Evidence map›Paper›PMID 33421513›Full record

ArticleGastroenterology2021

Zinc-Dependent Regulation of ZEB1 and YAP1 Coactivation Promotes Epithelial-Mesenchymal Transition Plasticity and Metastasis in Pancreatic Cancer.

Mingyang Liu, Yuqing Zhang, Jingxuan Yang, Hanxiang Zhan, Zhijun Zhou, Yuanyuan Jiang, Xiuhui Shi, Xiao Fan, Junxia Zhang, Wenyi Luo and 5 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Gastroenterology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 131 papers.

0numbers the graph read from it
0cells of the map it votes in
131citing papers in PubMed
16.1field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

131 citing papers in PubMed, 201 citations in OpenAlex.

  1. Role of ZEB1 in angiogenesis and therapeutic potential (Review).International journal of molecular medicine · 2026
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71 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

15 authors at 3 institutions in 2 countries.

Mingyang LiuDepartment 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.
Yuqing ZhangDepartment 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.
Jingxuan YangDepartment 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.
Hanxiang ZhanDepartment 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.
Zhijun ZhouDepartment 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.
Yuanyuan JiangDepartment 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, Shandong, China.
Xiuhui ShiDepartment 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.
Xiao FanDepartment of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
Junxia ZhangDepartment of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
Wenyi LuoDepartment of Pathology, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Kar-Ming A FungDepartment of Pathology, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Chao XuDepartment of Biostatistics and Epidemiology, Hudson College of Public Health, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Michael S BronzeDepartment of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Courtney W HouchenDepartment of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Min LiDepartment 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.
University of Oklahoma Health Sciences Center · USJiangsu Province Hospital · CNQilu Hospital of Shandong University · CN

Funding

Tissue Pathology Shared ResourceP30CA225520 · NCI · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · PI Michael S. Businelle · 2018 to 2026
$27.1M
Mechanism of Pancreatic CarcinogenesisR01CA136526 · NCI · MAYO CLINIC ROCHESTER · PI FERNANDEZ-ZAPICO, MARTIN ERNESTO · 2009 to 2019
$3.0M
Prognostic Biomarkers for ZIP4-mediated Cachexia in Pancreatic CancerR01CA203108 · NCI · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · PI LI, MIN, LI, YI-PING · 2016 to 2020
$2.7M
ZIP4 is a Novel Molecular Target in Human Pancreatic CancerR01CA186338 · NCI · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · PI FERNANDEZ-ZAPICO, MARTIN ERNESTO, LI, MIN · 2015 to 2019
$1.7M
Role of Zinc Dependent EMT-Transcription Factors (EMT-TF) in Pancreatic Cancer MetastasisR01CA247234 · NCI · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · PI LI, MIN · 2020 to 2024
$1.6M
NCI NIH HHS P30 CA225520NCI NIH HHS R01 CA136526NCI NIH HHS R01 CA186338NCI NIH HHS R01 CA203108NCI NIH HHS R01 CA247234
6 · The paper itself

Abstract

backgroundPancreatic 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.

methodsThe 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.

resultsThe 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.

conclusionWe 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.

Indexed as

Cell MovementCell PlasticityEpithelial-Mesenchymal TransitionAdaptor Proteins, Signal TransducingAnimalsCation Transport ProteinsCell Line, TumorGene Expression Regulation, NeoplasticHumansIntegrin alpha3MiceMicroRNAsNeoplasm InvasivenessNeoplasm MetastasisPancreatic NeoplasmsSignal TransductionAdaptor Proteins, Signal TransducingCation Transport ProteinsIntegrin alpha3ITGA3 protein, humanItga3 protein, mouseMicroRNAsMIRN373 microRNA, humanMIRN373 microRNA, mouseSLC39A4 protein, humanSlc39a4 protein, mouseTranscription FactorsYAP1 protein, humanYap1 protein, mouseYAP-Signaling ProteinsZEB1 protein, humanZEB1 protein, mouseZincZinc Finger E-box-Binding Homeobox 1Posttranscriptional RegulationTranscription CoactivationZinc Homeostasis

Identifiers

PMID33421513
PMCPMC8035249
OpenAlexW3118255846

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.