addition, LRIG1 induction triggered cell morphology changes and integrin inactivation, which coupled with reduced SNAI2 expression. By contrast, knockdown of endogenous LRIG1 in TW06 cells, a line with normal LRIG1 levels, significantly enhanced cell proliferation, migration and invasiveness. Such tumor-promoting effects could be abolished by specific MAPK or SPHK1 inhibitors. Our data suggest LRIG1 as a tumor suppressor for head and neck cancers; LRIG1 downregulation in cancer cells enhances EGFR-MAPK-SPHK1 signaling and ECM remodeling activity, leading to malignant phenotypes of head and neck cancers.

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Acquisition of EMT phenotype in the gefitinib-resistant cells of a head and neck squamous cell carcinoma cell line through Akt/GSK-3β/snail signalling pathway

Cited by 101 publications

References 29 publications

Fluid shear stress induces epithelial-mesenchymal transition (EMT) in Hep-2 cells

Fluid shear stress induces epithelial-mesenchymal transition (EMT) in Hep-2 cells

Galectin-3 gene silencing inhibits migration and invasion of human tongue cancer cells in vitro via downregulating β-catenin

LRIG1 modulates aggressiveness of head and neck cancers by regulating EGFR-MAPK-SPHK1 signaling and extracellular matrix remodeling

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