State Key Laboratory of Cellular Stress Biology and Department of Biomedical Sciences, School of Life Sciences, Xiamen University, Xiamen, People's Republic of China.
Gut. 2013 May;62(5):716-26. doi: 10.1136/gutjnl-2011-301083. Epub 2012 Apr 5.
Deficiency or reduced expression of signal transduction and activation of RNA family protein Quaking (Qki) is associated with developmental defects in neural and vascular tissues and the development of debilitating human diseases including colorectal cancer (CRC). However, the mechanisms underlying the aberrant downregulation or deficiency of Qki were uncertain.
Expression of miR-574-5p, Qki5/6/7/7b splicing variants, β-catenin and p27(Kip1) was determined in mouse and human CRC cells and tissues to investigate the post-transcriptional regulation of Qki isoforms by miR-574-5p and its impact on β-catenin/p27(Kip1) signalling, cell cycle progression, proliferation, migration, invasion and tumour growth.
In the CRC tissues of C57BL/6-Apc(min/+) mice, miR-574-5p was found to be significantly upregulated and negatively correlated with the expression of Qki but positively correlated with the expression of β-catenin. In mouse and human CRC cells, miR-574-5p was shown to regulate Qki isoforms (Qki6/7 in particular) post-transcriptionally and caused altered expression in β-catenin and p27(Kip1) , increased proliferation, migration and invasion and decreased differentiation and cell cycle exit. Furthermore, in clinical CRC tissues, miR-574-5p was shown to be greatly upregulated and inversely correlated with the expression of Qkis. Finally, inhibition of miR-574-5p was shown to suppress the growth of tumours in the nude mice.
Together, these novel findings suggest that miR-574-5p is a potent ribo-regulator for Qkis and that aberrant miR-574-5p upregulation can be oncogenic.
信号转导和 RNA 家族蛋白 Quaking（Qki）的表达缺失或下调与神经和血管组织的发育缺陷以及包括结直肠癌（CRC）在内的使人虚弱的人类疾病的发展有关。然而，Qki 异常下调或缺失的机制尚不清楚。
在小鼠和人 CRC 细胞和组织中测定 miR-574-5p、Qki5/6/7/7b 剪接变体、β-连环蛋白和 p27(Kip1)的表达，以研究 miR-574-5p 对 Qki 异构体的转录后调控及其对 β-连环蛋白/p27(Kip1)信号、细胞周期进程、增殖、迁移、侵袭和肿瘤生长的影响。
在 C57BL/6-Apc(min/+)小鼠的 CRC 组织中，发现 miR-574-5p 显著上调，与 Qki 的表达呈负相关，与 β-连环蛋白的表达呈正相关。在小鼠和人 CRC 细胞中，miR-574-5p 被证明可以在转录后水平调节 Qki 异构体（特别是 Qki6/7），导致 β-连环蛋白和 p27(Kip1)的表达改变，增殖、迁移和侵袭增加，分化和细胞周期退出减少。此外，在临床 CRC 组织中，发现 miR-574-5p 显著上调，与 Qki 的表达呈负相关。最后，抑制 miR-574-5p 可抑制裸鼠肿瘤的生长。
总之，这些新发现表明 miR-574-5p 是 Qki 的一种有效的核糖调节因子，异常的 miR-574-5p 上调可能具有致癌性。
