Prognostic Significance of TAZ Expression in Resected Non-Small Cell Lung Cancer

Xie, Mian; Zhang, Li; He, Chao; Hou, Jin Hui; Lin, Su Xia; Hu, Zhi; Xu, Fei; Zhao, Hong

doi:10.1097/jto.0b013e318248240b

Cited by 82 publications

(74 citation statements)

References 17 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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“…3). This is of relevance to therapy because increased expression of TAZ was reported in various cancers, including breast (42), colon (43), non-small cell lung cancer (44), and melanoma (45), making it a bona fide oncogene. TAZ is also believed to endow tumor cells with cancer stem cell properties (42) and cooperate with both b-catenin and Smads downstream of Wnt and TGF-b, respectively, to induce expression of pro-EMT genes (46).…”

Section: Discussionmentioning

confidence: 99%

Identification, Mechanism of Action, and Antitumor Activity of a Small Molecule Inhibitor of Hippo, TGF-β, and Wnt Signaling Pathways

Basu

Lettan

Damodaran

et al. 2014

Molecular Cancer Therapeutics

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Embryonic signaling pathways, in particular those mediated by Wnt and TGF-b, are known to play key roles in tumor progression through the induction of epithelial-mesenchymal transition (EMT). Their simultaneous targeting could therefore represent a desirable anticancer strategy. On the basis of recent findings that both Wnt and TGF-b-associated pathways are regulated by Hippo signaling in mammalian cells, we reasoned that targeting the latter would be more effective in inhibiting EMT. In a search for such inhibitors, we identified a small molecule (C19) with remarkable inhibitory activity not only against Hippo, but also against Wnt and TGF-b pathways. C19 inhibited cancer cell migration, proliferation, and resistance to doxorubicin in vitro, and exerted strong antitumor activity in a mouse tumor model. Mechanistically, C19 induced GSK3-b-mediated degradation of the Hippo transducer TAZ, through activation of the Hippo kinases Mst/Lats and the tumor suppressor kinase AMPK upstream of the degradation complex. Overall, this study identified C19 as a multi-EMT pathway inhibitor with a unique mechanism of action. The findings that both AMPK and Mst/Lats mediate the antitumor activity of C19 shed light on a potential cross-talk between metabolic and organ size control pathways in regulating cancer progression. By simultaneously targeting these two pathways, C19 may represent a new type of agents to suppress cancer progression and/or its recurrence.

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“…Upon phosphorylation, TAZ/YAP undergo ubiquitination-mediated degradation and/or are sequestered in the cytoplasm by anchoring proteins (Pan 2010, Zhao et al 2011. Elevated TAZ or YAP expression and nuclear localization have been observed in a broad range of different human cancers, and they often correlate with poor patient prognosis (Zender et al 2006, Chan et al 2008, Steinhardt et al 2008, Bhat et al 2011, de Cristofaro et al 2011, Xie et al 2012, Wang et al 2013. In breast cancer, TAZ seems to be the relevant Hippo effector, because TAZ but not YAP protein expression appeared to be modulated in breast cancer cell lines (Chan et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Nuclear TAZ expression associates with the triple-negative phenotype in breast cancer

Díaz‐Martín¹,

López-García²,

Romero‐Pérez³

et al. 2015

Endocrine-Related Cancer

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The Hippo signaling pathway, a conserved regulator of organ size, has emerged as an important regulatory pathway in cancer. The final transducer effectors of this pathway in mammals are the oncoproteins TAZ and YAP1, which are transcriptional coactivators of target genes involved in cell proliferation and survival. TAZ has been previously reported to play a role in tumorigenesis in breast cancer, but detailed analyses of the different breast cancer phenotypes have not been conducted thus far. We analyzed TAZ expression by immunohistochemistry in a retrospective series of 640 invasive breast carcinomas, comprising estrogen/progesterone receptor-positive (ERC/PRC), HER2-positive, and triple-negative (TN) tumors. We found a strong association of TAZ nuclear expression with the TN phenotype (60.5% TAZ-positive, P!0.001), which was strengthened when stratified into the basal-like subtype (70.8% TAZ-positive, P!0.001). Moreover, 90% of metaplastic breast carcinomas with morphological epithelial-mesenchymal transition features were TAZ-positive. We also investigated whether amplification or differential DNA methylation of the TAZ-encoding locus could account for the observed enhanced TAZ protein expression in the TN/basal phenotype. Amplification of the TAZ locus was analyzed by fluorescence in situ hybridization in 30 TN tumors, and we found gene amplification in some cases (6.45%). DNA methylation analysis was performed using the Sequenom MassArray MALDI-TOF platform, and we observed similar low methylation levels both in TN (nZ25) and ERC/PRC (nZ26) tumors. These results were further confirmed using a panel of breast cancer cell lines and using the TCGA dataset. Finally, patients with strong TAZ expression showed poorer clinical outcomes with respect to both recurrence and overall survival.

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Prognostic Significance of TAZ Expression in Resected Non-Small Cell Lung Cancer

Abstract: This study suggests that TAZ expression is a prognostic indicator of poorer survival probability for patients with resected NSCLC.

Cited by 82 publications

References 17 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

Identification, Mechanism of Action, and Antitumor Activity of a Small Molecule Inhibitor of Hippo, TGF-β, and Wnt Signaling Pathways

Nuclear TAZ expression associates with the triple-negative phenotype in breast cancer

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