miR-155 drives oncogenesis by promoting and cooperating with mutations in the c-Kit oncogene

• Published in: Oncogene 2019-03, Vol.38 (12), p.2151-2161
• Main Authors: Witten, Lisa W., Cheng, Christopher J., Slack, Frank J.
• Format: Article
• Language: English
• Subjects: 38/23; 38/77; 631/337/384; 631/67/395; 631/67/70; 64/110; Animals; Apoptosis; B cells; c-Kit protein; Cancer; Carcinogenesis; Carcinogenesis - genetics; Care and treatment; Cell Biology; Cell Line, Tumor; Cooperation; Dasatinib; Development and progression; DNA; DNA repair; Female; Gene expression; Gene Expression Regulation, Neoplastic; Gene mutation; Genetic aspects; Health aspects; Hematologic diseases; Hematology; Human Genetics; Imatinib; Inflammation; Internal Medicine; Malignancy; Medicine; Medicine & Public Health; Mice; MicroRNA; MicroRNAs - genetics; miRNA; Mutation; Oncogenes; Oncogenes - genetics; Oncology; Phenotypes; Proteins; Proto-Oncogene Proteins c-kit - genetics; Solid tumors; Transgenic mice; Tumorigenesis; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0571-y

MicroRNAs (miRNAs) have emerged as crucial players in the development and maintenance of disease. miR-155 is an inflammation-associated, oncogenic miRNA, frequently overexpressed in hematological malignancies and solid tumors. However, the mechanism of oncogenesis by miR-155 is not well characterized, and research has focused primarily on individual, direct targets, which does not recapitulate the complexities of cancer. Using a powerful, inducible transgenic mouse model that overexpresses miR-155 and develops miR-155-addicted hematological malignancy, we describe here a multi-step process of oncogenesis by miR-155, which involves cooperation between miR-155, its direct targets, and other oncogenes. miR-155 is known to target DNA-repair proteins, leading to a mutator phenotype, and we find that over 93% of tumors in our miR-155 overexpressing mice contain activating mutations in a single oncogene, c-Kit . Treating mice with dasatinib or imatinib, which target c-Kit , resulted in complete tumor regression, indicating that c-Kit activity is crucial in the oncogenic process. Interestingly, c-Kit expression is high when miR-155 is overexpressed, indicating further cooperation between miR-155 and c-Kit . Our findings support a multi-step model of oncogenesis by miR-155 in which miR-155 promotes both a mutator phenotype and a cellular environment particularly susceptible to mutations in a given oncogene.