Abstract
Objectives
Chemoresistance is one of the major obstacles for gastric cancer (GC) treatment. Exosome-mediated transfer of circular RNAs (circRNAs) is associated with the drug-resistance in GC. Circ_0032821 has been reported as an oncogene in GC. This study is designed to explore the function and mechanism of Exosomal circ_0032821 in oxaliplatin (OXA) resistance of GC.
Results
Circ_0032821 was highly expressed in OXA-resistant GC cells, and exosomes secreted by OXA-resistant GC cells. Moreover, circ_0032821-containing exosomes secreted by OXA-resistant GC cells could boost OXA resistance, proliferation, migration, and invasion in OXA-sensitive GC cells. The mechanical analysis discovered that circ_0032821 acted as a sponge of miR-515-5p to regulate SOX9 expression. Circ_0032821 silencing and OXA treatment repressed tumor growth in the GC mice model.
Conclusions
Exosomal circ_0032821 boosted OXA resistance of GC cells partly by the miR-515-5p/SOX9 axis, hinting a promising therapeutic target for GC treatment.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Azmi AS, Bao B, Sarkar FH (2013) Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review. Cancer Metastasis Rev 32:623–642. https://doi.org/10.1007/s10555-013-9441-9
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424. https://doi.org/10.3322/caac.21492
Chen JQ, Huang ZP, Li HF, Ou YL, Huo F, Hu LK (2020) MicroRNA-520f-3p inhibits proliferation of gastric cancer cells via targeting SOX9 and thereby inactivating Wnt signaling. Sci Rep 10:6197. https://doi.org/10.1038/s41598-020-63279-y
Cheshomi H, Matin MM (2018) Exosomes and their importance in metastasis, diagnosis, and therapy of colorectal cancer. J Cell Biochem. https://doi.org/10.1002/jcb.27582
Couto N, Caja S, Maia J, Strano Moraes MC, Costa-Silva B (2018) Exosomes as emerging players in cancer biology. Biochimie 155:2–10. https://doi.org/10.1016/j.biochi.2018.03.006
Couzin J (2005) Cell biology: the ins and outs of exosomes. Science 308:1862–1863. https://doi.org/10.1126/science.308.5730.1862
Ding C et al (2020) Exosome-mediated transfer of circRNA CircNFIX enhances temozolomide resistance in glioma. Cancer Lett 479:1–12. https://doi.org/10.1016/j.canlet.2020.03.002
Fanale D, Taverna S, Russo A, Bazan V (2018) Circular RNA in exosomes. Adv Exp Med Biol 1087:109–117. https://doi.org/10.1007/978-981-13-1426-1_9
Fu X et al (2018) Exosomal microRNA-32-5p induces multidrug resistance in hepatocellular carcinoma via the PI3K/Akt pathway. J Exp Clin Cancer Res 37:52. https://doi.org/10.1186/s13046-018-0677-7
Gong P, Xu R, Zhuang Q, He X (2020) A novel circular RNA (hsa_circRNA_102336), a plausible biomarker, promotes the tumorigenesis by sponging miR-515-5p in human bladder cancer. Biomed Pharmacother 126:110059. https://doi.org/10.1016/j.biopha.2020.110059
Hon KW, Ab-Mutalib NS (2019) Extracellular Vesicle-derived circular RNAs confers chemoresistance in Colorectal cancer. Sci Rep 9:16497. https://doi.org/10.1038/s41598-019-53063-y
Huang X et al (2019) Circular RNA AKT3 upregulates PIK3R1 to enhance cisplatin resistance in gastric cancer via miR-198 suppression. Mol Cancer 18:71. https://doi.org/10.1186/s12943-019-0969-3
Jiang Y, Zhang Y, Chu F, Xu L, Wu H (2020) Circ_0032821 acts as an oncogene in cell proliferation, metastasis and autophagy in human gastric cancer cells in vitro and in vivo through activating MEK1/ERK1/2 signaling pathway. Cancer Cell Int 20:74. https://doi.org/10.1186/s12935-020-1151-0
Li Y et al (2015) Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res 25:981–984. https://doi.org/10.1038/cr.2015.82
Li I, Nabet BY (2019) Exosomes in the tumor microenvironment as mediators of cancer therapy resistance. Mol Cancer 18:32. https://doi.org/10.1186/s12943-019-0975-5
Li B et al (2020a) Hsa_circ_0017639 expression promotes gastric cancer proliferation and metastasis by sponging miR-224-5p and upregulating USP3. Gene 750:144753. https://doi.org/10.1016/j.gene.2020.144753
Li J, Qin X, Wu R, Wan L, Zhang L, Liu R (2020b) Circular RNA circFBXO11 modulates hepatocellular carcinoma progress and oxaliplatin resistance through miR-605/FOXO3/ABCB1 axis. J Cell Mol Med 24:5152–5161. https://doi.org/10.1111/jcmm.15162
Lin S et al (2020) Oncogenic circular RNA Hsa-circ-000684 interacts with microRNA-186 to upregulate ZEB1 in gastric cancer. Faseb J. https://doi.org/10.1096/fj.201903246R
Liu S, Li X, Zhuang S (2019a) miR-30c impedes glioblastoma cell proliferation and migration by targeting SOX9. Oncol Res 27:165–171. https://doi.org/10.3727/096504018x15193506006164
Liu T et al (2019b) Exosome-transmitted miR-128-3p increase chemosensitivity of oxaliplatin-resistant colorectal cancer. Mol Cancer 18:43. https://doi.org/10.1186/s12943-019-0981-7
Liu X et al (2019c) Exosomal transfer of miR-501 confers doxorubicin resistance and tumorigenesis via targeting of BLID in gastric cancer. Cancer Lett 459:122–134. https://doi.org/10.1016/j.canlet.2019.05.035
Liu R, Zhang Y, Sun P, Wang C (2020a) DDP-resistant ovarian cancer cells-derived exosomal microRNA-30a-5p reduces the resistance of ovarian cancer cells to DDP. Open Biol 10:190173. https://doi.org/10.1098/rsob.190173
Liu Y, Chen S, Zong ZH, Guan X, Zhao Y (2020b) CircRNA WHSC1 targets the miR-646/NPM1 pathway to promote the development of endometrial cancer. J Cell Mol Med 24:6898–6907. https://doi.org/10.1111/jcmm.15346
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262
Pan L et al (2017) Exosomes-mediated transfer of long noncoding RNA ZFAS1 promotes gastric cancer progression. J Cancer Res Clin Oncol 143:991–1004. https://doi.org/10.1007/s00432-017-2361-2
Piao HY, Guo S (2020) Exosomal long non-coding RNA CEBPA-AS1 inhibits tumor apoptosis and functions as a non-invasive biomarker for diagnosis of gastric cancer. Onco Targets Ther 13:1365–1374. https://doi.org/10.2147/ott.s238706
Qi G, Li L (2020) Long non-coding RNA PVT1 contributes to cell growth and metastasis in non-small-cell lung cancer by regulating miR-361-3p/SOX9 axis and activating Wnt/β-catenin signaling pathway. Biomed Pharmacother 126:110100. https://doi.org/10.1016/j.biopha.2020.110100
Raposo G, Stoorvogel W (2013) Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 200:373–383. https://doi.org/10.1083/jcb.201211138
Sanderson BJ, Ferguson LR, Denny WA (1996) Mutagenic and carcinogenic properties of platinum-based anticancer drugs. Mutat Res 355:59–70. https://doi.org/10.1016/0027-5107(96)00022-x
Simons M, Raposo G (2009) Exosomes–vesicular carriers for intercellular communication. Curr Opin Cell Biol 21:575–581. https://doi.org/10.1016/j.ceb.2009.03.007
Song X et al (2020) circHMCU promotes proliferation and metastasis of breast cancer by sponging the let-7 family. Mol Ther Nucleic Acids 20:518–533. https://doi.org/10.1016/j.omtn.2020.03.014
Sun T et al (2020) Long non-coding RNA LEF1-AS1 promotes migration, invasion and metastasis of colon cancer cells through miR-30-5p/SOX9 axis. Onco Targets Ther 13:2957–2972. https://doi.org/10.2147/ott.s232839
Wagner T et al (1994) Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell 79:1111–1120. https://doi.org/10.1016/0092-8674(94)90041-8
Wang F, Nazarali AJ, Ji S (2016) Circular RNAs as potential biomarkers for cancer diagnosis and therapy. Am J Cancer Res 6:1167–1176
Wang X et al (2018) Exosomes serve as nanoparticles to deliver Anti-miR-214 to reverse chemoresistance to cisplatin in gastric cancer. Mol Ther 26:774–783. https://doi.org/10.1016/j.ymthe.2018.01.001
Wang M et al (2019) Paclitaxel–resistant gastric cancer MGC–803 cells promote epithelial–to–mesenchymal transition and chemoresistance in paclitaxel–sensitive cells via exosomal delivery of miR–155–5p. Int J Oncol 54:326–338. https://doi.org/10.3892/ijo.2018.4601
Wang D, Liu K, Chen E (2020a) LINC00511 promotes proliferation and invasion by sponging miR-515-5p in gastric cancer. Cell Mol Biol Lett 25:4. https://doi.org/10.1186/s11658-020-0201-x
Wang X, Xiang Z, Tsao GS, Tu W (2020b) Exosomes derived from nasopharyngeal carcinoma cells induce IL-6 production from macrophages to promote tumorigenesis. Cell Mol Immunol. https://doi.org/10.1038/s41423-020-0420-0
Wu X, Zheng Y, Han B, Dong X (2018) Long noncoding RNA BLACAT1 modulates ABCB1 to promote oxaliplatin resistance of gastric cancer via sponging miR-361. Biomed Pharmacother 99:832–838. https://doi.org/10.1016/j.biopha.2018.01.130
Yang AD et al (2006) Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines. Clin Cancer Res 12:4147–4153. https://doi.org/10.1158/1078-0432.ccr-06-0038
Yu Y, Yin W, Yu ZH, Zhou YJ, Chi JR, Ge J, Cao XC (2019) miR-190 enhances endocrine therapy sensitivity by regulating SOX9 expression in breast cancer. J Exp Clin Cancer Res 38:22. https://doi.org/10.1186/s13046-019-1039-9
Zhang H, Wang X, Huang H, Wang Y, Zhang F, Wang S (2019) Hsa_circ_0067997 promotes the progression of gastric cancer by inhibition of miR-515-5p and activation of X chromosome-linked inhibitor of apoptosis (XIAP). Artif Cells Nanomed Biotechnol 47:308–318. https://doi.org/10.1080/21691401.2018.1553787
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors have no conflict of interest to declare.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Zhong, Y., Wang, D., Ding, Y. et al. Circular RNA circ_0032821 contributes to oxaliplatin (OXA) resistance of gastric cancer cells by regulating SOX9 via miR-515-5p. Biotechnol Lett 43, 339–351 (2021). https://doi.org/10.1007/s10529-020-03036-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10529-020-03036-3