A set of microRNAs coordinately controls tumorigenesis, invasion, and metastasis.
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State: Public
Version: Final published version
License: CC BY-NC-ND 4.0
State: Public
Version: Final published version
License: CC BY-NC-ND 4.0
Serval ID
serval:BIB_CBDBEAF62F26
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A set of microRNAs coordinately controls tumorigenesis, invasion, and metastasis.
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN
1091-6490 (Electronic)
ISSN-L
0027-8424
Publication state
Published
Issued date
26/11/2019
Peer-reviewed
Oui
Volume
116
Number
48
Pages
24184-24195
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
MicroRNA-mediated gene regulation has been implicated in various diseases, including cancer. This study examined the role of microRNAs (miRNAs) during tumorigenesis and malignant progression of pancreatic neuroendocrine tumors (PanNETs) in a genetically engineered mouse model. Previously, a set of miRNAs was observed to be specifically up-regulated in a highly invasive and metastatic subtype of mouse and human PanNET. Using functional assays, we now implicate different miRNAs in distinct phenotypes: miR-137 stimulates tumor growth and local invasion, whereas the miR-23b cluster enables metastasis. An algorithm, Bio-miRTa, has been developed to facilitate the identification of biologically relevant miRNA target genes and applied to these miRNAs. We show that a top-ranked miR-137 candidate gene, Sorl1, has a tumor suppressor function in primary PanNETs. Among the top targets for the miR-23b cluster, Acvr1c/ALK7 has recently been described to be a metastasis suppressor, and we establish herein that it is down-regulated by the miR-23b cluster, which is crucial for its prometastatic activity. Two other miR-23b targets, Robo2 and P2ry1, also have demonstrable antimetastatic effects. Finally, we have used the Bio-miRTa algorithm in reverse to identify candidate miRNAs that might regulate activin B, the principal ligand for ALK7, identifying thereby a third family of miRNAs-miRNA-130/301-that is congruently up-regulated concomitant with down-regulation of activin B during tumorigenesis, suggestive of functional involvement in evasion of the proapoptotic barrier. Thus, dynamic up-regulation of miRNAs during multistep tumorigenesis and malignant progression serves to down-regulate distinctive suppressor mechanisms of tumor growth, invasion, and metastasis.
Keywords
Activin Receptors, Type I/genetics, Activins/genetics, Algorithms, Animals, Cell Line, Tumor, Cell Transformation, Neoplastic, Computational Biology/methods, Doxycycline/pharmacology, Gene Expression Regulation, Neoplastic/drug effects, Humans, LDL-Receptor Related Proteins/genetics, Liver Neoplasms/genetics, Liver Neoplasms/secondary, Membrane Transport Proteins/genetics, Mice, MicroRNAs/genetics, Neuroendocrine Tumors/genetics, Neuroendocrine Tumors/mortality, Neuroendocrine Tumors/pathology, Pancreatic Neoplasms/genetics, Pancreatic Neoplasms/mortality, Pancreatic Neoplasms/pathology, Prognosis, Receptors, LDL/genetics, Xenograft Model Antitumor Assays, Acvr1c/ALK7, PanNETs, cancer, metastasis, microRNAs
Pubmed
Web of science
Open Access
Yes
Create date
02/05/2020 15:57
Last modification date
23/04/2024 7:16