A set of microRNAs coordinately controls tumorigenesis, invasion, and metastasis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 48; pp. 24184 - 24195
• Main Authors: Michael, Iacovos P., Saghafinia, Sadegh, Hanahan, Douglas
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 26.11.2019
• Subjects: Activin; Activin Receptors, Type I - genetics; Activins - genetics; Algorithms; Animals; Apoptosis; Biological Sciences; Cell Line, Tumor; Cell Transformation, Neoplastic; Clusters; Computational Biology - methods; Doxycycline - pharmacology; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gene regulation; Genetic engineering; Humans; Invasiveness; LDL-Receptor Related Proteins - genetics; Liver Neoplasms - genetics; Liver Neoplasms - secondary; Membrane Transport Proteins - genetics; Metastases; Metastasis; Mice; MicroRNAs; MicroRNAs - genetics; miRNA; Neuroendocrine tumors; Neuroendocrine Tumors - genetics; Neuroendocrine Tumors - mortality; Neuroendocrine Tumors - pathology; Pancreas; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - mortality; Pancreatic Neoplasms - pathology; Phenotypes; Prognosis; Receptors, LDL - genetics; Ribonucleic acid; RNA; Tumor suppressor genes; Tumorigenesis; Tumors; Xenograft Model Antitumor Assays; microRNAs; PanNETs; Acvr1c/ALK7; cancer; metastasis
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1913307116

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.