Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, Guangdong, China.
Center for Digestive Disease, the Seventh Affiliated Hospital of Sun Yat-sen University, 628 Zhenyuan Road, Shenzhen, 518000, Guangdong, China.
J Exp Clin Cancer Res. 2020 Jul 22;39(1):141. doi: 10.1186/s13046-020-01619-6.
BACKGROUND: Long non-coding RNA H19 was demonstrated to be significantly correlated with tumor metastasis. However, the specific functions of H19 in colorectal cancer (CRC) metastasis and the underlying mechanism are still largely unclear. METHODS: Use public database to screen the potential lncRNA crucial for metastasis in colorectal cancer. The expression of H19 in clinical CRC specimens was detected by qRT-PCR. The effect of H19 on the metastasis of CRC cells was investigated by transwell, wound healing assays, CCK-8 assays and animal studies. The potential proteins binding to H19 were identified by LC-MS and verified by RNA immunoprecipitation (RIP). The expression of indicated RNA and proteins were measured by qRT-PCR or western blot. RESULTS: We found the expression of lncRNA H19 was significantly upregulated in primary tumor and metastatic tissues, correlated with poor prognosis in CRC. Ectopic H19 expression promoted the metastasis of colorectal cancer cells in vitro and in vivo, and induced epithelial-to-mesenchymal transition (EMT). Mechanistically, H19 directly bound to hnRNPA2B1. Knockdown of hnRNPA2B1 attenuated the H19-induce migration and invasion in CRC cells. Furthermore, H19 stabilized and upregulated the expression of Raf-1 by facilitated the interaction between hnRNPA2B1 and Raf-1 mRNA, resulting in activation of Raf-ERK signaling. CONCLUSIONS: Our findings demonstrate the role of H19/hnRNPA2B1/EMT axis in regulation CRC metastasis, suggested H19 could be a potential biomarker to predict prognosis as well as a therapeutic strategy for CRC.
背景:长链非编码 RNA H19 被证明与肿瘤转移显著相关。然而,H19 在结直肠癌(CRC)转移中的具体功能及其潜在机制仍很大程度上不清楚。
方法:使用公共数据库筛选与结直肠癌转移相关的潜在关键 lncRNA。通过 qRT-PCR 检测临床 CRC 标本中 H19 的表达。通过 Transwell、划痕愈合实验、CCK-8 实验和动物研究来研究 H19 对 CRC 细胞转移的影响。通过 LC-MS 鉴定与 H19 结合的潜在蛋白,并通过 RNA 免疫沉淀(RIP)验证。通过 qRT-PCR 或 Western blot 测量指示 RNA 和蛋白质的表达。
结果:我们发现 lncRNA H19 的表达在原发肿瘤和转移组织中显著上调,与 CRC 的不良预后相关。异位 H19 表达促进结直肠癌细胞在体外和体内的转移,并诱导上皮间质转化(EMT)。机制上,H19 直接与 hnRNPA2B1 结合。hnRNPA2B1 的敲低减弱了 H19 诱导的 CRC 细胞迁移和侵袭。此外,H19 通过促进 hnRNPA2B1 和 Raf-1 mRNA 之间的相互作用,稳定并上调 Raf-1 的表达,从而激活 Raf-ERK 信号通路。
结论:我们的研究结果表明 H19/hnRNPA2B1/EMT 轴在调节 CRC 转移中的作用,提示 H19 可作为预测预后的潜在生物标志物,以及 CRC 的治疗策略。
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