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THADA fusion is a mechanism of IGF2BP3 activation and IGF1R signaling in thyroid cancer. Proc Natl Acad Sci U S A 2017 02 28;114(9):2307-2312

Date

02/15/2017

Pubmed ID

28193878

Pubmed Central ID

PMC5338560

DOI

10.1073/pnas.1614265114

Scopus ID

2-s2.0-85014281044   20 Citations

Abstract

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.

Author List

Panebianco F, Kelly LM, Liu P, Zhong S, Dacic S, Wang X, Singhi AD, Dhir R, Chiosea SI, Kuan SF, Bhargava R, Dabbs D, Trivedi S, Gandhi M, Diaz R, Wald AI, Carty SE, Ferris RL, Lee AV, Nikiforova MN, Nikiforov YE

Author

Pengyuan Liu PhD Adjunct Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Antineoplastic Agents
Cell Line, Tumor
Cell Transformation, Neoplastic
Female
Gene Expression Regulation, Neoplastic
Genetic Loci
Genome-Wide Association Study
Humans
Imidazoles
Insulin-Like Growth Factor II
Mice
Mice, Nude
Mitogen-Activated Protein Kinases
Neoplasm Proteins
Oncogene Proteins, Fusion
Phosphatidylinositol 3-Kinases
Protein Biosynthesis
Protein Kinase Inhibitors
Pyrazines
RNA, Messenger
RNA-Binding Proteins
Receptors, Somatomedin
Signal Transduction
Thyroid Neoplasms
Xenograft Model Antitumor Assays
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