Circ_0081143 Contributes to Gastric Cancer Malignant Development and Doxorubicin Resistance by Elevating the Expression of YES1 by Targeting mziR-129-2-3p
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Background/Aims: The increased mortality of gastric cancer (GC) is mainly attributed to the development of chemoresistance. Circular RNAs, as the novel type of biomarkers in GC, have attracted wide attention. The purpose of this study was to investigate the functional role of circ_0081143 in GC with doxorubicin (DR) resistance and its potential action mechanism. Methods: The expression of circ_0081143, miR-129-2-3p and YES proto-oncogene 1 (YES1) in GC tissues and cells was measured by quantitative real-time polymerase chain reaction. The half maximal inhibitory concentration value was calculated based on the MTT cell viability assay. Cell proliferation and apoptosis were monitored by MTT and flow cytometry assays. Transwell assays were employed to check cell migration and invasion. The protein levels of YES1 and apoptosis-related proteins were detected by western blotting. The interaction between miR-129-2-3p and circ_0081143 or YES1 was verified by dual-luciferase reporter and pull-down assays. A tumorigenicity assay was conducted to verify the role of circ_0081143 in vivo. Results: Circ_0081143 was highly expressed in DR-resistant GC tumor tissues and cells. Depletion of circ_0081143 reduced DR resistance and inhibited DR-resistant GC cell proliferation, migration and invasion. Circ_0081143 targeted miR-129-2-3p and inhibited the role of miR-129-2-3p. In addition, YES1 was a target of miR-129-2-3p, and its function was suppressed by miR-129-2-3p. Importantly, circ_0081143 positively modulated the expression of YES1 through mediating miR-129-2-3p. Circ_0081143 knockdown weakened the DR-resistant GC tumor growth in vivo. Conclusions: Circ_0081143 knockdown weakened DR resistance and blocked the development of DR-resistant GC by regulating the miR-129-2-3p/YES1 axis. Our data suggest that circ_0081143 is a promising target for the treatment of GC with DR resistance.
Abstract
Background/Aims: The increased mortality of gastric cancer (GC) is mainly attributed to the development of chemoresistance. Circular RNAs, as the novel type of biomarkers in GC, have attracted wide attention. The purpose of this study was to investigate the functional role of circ_0081143 in GC with doxorubicin (DR) resistance and its potential action mechanism. Methods: The expression of circ_0081143, miR-129-2-3p and YES proto-oncogene 1 (YES1) in GC tissues and cells was measured by quantitative real-time polymerase chain reaction. The half maximal inhibitory concentration value was calculated based on the MTT cell viability assay. Cell proliferation and apoptosis were monitored by MTT and flow cytometry assays. Transwell assays were employed to check cell migration and invasion. The protein levels of YES1 and apoptosis-related proteins were detected by western blotting. The interaction between miR-129-2-3p and circ_0081143 or YES1 was verified by dual-luciferase reporter and pull-down assays. A tumorigenicity assay was conducted to verify the role of circ_0081143 in vivo. Results: Circ_0081143 was highly expressed in DR-resistant GC tumor tissues and cells. Depletion of circ_0081143 reduced DR resistance and inhibited DR-resistant GC cell proliferation, migration and invasion. Circ_0081143 targeted miR-129-2-3p and inhibited the role of miR-129-2-3p. In addition, YES1 was a target of miR-129-2-3p, and its function was suppressed by miR-129-2-3p. Importantly, circ_0081143 positively modulated the expression of YES1 through mediating miR-129-2-3p. Circ_0081143 knockdown weakened the DR-resistant GC tumor growth in vivo. Conclusions: Circ_0081143 knockdown weakened DR resistance and blocked the development of DR-resistant GC by regulating the miR-129-2-3p/YES1 axis. Our data suggest that circ_0081143 is a promising target for the treatment of GC with DR resistance.
참고문헌 (28)
- Ferlay J, "Cancer incidence and mortality worldwide : sources, methods and major patterns in GLOBOCAN 2012", Int J Cancer, 136, pp.E359~E386 (2015)
- Siegel RL, "Cancer statistics, 2017", CA Cancer J Clin, 67, pp.7~30 (2017)
- Figueiredo C, "Pathogenesis of gastric cancer : genetics and molecular classification", Curr Top Microbiol Immunol, 400, pp.277~304 (2017)
- Ferro A, "Worldwide trends in gastric cancer mortality(1980-2011), with predictions to 2015, and incidence by subtype", Eur J Cancer, 50, pp.1330~1344 (2014)
- Russo A, "Differences in the multimodal treatment of gastric cancer : east versus west", J Surg Oncol, 115, pp.603~614 (2017)
- Marin JJ, "Mechanisms of resistance to chemotherapy in gastric cancer", Anticancer Agents Med Chem, 16, pp.318~334 (2016)
- Padmanabhan N, "How to stomach an epigenetic insult : the gastric cancer epigenome", Nat Rev Gastroenterol Hepatol, 14, pp.467~478 (2017)
- Kristensen LS, "Circular RNAs in cancer : opportunities and challenges in the field", Oncogene, 37, pp.555~565 (2018)
- Ashwal-Fluss R, "circRNA biogenesis competes with pre-mRNA splicing", Mol Cell, 56, pp.55~66 (2014)
- Rybak-Wolf A, "Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed", Mol Cell, 58, pp.870~885 (2015)
- Memczak S, "Circular RNAs are a large class of animal RNAs with regulatory potency", Nature, 495, pp.333~338 (2013)
- Zhao ZJ, "Circular RNA participates in the carcinogenesis and the malignant behavior of cancer", RNA Biol, 14, pp.514~521 (2017)
- Huang X, "Circular RNA AKT3 upregulates PIK3R1 to enhance cisplatin resistance in gastric cancer via miR-198 suppression", Mol Cancer, 18, pp.71~ (2019)
- Kulcheski FR, "Circular RNAs are miRNA sponges and can be used as a new class of biomarker", J Biotechnol, 238, pp.42~51 (2016)
- Gu S, "Biological basis for restriction of microRNA targets to the 3' untranslated region in mammalian mRNAs", Nat Struct Mol Biol, 16, pp.144~150 (2009)
- Tang X, "Downregulation of miR-129-2by promoter hypermethylation regulates breast cancer cell proliferation and apoptosis", Oncol Rep, 35, pp.2963~2969 (2016)
- Zhao S, "MicroRNA-140 inhibit prostate cancer cell invasion and migration by targeting YES protooncogene 1", J Cell Biochem, 121, pp.482~488 (2020)
- Hansen RK, "Hsp27-induced MMP-9 expression is influenced by the Src tyrosine protein kinase yes", Biochem Biophys Res Commun, 282, pp.186~193 (2001)
- Liu L, "Long noncoding RNA H19 competitively binds miR-17-5p to regulate YES1expression in thyroid cancer", FEBS J, 283, pp.2326~2339 (2016)
- Hamanaka N, "YES1 is a targetable oncogene in cancers harboring YES1 gene amplification", Cancer Res, 79, pp.5734~5745 (2019)
- Hao S, "Identification of key genes and circular RNAs in human gastric cancer", Med Sci Monit, 25, pp.2488~2504 (2019)
- Cao L, "Identification of hub genes and potential molecular mechanisms in gastric cancer by integrated bioinformatics analysis", PeerJ, 6, pp.e5180~ (2018)
- Xue M, "hsa_circ_0081143 promotes cisplatin resistance in gastric cancer by targeting miR-646", CDK6 pathway, 2019, pp.19, 25~
- Yu X, "Growth inhibitory effects of three miR-129 family members on gastric cancer", Gene, 532, pp.87~93 (2013)
- Yu X, "Gastric juice miR-129 as a potential biomarker for screening gastric cancer", Med Oncol, 30, pp.365~ (2013)
- Yoshioka T, "Acquired resistance mechanisms to afatinib in HER2-amplified gastric cancer cells", Cancer Sci, 110, pp.2549~2557 (2019)
- Fang Z, "miR-140-5p suppresses the proliferation, migration and invasion of gastric cancer by regulating YES1", Mol Cancer, 16, pp.139~ (2017)
- Iida M, "Yes and Lyn play a role in nuclear translocation of the epidermal growth factor receptor", Oncogene, 32, pp.759~767 (2013)