Abstract
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.
Graphical Abstract
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.
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Data availability
The datasets generated/analyzed during the current study are available.
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Abbreviations
- lncRNAs:
-
Long non-coding RNAs
- GC:
-
Gastric cancer
- CDX2:
-
Caudal-type homeobox-2
- CDX2:
-
Caudal-type homeobox-2
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Yu Wang and Feng Li designed the study. Rongke Jiang and Hongying Zhao collated the data, carried out data analyses, and produced the initial draft of the manuscript. Yanfang Li and Mei Zhu contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.
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The study was ratified by the ethics committee of Xuzhou Cancer Hospital, Xuzhou Third People’s Hospital. Animal experimental procedures were approved by the Animal Ethical Committee of Xuzhou Cancer Hospital, Xuzhou Third People’s Hospital.
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Supplementary Fig. 1
A, Representative image of colony formation assay in Fig. 2G. B, Representative image of Transwell assay in Fig. 2H (scale bar = 50 μm). C, Representative image of Scratch assay in Fig. 2I. D, Representative image of colony formation assay in Fig. 5E. E, Representative image of colony formation assay in Fig. 5F. F, Representative image of Transwell assay in Fig. 5G (scale bar = 50 μm). G, Representative image of Transwell assay in Fig. 5H (scale bar = 50 μm). H, Representative image of Scratch assay in Fig. 5I. I, Representative image of Scratch assay in Fig. 5J. J, Representative image of colony formation assay in Fig. 6D. K, Representative image of Transwell assay in Fig. 6E (scale bar = 50 μm). L, Representative image of Scratch assay in Fig. 6F. (PNG 10612 kb)
Supplementary Fig. 2
A, Representative pictures of metastatic nodules on the liver surface and quantitative statistics. B, Representative pictures of peritoneal metastatic nodules and quantitative statistics of the number of peritoneal metastatic tumor nodules in each group of nude mice (scale bar = 50 μm). * indicates p < 0.05 compared with the PBS group; # indicates p < 0.05 compared with the AGS + sh-NC-Exo group. Ten nude mice per group. Independent sample t-test was used for comparison between groups. One-way analysis of variance (ANOVA) was used for comparison between multiple groups, with a Tukey's post hoc test followed. Data comparison at different time points was performed by repeated measures ANOVA and Tukey's post hoc test. (PNG 7031 kb)
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Wang, Y., Jiang, R., Zhao, H. et al. TTN-AS1 delivered by gastric cancer cell–derived exosome induces gastric cancer progression through in vivo and in vitro studies. Cell Biol Toxicol 39, 557–571 (2023). https://doi.org/10.1007/s10565-022-09762-w
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DOI: https://doi.org/10.1007/s10565-022-09762-w