The Hippo pathway effector TAZ induces TEAD-dependent liver inflammation and tumors

Hagenbeek, Thijs J.; Webster, Joshua D.; Kljavin, Noelyn M.; Chang, Matthew T.; Pham, Trang; Lee, Ho-June; Klijn, Christiaan; Cai, Allen G.; Tótpál, Klára; Ravishankar, Buvana; Yang, Nai‐Ying; Lee, Da-Hye; Walsh, Kevin B.; Hatzivassiliou, Georgia; Cruz, Cecile C. de la; Gould, Stephen E.; Wu, Xiumin; Lee, Wyne P.; Yang, Shuqun; Zhang, Zhixiang; Gu, Qing; Ji, Qunsheng; Jackson, Erica; Lim, Dae‐Sik; Dey, Anwesha

doi:10.1126/scisignal.aaj1757

Cited by 71 publications

(59 citation statements)

References 38 publications

(48 reference statements)

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“…Moreover, using the microRNA.org database to analyze miR‐223 targeted genes among these up‐regulated genes, we identified seven potential targets of miR‐223 that are related to liver carcinogenesis, including Cxcl10 , Taz , Serpinb9 , Nrxn1 , Slc1a4 , Slc16a6 , and Dock11 . Among these genes, Taz is a well‐documented oncogenic gene that encodes a protein to promote liver cancer development . Therefore, miR‐223 can directly target multiple oncogenic genes including Taz , thereby attenuating NASH‐associated HCC.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‐223 Ameliorates Nonalcoholic Steatohepatitis and Cancer by Targeting Multiple Inflammatory and Oncogenic Genes in Hepatocytes

et al. 2019

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Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of diseases ranging from simple steatosis to more severe forms of liver injury including nonalcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC). In humans, only 20%-40% of patients with fatty liver progress to NASH, and mice fed a high-fat diet (HFD) develop fatty liver but are resistant to NASH development. To understand how simple steatosis progresses to NASH, we examined hepatic expression of anti-inflammatory microRNA-223 (miR-223) and found that this miRNA was highly elevated in hepatocytes in HFD-fed mice and in human NASH samples. Genetic deletion of miR-223 induced a full spectrum of NAFLD in long-term HFD-fed mice including steatosis, inflammation, fibrosis, and HCC. Furthermore, microarray analyses revealed that, compared to wild-type mice, HFD-fed miR-223 knockout (miR-223KO) mice had greater hepatic expression of many inflammatory genes and cancer-related genes, including (C-X-C motif) chemokine 10 (Cxcl10) and transcriptional coactivator with PDZ-binding motif (Taz), two well-known factors that promote NASH development. In vitro experiments demonstrated that Cxcl10 and Taz are two downstream targets of miR-223 and that overexpression of miR-223 reduced their expression in cultured hepatocytes. Hepatic levels of miR-223, CXCL10, and TAZ mRNA were elevated in human NASH samples, which positively correlated with hepatic levels of several miR-223 targeted genes as well as several proinflammatory, cancer-related, and fibrogenic genes. Conclusion: HFD-fed miR-223KO mice develop a full spectrum of NAFLD, representing a clinically relevant mouse NAFLD model; miR-223 plays a key role in controlling steatosis-to-NASH progression by inhibiting hepatic Cxcl10 and Taz expression and may be a therapeutic target for the treatment of NASH. (Hepatology 2019;70:1150-1167).

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Section: Discussionmentioning

confidence: 99%

MicroRNA‐223 Ameliorates Nonalcoholic Steatohepatitis and Cancer by Targeting Multiple Inflammatory and Oncogenic Genes in Hepatocytes

et al. 2019

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“…The oncogenic role of nuclear YAP1 may also be linked to mechanical damage secondary to the accumulation of bile acids which activate YAP1 via a pathway dependent on the induction of the scaffold protein IQGAP1 [29]. On the other hand, in the liver, hyperactivated TAZ promotes inflammatory cytokine production and macrophage infiltration, playing a relevant role in tumor development [30]. Due to the relevance of inflammation in gallbladder cancer [31], we propose that nuclear translocation of YAP is a major event in the gallbladder carcinogenic process triggered by chronic inflammation.…”

Section: Discussionmentioning

confidence: 99%

Hippo-YAP1 Is a Prognosis Marker and Potentially Targetable Pathway in Advanced Gallbladder Cancer

García

Rosa

Vargas

et al. 2020

Cancers

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Gallbladder cancer is an aggressive disease with late diagnosis and no efficacious treatment. The Hippo-Yes-associated protein 1 (YAP1) signaling pathway has emerged as a target for the development of new therapeutic interventions in cancers. However, the role of the Hippo-targeted therapy has not been addressed in advanced gallbladder cancer (GBC). This study aimed to evaluate the expression of the major Hippo pathway components mammalian Ste20-like protein kinase 1 (MST1), YAP1 and transcriptional coactivator with PDZ-binding motif (TAZ) and examined the effects of Verteporfin (VP), a small molecular inhibitor of YAP1-TEA domain transcription factor (TEAD) protein interaction, in metastatic GBC cell lines and patient-derived organoids (PDOs). Immunohistochemical analysis revealed that advanced GBC patients had high nuclear expression of YAP1. High nuclear expression of YAP1 was associated with poor survival in GBC patients with subserosal invasion (pT2). Additionally, advanced GBC cases showed reduced expression of MST1 compared to chronic cholecystitis. Both VP treatment and YAP1 siRNA inhibited the migration ability in GBC cell lines. Interestingly, gemcitabine resistant PDOs with high nuclear expression of YAP1 were sensitive to VP treatment. Taken together, our results suggest that key components of the Hippo-YAP1 signaling pathway are dysregulated in advanced gallbladder cancer and reveal that the inhibition YAP1 may be a candidate for targeted therapy.

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“…The expression of TAZ, but not YAP, was found to correlate with the mRNA transcription of inflammatory cytokines CCL2 and CXCL1 in human liver tumors. Expression of TAZ in mouse livers increased the secretion of proinflammatory cytokines, recruitment of myeloid cells, and mice mortality in a TEADs dependent manner (90). Mooring et al found that the long-term expression of YAP/TAZ in hepatocyte positively correlated to the degree of liver inflammation.…”

Section: Hippo-yap and Nf-κb Signaling And Inflammationmentioning

confidence: 99%

The Crosstalk Between Hippo-YAP Pathway and Innate Immunity

et al. 2020

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Recognition of pathogen-associated molecular patterns (PAMPs) triggers expression of antiviral interferons and proinflammatory cytokines, which functions as the frontier of host defense against microbial pathogen invasion. Hippo-YAP pathway regulates cell proliferation, survival, differentiation and is involved in diverse life processes, including tissue homeostasis and tumor suppression. Emerging discoveries elucidated that the components of Hippo-YAP pathway, such as MST1/2, NDR1/2, and YAP/TAZ played crucial regulatory roles in innate immunity. Meanwhile the innate immune signaling also exhibited regulatory effect on Hippo-YAP pathway. As for the importance of these two pathways, it would be interesting to figure out the deeper biological implications of their interplays. This review focuses on the regulation between Hippo-YAP pathway and innate immune signaling. We also propose the possible contribution of these interplays to tumor development.

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The Hippo pathway effector TAZ induces TEAD-dependent liver inflammation and tumors

Cited by 71 publications

References 38 publications

MicroRNA‐223 Ameliorates Nonalcoholic Steatohepatitis and Cancer by Targeting Multiple Inflammatory and Oncogenic Genes in Hepatocytes

MicroRNA‐223 Ameliorates Nonalcoholic Steatohepatitis and Cancer by Targeting Multiple Inflammatory and Oncogenic Genes in Hepatocytes

Hippo-YAP1 Is a Prognosis Marker and Potentially Targetable Pathway in Advanced Gallbladder Cancer

The Crosstalk Between Hippo-YAP Pathway and Innate Immunity

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