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Zinc-Dependent Regulation of ZEB1 and YAP1 Coactivation Promotes Epithelial-Mesenchymal Transition Plasticity and Metastasis in Pancreatic Cancer.
Liu, Mingyang; Zhang, Yuqing; Yang, Jingxuan; Zhan, Hanxiang; Zhou, Zhijun; Jiang, Yuanyuan; Shi, Xiuhui; Fan, Xiao; Zhang, Junxia; Luo, Wenyi; Fung, Kar-Ming A; Xu, Chao; Bronze, Michael S; Houchen, Courtney W; Li, Min.
Afiliación
  • Liu M; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
  • Zhang Y; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
  • Yang J; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
  • Zhan H; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China.
  • Zhou Z; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
  • Jiang Y; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Pulmonary and Critical Care Medicine, Qilu Hospital, Shandong University, Jinan, Shando
  • Shi X; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
  • Fan X; Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
  • Zhang J; Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
  • Luo W; Department of Pathology, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
  • Fung KA; Department of Pathology, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
  • Xu C; Department of Biostatistics and Epidemiology, Hudson College of Public Health, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
  • Bronze MS; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
  • Houchen CW; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
  • Li M; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Electronic address: Min-Li@ouhsc.edu.
Gastroenterology ; 160(5): 1771-1783.e1, 2021 04.
Article en En | MEDLINE | ID: mdl-33421513
ABSTRACT

BACKGROUND:

Pancreatic cancer is characterized by extensive metastasis. Epithelial-mesenchymal transition (EMT) plasticity plays a critical role in tumor progression and metastasis by maintaining the transition between EMT and mesenchymal-epithelial transition states. Our aim is to understand the molecular events regulating metastasis and EMT plasticity in pancreatic cancer.

METHODS:

The interactions between a cancer-promoting zinc transporter ZIP4, a zinc-dependent EMT transcriptional factor ZEB1, a coactivator YAP1, and integrin α3 (ITGA3) were examined in human pancreatic cancer cells, clinical specimens, spontaneous mouse models (KPC and KPCZ) and orthotopic xenografts, and 3-dimensional spheroid and organoid models. Correlations between ZIP4, miR-373, and its downstream targets were assessed by RNA in situ hybridization and immunohistochemical staining. The transcriptional regulation of ZEB1, YAP1, and ITGA3 by ZIP4 was determined by chromatin immunoprecipitation, co-immunoprecipitation, and luciferase reporter assays.

RESULTS:

The Hippo pathway effector YAP1 is a potent transcriptional coactivator and forms a complex with ZEB1 to activate ITGA3 transcription through the YAP1/transcriptional enhanced associate domain (TEAD) binding sites in human pancreatic cancer cells and KPC-derived mouse cells. ZIP4 upregulated YAP1 expression via activation of miR-373 and inhibition of the YAP1 repressor large tumor suppressor 2 kinase (LATS2). Furthermore, upregulation of ZIP4 promoted EMT plasticity, cell adhesion, spheroid formation, and organogenesis both in human pancreatic cancer cells, 3-dimensional spheroid model, xenograft model, and spontaneous mouse models (KPC and KPCZ) through ZEB1/YAP1-ITGA3 signaling axis.

CONCLUSION:

We demonstrated that ZIP4 activates ZEB1 and YAP1 through distinct mechanisms. The ZIP4-miR-373-LATS2-ZEB1/YAP1-ITGA3 signaling axis has a significant impact on pancreatic cancer metastasis and EMT plasticity.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Factores de Transcripción / Zinc / Movimiento Celular / Proteínas Adaptadoras Transductoras de Señales / Transición Epitelial-Mesenquimal / Plasticidad de la Célula / Homeobox 1 de Unión a la E-Box con Dedos de Zinc Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Año: 2021 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Factores de Transcripción / Zinc / Movimiento Celular / Proteínas Adaptadoras Transductoras de Señales / Transición Epitelial-Mesenquimal / Plasticidad de la Célula / Homeobox 1 de Unión a la E-Box con Dedos de Zinc Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Año: 2021 Tipo del documento: Article