Abstract | BACKGROUND & AIMS: METHODS: Differentially expressed circRNAs and potential targets of microRNA were identified through in silico analysis. The RNA interactions were determined by means of biotinylated microRNA pulldown, RNA immunoprecipitation, and luciferase reporter assays. The function of circRNA in ZIP4-miR-373 signaling axis were examined in human pancreatic cancer cells, 3-dimensional spheroids and organoids, mouse models, and clinical specimens. Mouse skeletal muscles were analyzed by means of histology. RESULTS: We identified circANAPC7 as a sponge for miR-373, which inhibited tumor growth and muscle wasting in vitro and in vivo. Mechanistic studies showed that PHLPP2 is a downstream target of ZIP4/miR-373. CircANAPC7 functions through PHLPP2-mediated dephosphorylation of AKT, thus suppressing cancer cell proliferation by down-regulating cyclin D1 and inhibiting muscle wasting via decreasing the secretion of transforming growth factor-β through STAT5. We further demonstrated that PHLPP2 induced dephosphorylation of CREB, a zinc-dependent transcription factor activated by ZIP4, thereby forming a CREB-miR-373-PHLPP2 feed-forward loop to regulate tumor progression and cancer cachexia. CONCLUSION:
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Authors | Xiuhui Shi, Jingxuan Yang, Mingyang Liu, Yuqing Zhang, Zhijun Zhou, Wenyi Luo, Kar-Ming Fung, Chao Xu, Michael S Bronze, Courtney W Houchen, Min Li |
Journal | Gastroenterology
(Gastroenterology)
Vol. 162
Issue 7
Pg. 2004-2017.e2
(06 2022)
ISSN: 1528-0012 [Electronic] United States |
PMID | 35176309
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- Ccnd1 protein, mouse
- MicroRNAs
- RNA, Circular
- Transforming Growth Factor beta
- Cyclin D1
- Proto-Oncogene Proteins c-akt
- PHLPP2 protein, human
- PHLPP2 protein, mouse
- Phosphoprotein Phosphatases
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Topics |
- Animals
- Cachexia
(genetics, metabolism)
- Cell Line, Tumor
- Cell Proliferation
(genetics)
- Cyclin D1
(genetics, metabolism)
- Humans
- Mice
- MicroRNAs
(genetics)
- Muscles
(metabolism, pathology)
- Pancreatic Neoplasms
(genetics, metabolism, pathology)
- Phosphoprotein Phosphatases
(genetics, metabolism)
- Proto-Oncogene Proteins c-akt
(metabolism)
- RNA, Circular
(genetics, metabolism)
- Transforming Growth Factor beta
(genetics)
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