Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
EMBO Rep. 2021 Dec 6;22(12):e52124. doi: 10.15252/embr.202052124. Epub 2021 Oct 14.
This study explores the role of the long noncoding RNA (LncRNA) CRNDE in cisplatin (CDDP) resistance of gastric cancer (GC) cells. Here, we show that LncRNA CRNDE is upregulated in carcinoma tissues and tumor-associated macrophages (TAMs) of GC patients. In vitro experiments show that CRNDE is enriched in M2-polarized macrophage-derived exosomes (M2-exo) and is transferred from M2 macrophages to GC cells via exosomes. Silencing CRNDE in M2-exo reverses the promotional effect of M2-exo on cell proliferation in CDDP-treated GC cells and homograft tumor growth in CDDP-treated nude mice. Mechanistically, CRNDE facilitates neural precursor cell expressed developmentally downregulated protein 4-1 (NEDD4-1)-mediated phosphatase and tensin homolog (PTEN) ubiquitination. Silencing CRNDE in M2-exo enhances the CDDP sensitivity of GC cells treated with M2-exo, which is reduced by PTEN knockdown. Collectively, these data reveal a vital role for CRNDE in CDDP resistance of GC cells and suggest that the upregulation of CRNDE in GC cells may be attributed to the transfer of TAM-derived exosomes.
本研究探讨了长链非编码 RNA（LncRNA）CRNDE 在胃癌（GC）细胞顺铂（CDDP）耐药中的作用。研究结果表明，LncRNA CRNDE 在 GC 患者的癌组织和肿瘤相关巨噬细胞（TAM）中上调。体外实验表明，CRNDE 富集于 M2 极化巨噬细胞衍生的外泌体（M2-exo）中，并通过外泌体从 M2 巨噬细胞转移至 GC 细胞。沉默 M2-exo 中的 CRNDE 可逆转 M2-exo 对 CDDP 处理的 GC 细胞增殖和 CDDP 处理的裸鼠同种移植肿瘤生长的促进作用。机制上，CRNDE 促进了神经前体细胞表达发育下调蛋白 4-1（NEDD4-1）介导的磷酸酶和张力蛋白同源物（PTEN）泛素化。沉默 M2-exo 中的 CRNDE 可增强经 M2-exo 处理的 GC 细胞对 CDDP 的敏感性，而 PTEN 敲低可降低这种敏感性。综上所述，这些数据揭示了 CRNDE 在 GC 细胞 CDDP 耐药中的重要作用，并表明 GC 细胞中 CRNDE 的上调可能归因于 TAM 衍生的外泌体的转移。
