Suppression of SCARA5 by Snail1 is essential for EMT-associated cell migration of A549 cells

Liu, J.; Hu, Guoku; Chen, D.; Gong, Ai Yu; Soori, Gamini S.; Dobleman, Thomas J.; Chen, X. M.

doi:10.1038/oncsis.2013.37

Cited by 72 publications

(64 citation statements)

References 43 publications

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“…However, our findings point to a more complex mode of action, with MSI2 supporting expression of CDH1, VIM, SLUG, and SNAIL but suppressing that of Zeb1/2, FOXC2, and multiple claudins. TGF-β has previously been shown to directly support expression of SNAIL but not ZEB1/2 in an NSCLC cell model (34), suggesting these downstream effects of MSI2 include both TGF-β-dependent and -independent outputs. Together with MSI2-dependent expression of CDH1, these results are compatible with a model in which MSI2 creates conditions that favor collective migration (35), an idea bearing further investigation.…”

Section: Discussionmentioning

confidence: 99%

Musashi-2 (MSI2) supports TGF-β signaling and inhibits claudins to promote non-small cell lung cancer (NSCLC) metastasis

Kudinov

Deneka

Nikonova

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

131

140

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Non-small cell lung cancer (NSCLC) has a 5-y survival rate of ∼16%, with most deaths associated with uncontrolled metastasis. We screened for stem cell identity-related genes preferentially expressed in a panel of cell lines with high versus low metastatic potential, derived from NSCLC tumors of Kras LA1/+ ;P53 R172HΔG/+ (KP) mice. The Musashi-2 (MSI2) protein, a regulator of mRNA translation, was consistently elevated in metastasis-competent cell lines. MSI2 was overexpressed in 123 human NSCLC tumor specimens versus normal lung, whereas higher expression was associated with disease progression in an independent set of matched normal/primary tumor/lymph node specimens. Depletion of MSI2 in multiple independent metastatic murine and human NSCLC cell lines reduced invasion and metastatic potential, independent of an effect on proliferation. MSI2 depletion significantly induced expression of proteins associated with epithelial identity, including tight junction proteins [claudin 3 (CLDN3), claudin 5 (CLDN5), and claudin 7 (CLDN7)] and down-regulated direct translational targets associated with epithelial-mesenchymal transition, including the TGF-β receptor 1 (TGFβR1), the small mothers against decapentaplegic homolog 3 (SMAD3), and the zinc finger proteins SNAI1 (SNAIL) and SNAI2 (SLUG). Overexpression of TGFβRI reversed the loss of invasion associated with MSI2 depletion, whereas overexpression of CLDN7 inhibited MSI2-dependent invasion. Unexpectedly, MSI2 depletion reduced E-cadherin expression, reflecting a mixed epithelialmesenchymal phenotype. Based on this work, we propose that MSI2 provides essential support for TGFβR1/SMAD3 signaling and contributes to invasive adenocarcinoma of the lung and may serve as a predictive biomarker of NSCLC aggressiveness.on-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths in the world (1). Approximately 7% of individuals born in the United States in 2013 will ultimately be diagnosed with lung cancer, and 160,000 die from this disease each year (1). The 5-y survival rate for lung cancer is around 16% of diagnosed cases (2). Much of the lethality of lung cancer is due to frequent diagnosis of the malignancy at the metastatic stage, when fundamental changes in tumor biology cause the disease to be refractory to many treatments. A better understanding of the biological processes that promote NSCLC metastasis promises to further improve clinical care of the patients. Kras LA1/+ ;P53 R172HΔG/+ (KP) mice provide a useful and wellvalidated model for the study of NSCLC metastasis. These mice combine a mutant p53 allele (p53 R175HΔG) with an activating KrasG12D allele (Kras LA1 ) (3), leading to development of adenocarcinomas resembling human NSCLC, which are often characterized by mutation of KRAS (∼30%) (4) and loss of TP53 (∼60%) (5). Many of the KP tumors metastasize to sites commonly seen in NSCLC patients (3). These features make the KP murine model a useful tool with which to evaluate factors that underlie NSCLC metastasis. Among the pathways activated...

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Section: Discussionmentioning

confidence: 99%

Musashi-2 (MSI2) supports TGF-β signaling and inhibits claudins to promote non-small cell lung cancer (NSCLC) metastasis

Kudinov

Deneka

Nikonova

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

131

140

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“…Because TGF-␤1 has been shown to cause downregulation of E-cadherin in cells (26,33), we examined if TGF-␤1 could modulate the E-cadherin induction observed with serum starvation. A549 cells were incubated with or without TGF-␤1 in FBS-free media over time, and TGF-␤1 attenuated the serum starvation-mediated E-cadherin upregulation (Fig.…”

Section: Serum Starvation Upregulates E-cadherin Expression At the Trmentioning

confidence: 99%

“…TGF-␤1 signaling reduces E-cadherin expression and promotes cell motility through regulation of Snail expression (1,26,33). Snail is an E-cadherin transcriptional suppressor n.s.…”

Section: Serum Starvation Upregulates E-cadherin Expression At the Trmentioning

confidence: 99%

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Serum starvation regulates E-cadherin upregulation via activation of c-Src in non-small-cell lung cancer A549 cells

Dong

Khoo

Wei

et al. 2014

American Journal of Physiology-Cell Physiology

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. Serum starvation regulates E-cadherin upregulation via activation of c-Src in non-small-cell lung cancer A549 cells. Am J Physiol Cell Physiol 307: C893-C899, 2014. First published August 27, 2014 doi:10.1152/ajpcell.00132.2014.-E-cadherin is essential for the integrity of adherens junctions between lung epithelial cells, and the loss of E-cadherin allows cell motility and is thought to promote lung cancer metastasis. While the downregulation of E-cadherin expression has been well characterized and is seen with transforming growth factor-␤1 (TGF-␤1) exposure, few studies have focused on E-cadherin upregulation. Here, we show that serum starvation causes increased E-cadherin expression via the activation of c-Src kinase in non-small-cell lung cancer A549 cells. Serum starvation increased E-cadherin protein levels in a time-and dose-dependent manner. E-cadherin mRNA transcripts were unchanged with starvation, while protein translation inhibition with cycloheximide attenuated E-cadherin protein induction by starvation, suggesting that E-cadherin is regulated at the translational level by serum starvation. c-Src is a nonreceptor tyrosine kinase known to regulate protein translation machinery; serum starvation caused early and sustained activation of c-Src in A549 cells followed by Ecadherin upregulation. Furthermore, overexpression of a dominant negative c-Src attenuated the induction of E-cadherin by serum deprivation. Finally, we observed that TGF-␤1 treatment attenuated the serum activation of c-Src as well as E-cadherin expression when cells were deprived of serum. In conclusion, our data demonstrate that the c-Src kinase is activated by serum starvation to increase Ecadherin expression in A549 cells, and these phenomena are antagonized by TGF-␤1. These novel observations implicate the c-Src kinase as an upstream inducer of E-cadherin protein translation with serum starvation and TGF-␤1 diametrically regulating c-Src kinase activity and thus E-cadherin abundance in A549 cells.

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“…Epithelial-mesenchymal transition (EMT) is an important mechanism in embryonic progression and cancer development (10). Cells progressively lose their epithelial characteristics and acquire mesenchymal features during the process of EMT (11).…”

Section: Introductionmentioning

confidence: 99%

ERK5 regulates tobacco smoke-induced urocystic epithelial-mesenchymal transition in BALB/c mice

Min

Geng

Liu

et al. 2017

Molecular Medicine Reports

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Abstract. Tobacco smoke (TS) is an important risk factor of bladder cancer. Epithelial-mesenchymal transition (EMT) is involved in the initiation and development of cancer. The role of extracellular signal-regulated kinase (ERK) 5 in regulating TS-induced EMT remains to be elucidated. The aim of the present study was to investigate the regulatory role of ERK5 in TS-triggered EMT in the bladder of mice. BALB/c mice were used for an in vivo TS exposure model. Mice were treated for 6 h a day for 12 weeks. The results demonstrated that mice exposed to TS had decreased mRNA and protein expression levels of the epithelial markers E-cadherin and zonula occludens-1, whereas expression levels of the mesenchymal markers Vimentin and N-cadherin were increased. Treatment with XMD8-92, a highly specific ERK5 inhibitor, effectively abrogated TS-triggered activation of ERK5, activator protein-1 and EMT alterations in the bladder of BALB/c mice. The data suggested that ERK5 regulates TS-mediated urocystic EMT. These findings provide insight into the molecular mechanisms of TS-associated bladder tumorigenesis. IntroductionBladder cancer (BC) is the fifth most common type of malignant tumor worldwide (1) and one of the most frequently occurring in the urinary system. It is predominantly present in Europe, North America and Australia, with approximately 420,000 newly diagnosed cases each year and a leading cause of cancer-associated mortality (2,3). Of all urinary malignancies, BC is the primary cause of mortality in China (4,5).A number of studies have revealed that tobacco smoke (TS), the environment and diet are primary risk factors for BC, in addition to drinking water contaminants, including chlorinated byproducts and arsenic, the use of pioglitazone, obesity, hypertension and diabetes (2,6,7). A previous study reported that 23% of female and 50% of male BC cases have been attributed to TS (8). It has been reported that current tobacco smokers have a fourfold greater risk of developing BC, compared with non-smokers (9). Progress in the understanding of the molecular mechanisms underlying the initiation and progression of BC has been made; however, the molecular pathogenesis remains to be fully elucidated.Epithelial-mesenchymal transition (EMT) is an important mechanism in embryonic progression and cancer development (10). Cells progressively lose their epithelial characteristics and acquire mesenchymal features during the process of EMT (11). In addition to facilitating tumor invasion and metastasis, EMT is also involved in the initiation of tumorigenesis by promoting cell malignant transformation. TS has been previously demonstrated to promote the initial progression of . TS-triggered EMT has been revealed to regulate early events in carcinogenesis, including downregulation of E-cadherin, loss of cell-cell adhesion and increased mobility of cells. However, the underlying molecular mechanisms by which TS induces EMT remain to be fully elucidated.Extracellular signal-regulated kinase (ERK) 5 is the least studied member of the ...

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Suppression of SCARA5 by Snail1 is essential for EMT-associated cell migration of A549 cells

Cited by 72 publications

References 43 publications

Musashi-2 (MSI2) supports TGF-β signaling and inhibits claudins to promote non-small cell lung cancer (NSCLC) metastasis

Musashi-2 (MSI2) supports TGF-β signaling and inhibits claudins to promote non-small cell lung cancer (NSCLC) metastasis

Serum starvation regulates E-cadherin upregulation via activation of c-Src in non-small-cell lung cancer A549 cells

ERK5 regulates tobacco smoke-induced urocystic epithelial-mesenchymal transition in BALB/c mice

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