Department of Colorectal Cancer, Cancer Hospital of Tianjin Medical University, Key Laboratory of Cancer Prevention and Therapy, and National Clinical Research Center of Cancer, Tianjin 300060, P.R. China.
Int J Oncol. 2019 Mar;54(3):955-965. doi: 10.3892/ijo.2019.4691. Epub 2019 Jan 18.
RNA‑binding proteins (RBPs) play a fundamental role in the recurrence and metastasis of colorectal cancer (CRC). In this study, we identified muscleblind‑like 1 (MBNL1), an RBP implicated in developmental control, as a robust suppressor of CRC cell metastasis in vitro. By using a scratch assay coupled with time‑lapse live cell imaging, our findings revealed that the knockdown of MBNL1 induced epithelial‑to‑mesenchymal transition (EMT)‑like morphological changes in the HCT‑116 cells, accompanied by an enhanced cell motility, and by the downregulation of E‑cadherin and the upregulation of Snail expression. By contrast, the ectopic overexpression of MBNL1 suppressed EMT, characterized by the upregulation of E‑cadherin and the downregulation of Snail expression. Mechanistically, Snail rather than E‑cadherin, was identified as a direct downstream target gene of MBNL1. The ectopic the overexpression of MBNL1 markedly enhanced the recruitment of Snail transcripts to processing bodies (P‑bodies), leading to the increased degradation of Snail mRNA and consequent translational silencing. Furthermore, the effect of MBNL1 on CRC cell migration was confirmed in additional CRC cell lines. SW480 and HT‑29 cells exhibited similar changes in migratory capacity and the expression of Snail/E‑cadherin to those observed in HCT‑116 cells. On the whole, this study demonstrates that MBNL1 destabilizes Snail transcripts and, in turn, suppresses the EMT of CRC cells through the Snail/E‑cadherin axis in vitro. Therefore, this EMT‑related MBNL1/Snail/E‑cadherin axis may prove to be a novel therapeutic target for CRC metastasis.
RNA 结合蛋白（RBPs）在结直肠癌（CRC）的复发和转移中起着至关重要的作用。在这项研究中，我们鉴定出肌肉缺失样 1（MBNL1），一种参与发育调控的 RBP，作为体外 CRC 细胞转移的强大抑制剂。通过划痕实验和延时实时细胞成像，我们的发现表明，MBNL1 的敲低诱导 HCT-116 细胞发生上皮-间充质转化（EMT）样形态变化，伴随增强的细胞迁移能力，以及 E-钙黏蛋白的下调和 Snail 表达的上调。相反，MBNL1 的异位过表达抑制 EMT，表现为 E-钙黏蛋白的上调和 Snail 表达的下调。从机制上讲，Snail 而不是 E-钙黏蛋白被鉴定为 MBNL1 的直接下游靶基因。MBNL1 的异位过表达显著增强了 Snail 转录物到处理体（P 体）的募集，导致 Snail mRNA 的降解增加和随后的翻译沉默。此外，MBNL1 对其他 CRC 细胞系中 CRC 细胞迁移的影响也得到了证实。SW480 和 HT-29 细胞表现出与 HCT-116 细胞相似的迁移能力变化和 Snail/E-钙黏蛋白表达。总的来说，这项研究表明，MBNL1 使 Snail 转录物不稳定，并通过 Snail/E-钙黏蛋白轴在体外抑制 CRC 细胞的 EMT。因此，这个 EMT 相关的 MBNL1/Snail/E-钙黏蛋白轴可能成为 CRC 转移的一个新的治疗靶点。
