UMDNJ-New Jersey Medical School, 185 South Orange Avenue, MSB E-585, Newark, NJ 07103, United States.
Exp Cell Res. 2012 Dec 10;318(20):2604-15. doi: 10.1016/j.yexcr.2012.09.002. Epub 2012 Sep 12.
Neurokinin 1 (NK1) encodes full-length (NK1-FL) and truncated (NK1-Tr) receptors, with distinct 3' UTR. NK1-Tr exerts oncogenic functions and is increased in breast cancer (BC). Enhanced transcription of NK1 resulted in higher level of NK1-Tr. The 3' UTR of these two transcripts are distinct with NK1-Tr terminating at a premature stop codon. NK1-Tr mRNA gained an advantage over NK1-FL with regards to translation. This is due to the ability of miR519B to interact with sequences within the 3' UTR of NK1-FL, but not NK1-Tr since the corresponding region is omitted. MiR519b suppressed the translation of NK1-FL in T47D and MDA-MB-231 resulting in increased NK1-Tr protein. Cytokines can induce the transcription of NK1. However, our studies indicated that translation appeared to be independent of cytokine production by the BC cells (BCCs). This suggested that transcription and translation of NK1 might be independent. The findings were validated in vivo. MiR-519b suppressed the growth of MDA-MB-231 in 7/10 nude BALB/c. In total, increased NK1-Tr in BCCs is due to enhanced transcription and suppressed translation of NK1-FL by miR-519b to reduced tumor growth. In summary, we report on miRNA as a method to further regulate the expression of a spiced variant to promote oncogenesis. In addition, the findings have implications for therapy with NK1 antagonists. The oncogenic effect of NK1-Tr must be considered to improve the efficacy of current drugs to NK1.
神经激肽 1（NK1）编码全长（NK1-FL）和截断（NK1-Tr）受体，具有不同的 3'UTR。NK1-Tr 发挥致癌作用，在乳腺癌（BC）中增加。NK1 的转录增强导致 NK1-Tr 的水平更高。这两个转录物的 3'UTR 不同，NK1-Tr 在提前终止密码子处终止。NK1-Tr mRNA 在翻译方面相对于 NK1-FL 具有优势。这是由于 miR519B 能够与 NK1-FL 的 3'UTR 内的序列相互作用，但不能与 NK1-Tr 相互作用，因为相应的区域被省略。miR519b 抑制 T47D 和 MDA-MB-231 中 NK1-FL 的翻译，导致 NK1-Tr 蛋白增加。细胞因子可以诱导 NK1 的转录。然而，我们的研究表明，翻译似乎独立于 BC 细胞（BCC）产生细胞因子。这表明 NK1 的转录和翻译可能是独立的。这一发现在体内得到了验证。miR-519b 在 7/10 只裸鼠 BALB/c 中抑制 MDA-MB-231 的生长。总之，BCC 中 NK1-Tr 的增加是由于 miR-519b 增强 NK1-FL 的转录和抑制翻译，导致肿瘤生长减少。总之，我们报告了 miRNA 作为进一步调节剪接变体表达以促进致癌作用的一种方法。此外，这些发现对 NK1 拮抗剂的治疗具有重要意义。必须考虑 NK1-Tr 的致癌作用，以提高现有药物对 NK1 的疗效。
