Lu Wenbao, Li Hongwei, Liu Xueting, Li Ailing, Xiu Ruijuan
Institute of Microcirculation, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
FASEB J. 2025 May 31;39(10):e70594. doi: 10.1096/fj.202500461R.
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.
肿瘤血管生成对于实体瘤的进一步生长和转移至关重要。然而，血管生成相关基因表达的潜在机制尚未阐明。在此，我们发现RNA结合蛋白单核细胞趋化蛋白诱导蛋白2（MCPIP2）和胰岛素样生长因子2 mRNA结合蛋白1（IGF2BP1）作为一对拮抗剂发挥作用，通过竞争性调节包括血管内皮生长因子A（VEGFA）、表皮生长因子受体-2（ERBB2）、白细胞介素-8（IL8）、CXC趋化因子配体1（CXCL1）和ephrin A1（EFNA1）在内的促血管生成基因转录本的mRNA稳定性来调节乳腺肿瘤血管生成。从机制上讲，MCPIP2通过其RNase结构域与促血管生成转录本3'-非翻译区的茎环结构发生物理相互作用，从而使其mRNA不稳定。核糖体蛋白可能是MCPIP2介导的促血管生成mRNA不稳定所必需的。另一方面，IGF2BP1可以通过与常见的RNA茎环结构结合来稳定促血管生成mRNA。此外，我们发现人乳腺肿瘤中MCPIP2的表达受到抑制，而IGF2BP1的表达增加。人乳腺肿瘤中较低的MCPIP2表达和较高的IGF2BP1表达分别与乳腺癌患者的不良生存显著相关。值得注意的是，在人乳腺肿瘤样本中，MCPIP2、IGF2BP1表达与促血管生成基因表达之间存在反向相关关系。总体而言，我们的结果阐明了一种新机制，即MCPIP2和IGF2BP1竞争性调节促血管生成转录本的表达，这为乳腺癌的抗血管生成治疗提供了新的见解。
