Department of General Surgery, Xuzhou Cancer Hospital, Xuzhou Third People's Hospital, Xuzhou, 221000, People's Republic of China.
Department of Hematology and Oncology, Xuzhou Cancer Hospital, Xuzhou Third People's Hospital, Xuzhou, 221000, People's Republic of China.
Cell Biol Toxicol. 2023 Apr;39(2):557-571. doi: 10.1007/s10565-022-09762-w. Epub 2022 Oct 10.
Extracellular communication within the tumor microenvironment exerts critical functions in tumor progression. Moreover, exosomes are capable of packaging into long non-coding RNAs (lncRNAs) to regulate extracellular communication. We tried to discuss the role of exosomal lncRNA TTN-AS1 and its molecular mechanism on gastric cancer (GC) progression. Bioinformatics analysis depicted increased TTN-AS1 in GC which shared correlation with poor prognosis. Clinical tissue and cellular experiments also confirmed the elevation of TTN-AS1 in GC tissues and cells. GC cell (AGS)-derived Exo could be uptake by NCI-N87 cells to induce malignant features of GC cells. Functionally, TTN-AS1 could upregulate ZEB1 expression by binding to miR-499a-5p. In addition, in vitro experiments demonstrated that ZEB1 targeted and activated CDX2 transcription and promoted CDX2 expression; silencing CDX2 inhibited malignant phenotypes of AGS and NCI-N87 cells. Furthermore, Exo-TTN-AS1 promoted GC cell growth and migration by promoting CDX2 expression. Exosomal TTN-AS1 from GC cells could also promote metastasis of GC in vivo. In conclusion, our findings provided evidence describing that exosomes derived from GC cells transferred TTN-AS1 to GC cells, which aggravate GC through the miR-499a-5p/ZEB1/CDX2 axis. 1. Exo derived from GC cells promotes the growth and metastasis of GC cells by carrying TTN-AS1. 2. TTN-AS1 acts as a ceRNA to adsorb miR-499a-5p to regulate the expression of ZEB1. 3. ZEB1 targets and activates CDX2 transcription. 4. GC cell-derived Exo-TTN-AS1 enhances the growth and metastasis of GC cell xenografts in vivo.
肿瘤微环境中的细胞外通讯在肿瘤进展中发挥着关键作用。此外，外泌体能够将长链非编码 RNA（lncRNA）包装起来，从而调节细胞外通讯。我们试图探讨外泌体 lncRNA TTN-AS1 的作用及其对胃癌（GC）进展的分子机制。生物信息学分析表明，GC 中 TTN-AS1 水平升高，与预后不良相关。临床组织和细胞实验也证实了 GC 组织和细胞中 TTN-AS1 的升高。GC 细胞（AGS）衍生的外泌体可被 NCI-N87 细胞摄取，诱导 GC 细胞发生恶性特征。功能上，TTN-AS1 可通过与 miR-499a-5p 结合而上调 ZEB1 的表达。此外，体外实验表明，ZEB1 靶向并激活 CDX2 转录，促进 CDX2 表达；沉默 CDX2 抑制了 AGS 和 NCI-N87 细胞的恶性表型。此外，外泌体 TTN-AS1 通过促进 CDX2 表达促进 GC 细胞的生长和迁移。GC 细胞来源的外泌体 TTN-AS1 也可促进 GC 在体内的转移。总之，我们的研究结果提供了证据，描述了 GC 细胞来源的外泌体将 TTN-AS1 转移到 GC 细胞，通过 miR-499a-5p/ZEB1/CDX2 轴加重 GC。1. 来自 GC 细胞的外泌体通过携带 TTN-AS1 促进 GC 细胞的生长和转移。2. TTN-AS1 作为 ceRNA 吸附 miR-499a-5p 调节 ZEB1 的表达。3. ZEB1 靶向并激活 CDX2 转录。4. GC 细胞来源的 Exo-TTN-AS1 增强 GC 细胞异种移植在体内的生长和转移。
