Evidence map›Paper›PMID 30342032›Full record

ArticleGastroenterology2019

ZIP4 Promotes Muscle Wasting and Cachexia in Mice With Orthotopic Pancreatic Tumors by Stimulating RAB27B-Regulated Release of Extracellular Vesicles From Cancer Cells.

Jingxuan Yang, Zicheng Zhang, Yuqing Zhang, Xiaoling Ni, Guohua Zhang, Xiaobo Cui, Mingyang Liu, Can Xu, Qiang Zhang, Huiyun Zhu and 14 more

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

Article in Gastroenterology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 95 papers.

0numbers the graph read from it
0cells of the map it votes in
95citing papers in PubMed
5.4field-weighted citation impact, top 3% 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

95 citing papers in PubMed, 128 citations in OpenAlex.

  1. Review
  2. Article
  3. Review
  4. Article
  5. Review
  6. Article
  7. Article
  8. Cancer cachexia: molecular basis and therapeutic advances.Signal transduction and targeted therapy · 2026
    Review
  9. Review
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  11. Review
  12. Article
  13. Review
  14. Article
  15. An alternative pocket for binding the N-degrons by the UBR1 and UBR2 ubiquitin E3 ligases.Protein science : a publication of the Protein Society · 2025
    Article
  16. Review
  17. Review
  18. A zinc transporter drives glioblastoma progression via extracellular vesicles-reprogrammed microglial plasticity.Proceedings of the National Academy of Sciences of the United States of America · 2025
    Article
  19. Review
  20. Review

35 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

24 authors at 8 institutions in 2 countries.

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; The Vivian L. Smith Department of Neurosurgery, the University of Texas Health Science Center at Houston, Houston, Texas.
Zicheng ZhangDepartment of Integrative Biology and Pharmacology, the University of Texas Health Science Center at Houston, Houston, Texas.
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.
Xiaoling NiThe Vivian L. Smith Department of Neurosurgery, the University of Texas Health Science Center at Houston, Houston, Texas; Department of General Surgery, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Guohua ZhangDepartment of Integrative Biology and Pharmacology, the University of Texas Health Science Center at Houston, Houston, Texas.
Xiaobo CuiDepartment 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; The Vivian L. Smith Department of Neurosurgery, the University of Texas Health Science Center at Houston, Houston, Texas.
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.
Can XuThe Vivian L. Smith Department of Neurosurgery, the University of Texas Health Science Center at Houston, Houston, Texas; Department of Gastroenterology, Changhai Hospital, Shanghai, China.
Qiang ZhangThe Vivian L. Smith Department of Neurosurgery, the University of Texas Health Science Center at Houston, Houston, Texas.
Huiyun ZhuDepartment 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 Gastroenterology, Changhai Hospital, Shanghai, China.
Jie YanDepartment 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.
Vivian F ZhuThe Vivian L. Smith Department of Neurosurgery, the University of Texas Health Science Center at Houston, Houston, Texas.
Yusheng LuoThe Vivian L. Smith Department of Neurosurgery, the University of Texas Health Science Center at Houston, Houston, Texas.
John P HaganThe Vivian L. Smith Department of Neurosurgery, the University of Texas Health Science Center at Houston, Houston, Texas.
Zhaoshen LiDepartment of Gastroenterology, Changhai Hospital, Shanghai, China.
Jing FangThe Key Lab of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China.
Aminah JatoiDepartment of Oncology, Mayo Clinic, Rochester, Minnesota.
Martin E Fernandez-ZapicoSchulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota.
Lei ZhengThe Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Barish H EdilDepartment of Surgery, 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.
Yi-Ping LiDepartment of Integrative Biology and Pharmacology, the University of Texas Health Science Center at Houston, Houston, Texas. Electronic address: Yi-Ping.Li@uth.tmc.edu.
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; The Vivian L. Smith Department of Neurosurgery, the University of Texas Health Science Center at Houston, Houston, Texas; Department of Integrative Biology and Pharmacology, the University of Texas Health Science Center at Houston, Houston, Texas. Electronic address: Min-Li@ouhsc.edu.
University of Oklahoma Health Sciences Center · USSecond Military Medical University · CNMayo Clinic · USThe University of Texas Health Science Center at Houston · USJohns Hopkins University · USQingdao University · CNShanghai Medical College of Fudan University · CNThe University of Texas Health Science Center · US

Funding

Tissue Pathology Shared ResourceP30CA225520 · NCI · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · PI Michael S. Businelle · 2018 to 2026
$27.1M
Identification of key tumor cell-released factors that induce cachexiaR01AR063786 · NIAMS · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI JAFRI, SYED H, LI, YI-PING · 2013 to 2024
$4.3M
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
NCI NIH HHS P30 CA225520NCI NIH HHS R01 CA203108NIAMS NIH HHS R01 AR063786
6 · The paper itself

Abstract

BACKGROUND &

aimsCachexia, which includes muscle wasting, is a frequent complication of pancreatic cancer. There are no therapies that reduce cachexia and increase patient survival, so it is important to learn more about its mechanisms. The zinc transporter ZIP4 promotes growth and metastasis of pancreatic tumors. We investigated its effects on muscle catabolism via extracellular vesicle (EV)-mediated stimulation of mitogen-activated protein kinase 14 (p38 MAPK).

methodsWe studied nude mice with orthotopic tumors grown from human pancreatic cancer cell lines (AsPC-1 and BxPC-3); tumors were removed 8 days after cell injection and analyzed by histology. Mouse survival was analyzed by Kaplan-Meier curves. ZIP4 was knocked down in AsPC-1 and BxPC-3 cells with small hairpin RNAs; cells with empty vectors were used as controls. Muscle tissues were collected from mice and analyzed by histology and immunohistochemistry. Conditioned media from cell lines and 3-dimensional spheroid/organoid cultures of cancer cells were applied to C2C12 myotubes. The myotubes and the media were analyzed by immunoblots, enzyme-linked immunosorbent assays, and immunofluorescence microscopy. EVs were isolated from conditioned media and analyzed by immunoblots.

resultsMice with orthotopic tumors grown from pancreatic cancer cells with knockdown of ZIP4 survived longer and lost less body weight and muscle mass than mice with control tumors. Conditioned media from cancer cells activated p38 MAPK, induced expression of F-box protein 32 and UBR2 in C2C12 myotubes, and also led to loss of myofibrillar protein myosin heavy chain and myotube thinning. Knockdown of ZIP4 in cancer cells reduced these effects. ZIP4 knockdown also reduced pancreatic cancer cell release of heat shock protein (HSP) 70 and HSP90, which are associated with EVs, by decreasing CREB-regulated expression of RAB27B.

conclusionsZIP4 promotes growth of orthotopic pancreatic tumors in mice and loss of muscle mass by activating CREB-regulated expression of RAB27B, required for release of EVs from pancreatic cancer cells. These EVs activate p38 MAPK and induce expression of F-box protein 32 and UBR2 in myotubes, leading to loss of myofibrillar myosin heavy chain and myotube thinning. Strategies to disrupt these pathways might be developed to reduce pancreatic cancer progression and accompanying cachexia.

Indexed as

AnimalsCachexiaCation Transport ProteinsCell Line, TumorExtracellular VesiclesGene Expression Regulation, NeoplasticHumansKaplan-Meier EstimateMiceMice, NudeMuscle, Skeletalp38 Mitogen-Activated Protein KinasesPancreatectomyPancreatic Neoplasmsrab GTP-Binding ProteinsRandom AllocationCation Transport Proteinsp38 Mitogen-Activated Protein KinasesRab27b protein, mouserab GTP-Binding ProteinsSlc39a4 protein, mouseMouse ModelMuscle LossPancreasSignal Transduction

Identifiers

PMID30342032
PMCPMC6878980
OpenAlexW2896710157

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Registered trials

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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.