The RNA-Binding Proteins MCPIP2 and IGF2BP1 Competitively Modulate Breast Tumor Angiogenesis by Antagonizing VEGFA...

Tumor angiogenesis is essential for further growth and metastasis of solid tumors. However, the mechanisms underlying angiogenesis-related gene expression have yet to be clarified. Here, we discovered RNA-binding proteins monocyte chemotactic protein-induced protein 2 (MCPIP2) and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) function as a pair of antagonists that modulate breast tumor angiogenesis by competitively regulating mRNA stability of proangiogenic gene transcripts, including vascular endothelial growth factor A (VEGFA), Erb-B2 receptor tyrosine kinase 2 (ERBB2), interleukin-8 (IL8), C-X-C motif chemokine ligand 1 (CXCL1), and ephrin A1 (EFNA1). Mechanistically, MCPIP2 physically interacted with the stem-loop structures in the 3'-untranslated region of proangiogenic transcripts through its RNase domain to destabilize their mRNAs. Ribosomal proteins might be required for MCPIP2-mediated destabilization of proangiogenic mRNAs. On the other hand, IGF2BP1 can stabilize the proangiogenic mRNAs by binding to the common RNA stem-loop structures. Furthermore, we found that MCPIP2 expression in human breast tumors was repressed, whereas IGF2BP1 expression increased. Lower MCPIP2 expression and higher IGF2BP1 expression in human breast tumors were significantly associated with poor survival of breast cancer patients, respectively. Notably, there was a reversed correlation relationship between MCPIP2, IGF2BP1 expression, and proangiogenic gene expression in human breast tumor samples. Collectively, our results elucidate a novel mechanism by which MCPIP2 and IGF2BP1 competitively modulate the expression of proangiogenic transcripts, which provides new insights into antiangiogenic therapy of breast cancer.