Tumor-propagating cells and Yap/Taz activity contribute to lung tumor progression and metastasis

Lau, Allison N.; Curtis, Stephen J.; Fillmore, Christine M.; Rowbotham, Samuel P.; Mohseni, Morvarid; Wagner, Darcy E.; Beede, Alexander M.; Montoro, Daniel T.; Sinkevicius, Kerstin W.; Walton, Zandra E.; Barrios, Juliana; Weiss, Daniel J.; Camargo, Fernando D.; Wong, Kwok-Kin; Kim, Carla F.

doi:10.1002/embj.201386082

Cited by 191 publications

(192 citation statements)

References 55 publications

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“…1f,g). TAZ, the YAP paralogue that shares many transcription factor targets with YAP, is previously shown to contribute to lung cancer progression and metastasis [22][23][24] . However, unlike YAP, TAZ expression showed no significant correlation with lung cancer pathologies ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression

et al. 2014

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Whether the Hippo pathway contributes to cell lineage transition under pathological conditions, especially tumorigenesis, remains largely unknown. Here we show that YAP, the major effector of the Hippo pathway, displays a distinct activation pattern in lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC); YAP is initially activated by LKB1 loss in lung ADC, which upregulates ZEB2 expression and represses DNp63 transcription in a default manner. During transdifferentiation, YAP is inactivated, which in turn relieves ZEB2-mediated default repression of DNp63 and triggers squamous differentiation reprogramming. Disruption of the YAP barrier for phenotypic transition significantly accelerates squamous transdifferentiation, whereas constitutive YAP activation conversely inhibits this transition. More importantly, ectopic DNp63 expression rescues the inhibitory effect of YAP on squamous transdifferentiation. These findings have established YAP as an essential barrier for lung cancer cell fate conversion and provided a mechanism for regulating cancer plasticity, which might hold important implication for YAP-targeted therapies.

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Section: Resultsmentioning

confidence: 99%

YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression

et al. 2014

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“…We demonstrated that miR-506 could suppress the proliferation of hepatoma cells through direct targeting of YAP mRNA in functional assays. YAP, an essential downstream effector of the Hippo pathway, is frequently highly expressed in a wide spectrum of human solid tumors [26,27] . It has been reported that YAP promotes proliferation in liver by regulating the transcription of certain target genes, including Ki-67, CTGF, c-Myc, sex-determining region Y-related high-mobility group box 4 (SOX4), H19, and alpha-fetoprotein (AFP) [19,20,28] .…”

Section: Discussionmentioning

confidence: 99%

MiR-506 suppresses proliferation of hepatoma cells through targeting YAP mRNA 3′UTR

et al. 2014

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Aim: MiR-506 is a miRNA involved in carcinogenesis of several kinds of cancer. In this study, we explored whether miR-506 played a critical role in hepatocellular carcinoma (HCC). Methods: Twenty HCC and adjacent normal liver tissue samples were collected. Human hepatoma cell lines HepG2 and H7402 were used for in vitro studies. The expression of miR-506 and transcriptional co-activator YAP was examined using qRT-PCR. Western blot analysis was used to measure the expression of YAP and its target genes. Luciferase reporter gene assay was used to identify YAP as a target gene of miR-506. MTT and EdU assays were carried out for functional analysis. Results: The expression of miR-506 was significantly lower in HCC than in adjacent normal liver tissues. Bioinformatics analysis revealed that YAP mRNA might be one of the targets of miR-506, and miR-506 in HCC tissues was found to be negatively correlated with YAP (r=-0.605). In both HepG2 and H7402 cells, miR-506 dose-dependently down-regulated YAP and its target genes c-Myc and the connective tissue growth factor (CTGF). Luciferase reporter gene assays demonstrated that miR-506 targeted the wild type 3′UTR of YAP mRNA, but not a 3′UTR with a mutant seed site. Furthermore, miR-506 significantly inhibited the proliferation of HepG2 and H7402 cells, while anti-miR-506 enhanced the cell proliferation, which was blocked by YAP siRNA. Conclusion: MiR-506 suppresses the proliferation of hepatoma cells by targeting YAP mRNA.

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“…The syntenic chromosomal region in mouse contains YAP gene that is amplified in mammary and liver tumors (Overholtzer et al, 2006;Zender et al, 2006). Ectopic expression or hyperactivation of YAP promotes cell growth and induces oncogenic transformation and epithelial-mesenchimal transition (EMT) that is often associated with metastasis (Lamar et al, 2012;Lau et al, 2014;Nallet-Staub et al, 2013;Overholtzer et al, 2006;Zhao et al, 2009;Zhao et al, 2008). In mouse, transgenic YAP overexpression or liverspecific knockout of Mst1/2 and Sav1 increases the number of stem/progenitor cells and determines liver overgrowth in a reversible manner, ultimately leading to hepatocellular carcinoma (HCC) (Camargo et al, 2007;Dong et al, 2007;Lee et al, 2010;Lu et al, 2010;Song et al, 2010;Zhou et al, 2009).…”

Section: Yap As An Oncogenementioning

confidence: 99%

The Hippo Kinase Pathway: a master regulator of proliferation, development and differentiation

Lo¹,

Strano²,

Blandino³

2014

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Hippo signaling transduction pathway is widely conserved through evolution and controls cell growth, homeostasis, apoptosis, commitment, differentiation and senescence. It consists of a conserved kinase cascade whose final targets are the transcriptional coactivator Yorkie (Yki) in Drosophila and the homologues YAP and TAZ in mammals. These transcriptional coactivators are unable to bind DNA per se, and can regulate the activity of their target genes only in association with transcription factors. In Drosophila, Yki associates with the transcription factors Sd and Hth regulating pro-proliferative and anti-apoptotic genes. In mammals instead, YAP/TAZ can associate with several distinct transcription factors. This depends from the type of signals to which cells are subjected, the cell type and the developmental stage. The transcriptional outcome resulting from this association can be either pro-apoptotic or pro-proliferative. Hippo pathway dysregulation has been associated with several pathologic conditions (tissue overgrowth, developmental defects and cancer). In particular, solid tumors show an upregulation or hyperactivation of YAP/TAZ, while several hematologic tumors are associated with YAP downregulation. This might suggest that the Hippo pathway holds the potential to be an attractive target for novel therapeutic approaches for cancer.

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Tumor-propagating cells and Yap/Taz activity contribute to lung tumor progression and metastasis

Cited by 191 publications

References 55 publications

YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression

YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression

MiR-506 suppresses proliferation of hepatoma cells through targeting YAP mRNA 3′UTR

The Hippo Kinase Pathway: a master regulator of proliferation, development and differentiation

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