Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, and Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China.
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China.
Mol Cancer. 2019 Apr 13;18(1):87. doi: 10.1186/s12943-019-1014-2.
Long noncoding RNAs (lncRNAs) have emerged as critical players in cancer progression, but their functions in colorectal cancer (CRC) metastasis have not been systematically clarified.
lncRNA expression profiles in matched normal and CRC tissue were checked using microarray analysis. The biological roles of a novel lncRNA, namely RP11-138 J23.1 (RP11), in development of CRC were checked both in vitro and in vivo. Its association with clinical progression of CRC was further analyzed.
RP11 was highly expressed in CRC tissues, and its expression increased with CRC stage in patients. RP11 positively regulated the migration, invasion and epithelial mesenchymal transition (EMT) of CRC cells in vitro and enhanced liver metastasis in vivo. Post-translational upregulation of Zeb1, an EMT-related transcription factor, was essential for RP11-induced cell dissemination. Mechanistically, the RP11/hnRNPA2B1/mRNA complex accelerated the mRNA degradation of two E3 ligases, Siah1 and Fbxo45, and subsequently prevented the proteasomal degradation of Zeb1. mA methylation was involved in the upregulation of RP11 by increasing its nuclear accumulation. Clinical analysis showed that mA can regulate the expression of RP11, further, RP11 regulated Siah1-Fbxo45/Zeb1 was involved in the development of CRC.
mA-induced lncRNA RP11 can trigger the dissemination of CRC cells via post-translational upregulation of Zeb1. Considering the high and specific levels of RP11 in CRC tissues, our present study paves the way for further investigations of RP11 as a predictive biomarker or therapeutic target for CRC.
长链非编码 RNA（lncRNA）已成为癌症进展的关键参与者，但它们在结直肠癌（CRC）转移中的功能尚未得到系统阐明。
使用微阵列分析检查匹配的正常和 CRC 组织中的 lncRNA 表达谱。在体外和体内检查一种新型 lncRNA，即 RP11-138J23.1（RP11）在 CRC 发展中的生物学作用。进一步分析其与 CRC 临床进展的相关性。
RP11 在 CRC 组织中高表达，其表达在患者中随 CRC 分期增加而增加。RP11 可正向调节 CRC 细胞的迁移、侵袭和上皮间质转化（EMT），并增强体内肝转移。EMT 相关转录因子 Zeb1 的翻译后上调对于 RP11 诱导的细胞扩散至关重要。从机制上讲，RP11/hnRNPA2B1/mRNA 复合物加速了两个 E3 连接酶 Siah1 和 Fbxo45 的 mRNA 降解，随后阻止了 Zeb1 的蛋白酶体降解。mA 甲基化通过增加其核积累参与 RP11 的上调。临床分析表明，mA 可以调节 RP11 的表达，进一步表明，RP11 调节 Siah1-Fbxo45/Zeb1 参与 CRC 的发展。
mA 诱导的 lncRNA RP11 可以通过 Zeb1 的翻译后上调触发 CRC 细胞的扩散。鉴于 RP11 在 CRC 组织中的高特异性水平，我们的研究为进一步研究 RP11 作为 CRC 的预测生物标志物或治疗靶点铺平了道路。
