| First Author | Witten LW | Year | 2019 |
| Journal | Oncogene | Volume | 38 |
| Issue | 12 | Pages | 2151-2161 |
| PubMed ID | 30459357 | Mgi Jnum | J:320367 |
| Mgi Id | MGI:6871604 | Doi | 10.1038/s41388-018-0571-y |
| Citation | Witten LW, et al. (2019) miR-155 drives oncogenesis by promoting and cooperating with mutations in the c-Kit oncogene. Oncogene 38(12):2151-2161 |
| abstractText | 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. |
