NF-κB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2

Chua, Hui Lin; Bhat‐Nakshatri, Poornima; Clare, Susan E.; Morimiya, Akira; Badve, Sunil; Nakshatri, H

doi:10.1038/sj.onc.1209808

Cited by 547 publications

(497 citation statements)

References 69 publications

(87 reference statements)

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“…The following target sequences were used: sh-Zeb1 #1 5 0 -GGAAAGCGTTCAAGTACAA-3 0 and sh-Zeb1 #2 5 0 -GAAAGGCATTTAAACACAA-3 0 . The pQXCIN-Zeb1 construct was a kind gift from Dr Nakshatri (Chua et al, 2007), pBP-Twist was a kind gift from R Weinberg (Yang et al, 2004), pBP-HA-Twist was described previously (Smit et al, 2009) and pRV-ires-GFP-Snail-HA was a kind gift from A Munoz (Palmer et al, 2004).…”

Section: Vector Constructsmentioning

confidence: 99%

Zeb1 is required for TrkB-induced epithelial-mesenchymal transition, anoikis resistance and metastasis

Smit

Peeper

2011

Oncogene

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Anoikis (detachment-induced apoptosis) prevents the survival of cells at inappropriate sites of the body and can therefore act as a barrier to metastasis. In a functionbased genome-wide screen, we have previously identified the neurotrophic tyrosine kinase receptor TrkB as a potent suppressor of anoikis. Consistently, activated TrkB oncogenically transforms non-malignant epithelial cells and causes them to invade and produce metastatic tumors in vivo. Overexpression of activated TrkB also results in morphological transformation, resembling epithelial-mesenchymal transition (EMT). E-cadherin, an important EMT regulator, and two E-cadherin repressors, Twist and Snail, are critical for these TrkB functions. As Snail has been shown to induce Zeb1, another E-cadherin repressor, we hypothesized that Zeb1 could be a TrkB target, too. We show here that Zeb1 is required for TrkB-induced EMT in epithelial cells, as RNAi-mediated knockdown of Zeb1 reverted the morphological changes induced by TrkB. Furthermore, Zeb1 is involved in TrkB-induced anoikis resistance, migration and invasion. In vivo, knockdown of Zeb1 strongly reduced TrkB-induced metastasis. Finally, epistasis experiments showed that Zeb1 acts downstream of Twist and Snail. We conclude that Zeb1 is required for several TrkB-induced effects in vitro and in vivo, including metastasis.

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Section: Vector Constructsmentioning

confidence: 99%

Zeb1 is required for TrkB-induced epithelial-mesenchymal transition, anoikis resistance and metastasis

Smit

Peeper

2011

Oncogene

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“…Retrovirus packaging, transduction and selection of cells overexpressing miR-22 have been described previously (Chua et al, 2007). Cell migration assay was performed using CytoSelect 24-well Cell Migration assay kit as per instruction from manufacturers (Cell Biolabs, Inc., San Diego, CA, USA).…”

Section: Mirna Expression Analysismentioning

confidence: 99%

Control of EVI-1 oncogene expression in metastatic breast cancer cells through microRNA miR-22

et al. 2010

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Metastasis in breast cancer carries a disproportionately worse prognosis than localized primary disease. To identify microRNAs (miRNA) involved in metastasis, the expression of 254 miRNAs was measured across the following cell lines using microarray analysis: MDA-MB-231 breast cancer cells, cells that grew as a tumor in the mammary fat pad of nude mice (TMD-231), metastatic disease to the lungs (LMD-231), bone (BMD-231) and adrenal gland (ADMD-231). A brain-seeking variant of this cell line (231-BR) was used additionally in validation studies. Twenty miRNAs were upregulated and seven were downregulated in metastatic cancer cells compared with TMD-231 cells. The expression of the tumor suppressor miRNAs let-7 and miR-22 was consistently downregulated in metastatic cancer cells. These metastatic cells expressed higher levels of putative/proven miR-22 target oncogenes ERBB3, CDC25C and EVI-1. Introduction of miR-22 into cancer cells reduced the levels of ERBB3 and EVI-1 as well as phospho-AKT, an EVI-1 downstream target. The miR-22 primary transcript is located in the 5 0 -untranslated region of an open reading frame C17orf91, and the promoter/enhancer of C17orf91 drives miR-22 expression. We observed elevated C17orf91 expression in non-basal subtype compared with basal subtype breast cancers. In contrast, elevated expression of EVI-1 was observed in basal subtype and was associated with poor outcome in estrogen receptor-negative breast cancer patients. These results suggest that metastatic cancer cells increase specific oncogenic signaling proteins through downregulation of miRNAs. Identifying such metastasisspecific oncogenic pathways may help to manipulate tumor behavior and aid in the design of more effective targeted therapies.

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“…These, in turn, produce more NFκB and HIFlα and release more cytokines creating a microenvironment conducive for tumor growth [2]. NFκB also transcriptionally upregulates potent epithelial to mesenchymal transition (EMT) inducers such as Snail1 and Zeb1 [3,4] and given the central role EMT plays in tumor metastasis (reviewed in [5]), NFκB could be thought of as a bridge connecting the inflammatory response, tumor growth and tumor metastasis.…”

mentioning

confidence: 99%

Contribution of Fibroblast and Mast Cell (Afferent) and Tumor (Efferent) IL-6 Effects within the Tumor Microenvironment

Hugo

Lebret

Tomaskovic-Crook

et al. 2012

Cancer Microenvironment

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Hyperactive inflammatory responses following cancer initiation have led to cancer being described as a 'wound that never heals'. These inflammatory responses elicit signals via NFκB leading to IL-6 production, and IL-6 in turn has been shown to induce epithelial to mesenchymal transition in breast cancer cells in vitro, implicating a role for this cytokine in cancer cell invasion. We previously have shown that conditioned medium derived from cancerassociated fibroblasts induced an Epithelial to Mesenchymal transition (EMT) in PMC42-LA breast cancer cells and we have now identify IL-6 as present in this medium. We further show that IL-6 is expressed approximately 100 fold higher in a cancer-associated fibroblast line compared to normal fibroblasts. Comparison of mouse-specific (stroma) and human-specific (tumor) IL-6 mRNA expression from MCF-7, MDA MB 468 and MDA MB 231 xenografts also indicated the stroma rather than tumor as a significantly higher source of IL-6 expression. Mast cells (MCs) feature in inflammatory cancer-associated stroma, and activated MCs secrete IL-6. We observed a higher MC index (average number of mast cells per xenograft section/average tumor size) in MDA MB 468 compared to MDA MB 231 xenografts, where all MC were observed to be active (degranulating). This higher MC index correlated with greater mouse-specific IL-6 expression in the MDA MB 468 xenografts, implicating MC as an important source of stromal IL-6. Furthermore, immunohistochemistry on these xenografts for pSTAT3, which lies downstream of the IL-6 receptor indicated frequent correlations between pSTAT3 and mast cell positive cells. Analysis of publically available databases for IL-6 expression in patient tissue revealed higher IL-6 in laser capture microdissected stroma compared to adjacent tissue epithelium from patients with inflammatory breast cancer (IBC) and invasive non-inflammatory breast cancer (non-IBC) and we show that IL-6 expression was significantly higher in Basal versus Luminal molecular/phenotypic Microenvironment (2012) 5:83-93 DOI 10.1007 groupings of breast cancer cell lines. Finally, we discuss how afferent and efferent IL-6 pathways may participate in a positive feedback cycle to dictate tumor progression.

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NF-κB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2

Cited by 547 publications

References 69 publications

Zeb1 is required for TrkB-induced epithelial-mesenchymal transition, anoikis resistance and metastasis

Zeb1 is required for TrkB-induced epithelial-mesenchymal transition, anoikis resistance and metastasis

Control of EVI-1 oncogene expression in metastatic breast cancer cells through microRNA miR-22

Contribution of Fibroblast and Mast Cell (Afferent) and Tumor (Efferent) IL-6 Effects within the Tumor Microenvironment

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