Transcriptional crosstalk between TGFβ and stem cell pathways in tumor cell invasion: Role of EMT promoting Smad complexes

Fuxe, Jonas; Vincent, C. Theresa; Herreros, Antonio Garcı́a de

doi:10.4161/cc.9.12.12050

Cited by 294 publications

(251 citation statements)

References 177 publications

(213 reference statements)

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“…38,39 Comparison to human samples that contained a progression spectrum of grade and stage confirmed that phosphorylation of SMAD2 was increased in advanced lesions. A similar result was seen in our cell lines, in which the high-grade bladder cancer cells UMUC3, T24, and J82 showed TGF-b pathway activation relative to the more epithelioid RT4 bladder cancer cells, which lacked critical elements, such as the TGF-bR1 isoform and SMAD4, and which expressed E-cadherin.…”

Section: Tgf-b/mtorc2 In Bladder Cancer Invasionmentioning

confidence: 89%

Transforming Growth Factor-β Is an Upstream Regulator of Mammalian Target of Rapamycin Complex 2–Dependent Bladder Cancer Cell Migration and Invasion

Gupta

Hau

Al‐Ahmadie

et al. 2016

The American Journal of Pathology

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Our prior work identified the mammalian target of rapamycin complex 2 (mTORC2) as a key regulator of bladder cancer cell migration and invasion, although upstream growth factor mediators of this pathway in bladder cancer have not been well delineated. We tested whether transforming growth factor (TGF)-b, which can function as a promotility factor in bladder cancer cells, could regulate mTORC2-dependent bladder cancer cell motility and invasion. In human bladder cancers, the highest levels of phosphorylated SMAD2, a TGF-b signaling intermediate, were present in high-grade invasive bladder cancers and associated with more frequent recurrence and decreased disease-specific survival. Increased expression of TGF-b isoforms, receptors, and signaling components was detected in invasive high-grade bladder cancer cells that expressed Vimentin and lacked E-cadherin. Application of TGF-b induced phosphorylation of the Ser473 residue of AKT, a selective target of mTORC2, in a SMAD2-and SMAD4-independent manner and increased bladder cancer cell migration in a modified scratch wound assay and invasion through Matrigel. Inhibition of TGF-b receptor I using SB431542 ablated TGF-beinduced migration and invasion. A similar effect was seen when Rictor, a key mTORC2 component, was selectively silenced. Our results suggest that TGF-b can induce bladder cancer cell invasion via mTORC2 signaling, which may be applicable in most bladder cancers. (Am J Pathol 2016, 186: 1351e1360; http://dx

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Section: Tgf-b/mtorc2 In Bladder Cancer Invasionmentioning

confidence: 89%

Transforming Growth Factor-β Is an Upstream Regulator of Mammalian Target of Rapamycin Complex 2–Dependent Bladder Cancer Cell Migration and Invasion

Gupta

Hau

Al‐Ahmadie

et al. 2016

The American Journal of Pathology

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“…This is consistent with the reported crosstalk between Zeb and Smad proteins on Smadresponsive promoters. 41 Reduced snai2/Slug was also observed upon Zeb1/2 knockdown (Figures 6a and c), likely due to decreased TGFβ pathway activity. These data indicate that decreasing Zeb1 and/or Zeb2 in EpFra1 cells restored a significant part of the epithelial programme.…”

Section: Epfra1-sz2mentioning

confidence: 94%

Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression

et al. 2014

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Epithelial-to-mesenchymal transition (EMT) is essential for embryonic morphogenesis and wound healing and critical for tumour cell invasion and dissemination. The AP-1 transcription factor Fra-1 has been implicated in tumorigenesis and in tumour-associated EMT in human breast cancer. We observed a significant inverse correlation between Fra-1 mRNA expression and distant-metastasis-free survival in a large cohort of breast cancer patients derived from multiple array data sets. This unique correlation among Fos genes prompted us to assess the evolutionary conservation between Fra-1 functions in EMT of human and mouse cells. Ectopic expression of Fra-1 in fully polarized, non-tumourigenic, mouse mammary epithelial EpH4 cells induced a mesenchymal phenotype, characterized by a loss of epithelial and gain of mesenchymal markers. Proliferation, motility and invasiveness were also increased in the resulting EpFra1 cells, and the cells were tumourigenic and efficiently colonized the lung upon transplantation. Molecular analyses revealed increased expression of Tgfβ1 and the EMT-inducing transcription factors Zeb1, Zeb2 and Slug. Mechanistically, Fra-1 binds to the tgfb1 and zeb2 promoters and to an evolutionarily conserved region in the first intron of zeb1. Furthermore, increased activity of a zeb2 promoter reporter was detected in EpFra1 cells and shown to depend on AP-1-binding sites. Inhibiting TGFβ signalling in EpFra1 cells moderately increased the expression of epithelial markers, whereas silencing of zeb1 or zeb2 restored the epithelial phenotype and decreased migration in vitro and tumorigenesis in vivo. Thus Fra-1 induces changes in the expression of genes encoding EMT-related transcription factors leading to the acquisition of mesenchymal, invasive and tumorigenic capacities by epithelial cells. This study defines a novel function of Fra-1/AP-1 in modulating tgfb1, zeb1 and zeb2 expression through direct binding to genomic regulatory regions, which establishes a basis for future in vivo genetic manipulations and preclinical studies using mouse models. Epithelial-to-mesenchymal transition (EMT) is a complex biological programme that occurs in physiological processes during embryonic development and wound healing as well as in pathological conditions, such as organ fibrosis and carcinogenesis. During EMT, cells lose epithelial features and acquire mesenchymal characteristics. The acquisition of a mesenchymal state by malignant cancer cells is associated with decreased cell-cell adhesion, and increased migratory and invasive properties, which are crucial for metastasis. [1][2][3][4][5] The adherens junction (AJ) protein E-cadherin, encoded by cdh1, is a central determinant of the epithelial state and its downregulation is the hallmark of EMT. A number of molecular pathways converging on E-cadherin have been implicated in EMT. Transcription factors (TF) of the Snail, Zeb and Twist families, initially identified as regulators of epithelialmesenchymal plasticity during morphogenesis were shown to orchestrate EMT by...

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“…43,44 TGF-b, which induces the TGFBI protein, has a reported role in the regulation of TCF4 and ZEB1 through signaling pathways in EMT. 26 Mutations in TGFBI cause some human corneal dystrophies, but have not been reported to cause FED. 2 Our study has revealed the first possible association of TGFBI with FED and upregulation of TGFBI in the corneal epithelium in FED.…”

Section: Association Of Tcf4 and Clu Polymorphisms With Fedmentioning

confidence: 99%

“…TGFBI is induced by the TGF-b (transforming growth factor-b) gene. 26 Interestingly, TGF-b reportedly regulates both TCF4 and ZEB1, which have been implicated in FED. 27 This study investigated association of the reported polymorphisms in the TCF4 and PTPRG genes in Australian FED cases.…”

Section: Introductionmentioning

confidence: 99%

Association of TCF4 and CLU polymorphisms with Fuchs’ endothelial dystrophy and implication of CLU and TGFBI proteins in the disease process

et al. 2012

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Fuchs' endothelial dystrophy (FED) is a disease affecting the corneal endothelium. Recent studies reported significant association of polymorphisms in the TCF4 (transcription factor 4) gene, and a borderline association of PTPRG (protein tyrosine phosphatase, receptor type, G) variants with late-onset FED in Caucasians from the United States. Association of TCF4 has also been reported in the Chinese population. We aimed to determine association of the reported polymorphisms in TCF4 and PTPRG, and association of polymorphisms in the candidate genes ZEB1 (zinc-finger E-box binding homoebox 1), COL8A2 (collagen, type VIII, alpha 2), TGFBI (transforming growth factor, b-induced) and CLU (clusterin) in Australian cases. We also compared the expression of TGFBI and CLU proteins between FED and normal whole corneas. In all, 30 single-nucleotide polymorphisms (SNPs) from the candidate genes were genotyped in 103 cases and 275 controls. Each SNP and haplotype was assessed for association with the disease. SNP analysis identified an association of TCF4 (rs613872 (P¼5.25Â10 À15 , OR¼4.05), rs9954153 (P¼3.37Â10 À7 , OR¼2.58), rs2286812 (P¼4.23Â10 À6 , OR¼2.55) and rs17595731 (P¼3.57Â10 À5 , OR¼3.79)), CLU (rs17466684; P¼0.003, OR¼1.85) and one haplotype of TGFBI SNPs (P¼0.011, OR¼2.29) with FED in Caucasian Australians. No evidence for genetic association of PTPRG, ZEB1 and COL8A2 was found. Immunohistochemistry showed differential expression of CLU and TGFBI proteins in FED-affected compared with normal corneas. In conclusion, variation in TCF4, CLU and TGFBI, but not PTPRG, ZEB1 and COL8A2 genes are associated with FED in Caucasian Australian cases. Differential expression of CLU and TGFBI proteins in FED-affected corneas provides novel insights into the disease mechanism.

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Transcriptional crosstalk between TGFβ and stem cell pathways in tumor cell invasion: Role of EMT promoting Smad complexes

Cited by 294 publications

References 177 publications

Transforming Growth Factor-β Is an Upstream Regulator of Mammalian Target of Rapamycin Complex 2–Dependent Bladder Cancer Cell Migration and Invasion

Transforming Growth Factor-β Is an Upstream Regulator of Mammalian Target of Rapamycin Complex 2–Dependent Bladder Cancer Cell Migration and Invasion

Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression

Association of TCF4 and CLU polymorphisms with Fuchs’ endothelial dystrophy and implication of CLU and TGFBI proteins in the disease process

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