Liver Disease Department of Integrative Medicine, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315000, China; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Department of Medical Oncology & Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Int J Biol Macromol. 2024 Jul;273(Pt 2):133112. doi: 10.1016/j.ijbiomac.2024.133112. Epub 2024 Jun 14.
Tumor metastasis is the leading cause of cancer-related death in patients with colorectal cancer (CRC). Heterogeneous nuclear ribonucleoproteins (hnRNPs) are RNA-binding proteins, involved in the tumorigenesis and metastasis of various cancers. However, the molecular mechanisms of hnRNPs in CRC metastasis remain unclear. This study aims to uncover the pivotal roles and molecular mechanisms of hnRNPs in CRC metastasis. Clinical database analysis suggested that the expression of hnRNP-Associated with Lethal Yellow (RALY, an important member of hnRNPs) was strongly correlated with the aggressiveness and survival of CRC patients. Gain- and loss-of-function studies demonstrated that RALY promotes the production of exosomes by increasing the formation of multivesicular bodies (MVBs) and enhancing the fusion of MVBs with the plasma membrane. Notably, RALY directly interacts with phospholipase D2 (PLD2) to enable exosome biogenesis, and cooperates with RBM15b to control PLD2 mRNA stability in an m6A-dependent manner. RALY-mediated exosome secretion activates pro-tumor macrophages and further facilitates CRC metastasis, while rescue experiments in vivo further confirmed that RALY-mediated exosome biogenesis facilitates CRC metastasis. Collectively, our findings demonstrate that RALY promotes exosome biogenesis and facilitates colorectal cancer metastasis by upregulating PLD2 and enhancing exosome production in an m6A-dependent manner, suggesting potential therapeutic strategies for combating CRC metastasis.
肿瘤转移是导致结直肠癌(CRC)患者癌症相关死亡的主要原因。异质性核核糖核蛋白(hnRNPs)是 RNA 结合蛋白,参与多种癌症的发生和转移。然而,hnRNPs 在 CRC 转移中的分子机制尚不清楚。本研究旨在揭示 hnRNPs 在 CRC 转移中的关键作用和分子机制。临床数据库分析表明,hnRNPs 相关致死性黄(RALY,hnRNPs 的重要成员)的表达与 CRC 患者的侵袭性和生存密切相关。功能获得和缺失研究表明,RALY 通过增加多泡体(MVBs)的形成并增强 MVB 与质膜的融合来促进外泌体的产生。值得注意的是,RALY 直接与磷脂酶 D2(PLD2)相互作用以促进外泌体的生物发生,并与 RBM15b 合作以 m6A 依赖性方式控制 PLD2 mRNA 的稳定性。RALY 介导的外泌体分泌激活促肿瘤巨噬细胞,进一步促进 CRC 转移,而体内的挽救实验进一步证实 RALY 介导的外泌体生物发生促进 CRC 转移。总之,我们的研究结果表明,RALY 通过上调 PLD2 和增强 m6A 依赖性外泌体的产生来促进外泌体的生物发生,并促进结直肠癌的转移,提示了针对 CRC 转移的潜在治疗策略。