A set of microRNAs coordinately controls tumorigenesis, invasion, and metastasis
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 m...
Saved in:
Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 48; pp. 24184 - 24195 |
---|---|
Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
26.11.2019
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | 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. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Contributed by Douglas Hanahan, October 9, 2019 (sent for review August 5, 2019; reviewed by Eduard Batlle and Andrea Ventura) Author contributions: I.P.M. and D.H. designed research; I.P.M. and S.S. performed research; I.P.M. and S.S. contributed new reagents/analytic tools; I.P.M. and S.S. analyzed data; and I.P.M. and D.H. wrote the paper. Reviewers: E.B., Institut de Recerca en Biomedicina Barcelona; and A.V., Memorial Sloan Kettering Cancer Center. |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.1913307116 |