THADA fusion is a mechanism of IGF2BP3 activation and IGF1R signaling in thyroid cancer
| Autor: | David J. Dabbs, Xiaosong Wang, Adrian V. Lee, Rohit Bhargava, Federica Panebianco, Robert L. Ferris, Sally E. Carty, Sanja Dacic, Shan Zhong, Abigail I. Wald, Marina N. Nikiforova, Rachel Diaz, Rajiv Dhir, Simion I. Chiosea, Sumita Trivedi, Yuri E. Nikiforov, Shih-Fan Kuan, Manoj Gandhi, Aatur D. Singhi, Lindsey M. Kelly, Pengyuan Liu |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
endocrine system Multidisciplinary Point mutation Cancer Biology Biological Sciences medicine.disease Bioinformatics Fusion protein Fusion gene 03 medical and health sciences 030104 developmental biology 0302 clinical medicine 030220 oncology & carcinogenesis Cancer cell medicine Cancer research Thyroid cancer PI3K/AKT/mTOR pathway Insulin-like growth factor 1 receptor |
| Popis: | Thyroid cancer development is driven by known point mutations or gene fusions found in ∼90% of cases, whereas driver mutations in the remaining tumors are unknown. The insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) plays an important role in cancer, yet the mechanisms of its activation in cancer cells remain poorly understood. Using whole-transcriptome and whole-genome analyses, we identified a recurrent fusion between the thyroid adenoma-associated (THADA) gene on chromosome 2 and the LOC389473 gene on chromosome 7 located 12 kb upstream of the IGF2BP3 gene. We show that THADA fusion to LOC389473 and other regions in the vicinity does not result in the formation of a chimeric protein but instead leads to strong overexpression of the full-length IGF2BP3 mRNA and protein, increased IGF2 translation and IGF1 receptor (IGF1R) signaling via PI3K and MAPK cascades, and promotion of cell proliferation, invasion, and transformation. THADA fusions and IGF2BP3 overexpression are found in ∼5% of thyroid cancers that lack any other driver mutations. We also find that strong IGF2BP3 overexpression via gene fusion, amplification, or other mechanisms occurs in 5 to 15% of several other cancer types. Finally, we provide in vitro and in vivo evidence that growth of IGF2BP3-driven cells and tumors may be blocked by IGF1R inhibition, raising the possibility that IGF2BP3 overexpression in cancer cells may predict an anti-IGF1R benefit. |
| Databáze: | OpenAIRE |
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