fusion is a mechanism of IGF2BP3 activation and IGF1R signaling in thyroid cancer. Panebianco Federica,Kelly Lindsey M,Liu Pengyuan,Zhong Shan,Dacic Sanja,Wang Xiaosong,Singhi Aatur D,Dhir Rajiv,Chiosea Simion I,Kuan Shih-Fan,Bhargava Rohit,Dabbs David,Trivedi Sumita,Gandhi Manoj,Diaz Rachel,Wald Abigail I,Carty Sally E,Ferris Robert L,Lee Adrian V,Nikiforova Marina N,Nikiforov Yuri E Proceedings of the National Academy of Sciences of the United States of America 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 () gene on chromosome 2 and the gene on chromosome 7 located 12 kb upstream of the gene. We show that fusion to 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. 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. 10.1073/pnas.1614265114

IGF2BP3 From Physiology to Cancer: Novel Discoveries, Unsolved Issues, and Future Perspectives. Mancarella Caterina,Scotlandi Katia Frontiers in cell and developmental biology RNA network control is a key aspect of proper cellular homeostasis. In this context, RNA-binding proteins (RBPs) play a major role as regulators of the RNA life cycle due to their capability to bind to RNA sequences and precisely direct nuclear export, translation/degradation rates, and the intracellular localization of their target transcripts. Alterations in RBP expression or functions result in aberrant RNA translation and may drive the emergence and progression of several pathological conditions, including cancer. Among the RBPs, insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is of particular interest in tumorigenesis and tumor progression. This review highlights the molecular mechanisms underlying the oncogenic functions of IGF2BP3, summarizes the therapeutic potential related to its inhibition and notes the fundamental issues that remain unanswered. To fully exploit IGF2BP3 for tumor diagnosis and therapy, it is crucial to dissect the mechanisms governing IGF2BP3 re-expression and to elucidate the complex interactions between IGF2BP3 and its target mRNAs as normal cells become tumor cells. 10.3389/fcell.2019.00363

miR-9-5p Inhibits Skeletal Muscle Satellite Cell Proliferation and Differentiation by Targeting IGF2BP3 through the IGF2-PI3K/Akt Signaling Pathway. Yin Huadong,He Haorong,Shen Xiaoxu,Zhao Jing,Cao Xinao,Han Shunshun,Cui Can,Chen Yuqi,Wei Yuanhang,Xia Lu,Wang Yan,Li Diyan,Zhu Qing International journal of molecular sciences MicroRNAs are evolutionarily conserved, small non-coding RNAs that play critical post-transcriptional regulatory roles in skeletal muscle development. We previously found that miR-9-5p is abundantly expressed in chicken skeletal muscle. Here, we demonstrate a new role for miR-9-5p as a myogenic microRNA that regulates skeletal muscle development. The overexpression of miR-9-5p significantly inhibited the proliferation and differentiation of skeletal muscle satellite cells (SMSCs), whereas miR-9-5p inhibition had the opposite effect. We show that insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is a target gene of miR-9-5p, using dual-luciferase assays, RT-qPCR, and Western Blotting, and that it promotes proliferation and differentiation of SMSCs. In addition, we found that IGF2BP3 regulates IGF-2 expression, using overexpression and knockdown studies. We show that Akt is activated by IGF2BP3 and is essential for IGF2BP3-induced cell development. Together, our results indicate that miR-9-5p could regulate the proliferation and differentiation of myoblasts by targeting IGF2BP3 through IGF-2 and that this activity results in the activation of the PI3K/Akt signaling pathway in skeletal muscle cells. 10.3390/ijms21051655