Circular RNA FOXO3 accelerates glycolysis and improves cisplatin sensitivity in lung cancer cells via the miR‑543/Foxo3 axis

Zhang,Yanni; Ge,Pan; Zhou,Dangxia; Xing,Rong; Bai,Lizhi

doi:10.3892/ol.2021.13100

Circular RNA FOXO3 accelerates glycolysis and improves cisplatin sensitivity in lung cancer cells via the miR‑543/Foxo3 axis

Authors:
- Yanni Zhang
- Pan Ge
- Dangxia Zhou
- Rong Xing
- Lizhi Bai
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Affiliations: Department of Emergency Respiratory, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P.R. China, Department of Pathology and Pathophysiology, School of Medicine, Xi'an Jiaotong University, Xian, Shanxi 710049, P.R. China, Department of Pathology and Pathophysiology, Dalian Medical University, Dalian, Liaoning 116023, P.R. China, Department of Thoracic Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P.R. China
Published online on: October 18, 2021 https://doi.org/10.3892/ol.2021.13100
Article Number: 839
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Non‑small cell lung cancer (NSCLC) is the most common cause of cancer‑associated mortality worldwide. Our previous study revealed that circular RNA (circRNA)‑FOXO3 is highly expressed in lung cancer and inhibits cell proliferation. However, to the best of our knowledge, at present, no study has focused on the specific mechanism of circRNA‑FOXO3 in drug resistance. Therefore, the present study aimed to provide novel perspectives on the role of circRNA‑FOXO3 in cisplatin (DDP) resistance in NSCLC. A Cell Counting Kit‑8 assay was used to determine the viability of cells overexpressed with circRNA‑FOXO3 and under DDP treatment. Glycolysis was analyzed by measuring glucose consumption and lactate production. The interaction of circRNA‑FOXO3, microRNA 543 (miR‑543) and Foxo3 was confirmed using a dual‑luciferase reporter assay. It was revealed that circRNA‑FOXO3 improved cell sensitivity to DDP and repressed glycolysis in DDP‑sensitive and DDP‑resistant NSCLC cells. Bioinformatics analysis, luciferase reporter assays, quantitative PCR and RNA pull‑down assays were employed to verify the binding of circRNA‑FOXO3 to miR‑543. Functionally, inhibition of miR‑543 could sensitize NSCLC cells to DDP, and overexpression of miR‑543 at least partially abolished the circRNA‑FOXO3‑induced decrease in chemoresistance. Furthermore, it was revealed that Foxo3 was a direct target of miR‑543. Notably, the inhibitory action of miR‑543 silencing on DDP resistance and glycolysis was reversed by overexpression of Foxo3 in DDP‑sensitive and DDP‑resistant NSCLC cells. In conclusion, the present study demonstrated that circRNA‑FOXO3 promoted DDP sensitivity in NSCLC cells by regulating the miR‑543/Foxo3 axis‑mediated glycolysis balance. The present findings may provide novel perspectives for the treatment of patients with NSCLC resistant to DDP.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2019. CA Cancer J Clin. 69:7–34. 2019. View Article : Google Scholar : PubMed/NCBI
2	Li C, Zhang L, Meng G, Wang Q, Lv X, Zhang J and Li J: Circular RNAs: Pivotal molecular regulators and novel diagnostic and prognostic biomarkers in non-small cell lung cancer. J Cancer Res Clin Oncol. 145:2875–2889. 2019. View Article : Google Scholar : PubMed/NCBI
3	Zhang J, Xu C, Gao Y, Wang Y, Ding Z, Zhang Y, Shen W, Zheng Y and Wan Y: A novel long non-coding RNA, MSTRG.51053.2 regulates cisplatin resistance by sponging the miR-432-5p in non-small cell lung cancer cells. Front Oncol. 10:215. 2020. View Article : Google Scholar : PubMed/NCBI
4	Sun M, He L, Fan Z, Tang R and Du J: Effective treatment of drug-resistant lung cancer via a nanogel capable of reactivating cisplatin and enhancing early apoptosis. Biomaterials. 257:1202522020. View Article : Google Scholar : PubMed/NCBI
5	Schmidtova S, Kalavska K and Kucerova L: Molecular mechanisms of cisplatin chemoresistance and its circumventing in testicular germ cell tumors. Curr Oncol Rep. 20:882018. View Article : Google Scholar : PubMed/NCBI
6	Wang Y, Mo Y, Gong Z, Yang X, Yang M, Zhang S, Xiong F, Xiang B, Zhou M, Liao Q, et al: Circular RNAs in human cancer. Mol Cancer. 16:252017. View Article : Google Scholar : PubMed/NCBI
7	Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M, et al: Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 495:333–338. 2013. View Article : Google Scholar : PubMed/NCBI
8	Zhang N, Nan A, Chen L, Li X, Jia Y, Qiu M, Dai X, Zhou H, Zhu J, Zhang H, et al: Circular RNA circSATB2 promotes progression of non-small cell lung cancer cells. Mol Cancer. 19:101. 2020. View Article : Google Scholar : PubMed/NCBI
9	Wang C, Tan S, Li J, Liu WR, Peng Y and Li W: CircRNAs in lung cancer - Biogenesis, function and clinical implication. Cancer Lett. 492:106–115. 2020. View Article : Google Scholar : PubMed/NCBI
10	Wang L, Zhao L and Wang Y: Circular RNA circ_0020123 promotes non-small cell lung cancer progression by sponging miR-590-5p to regulate THBS2. Cancer Cell Int. 20:3872020. View Article : Google Scholar : PubMed/NCBI
11	Dong Y, Xu T, Zhong S, Wang B, Zhang H, Wang X, Wang P, Li G and Yang S: Circ_0076305 regulates cisplatin resistance of non-small cell lung cancer via positively modulating STAT3 by sponging miR-296-5p. Life Sci. 239:1169842019. View Article : Google Scholar : PubMed/NCBI
12	Wu Z, Gong Q, Yu Y, Zhu J and Li W: Knockdown of circ-ABCB10 promotes sensitivity of lung cancer cells to cisplatin via miR-556-3p/AK4 axis. BMC Pulm Med. 20:102020. View Article : Google Scholar : PubMed/NCBI
13	Zhang Y, Zhao H and Zhang L: Identification of the tumor suppressive function of circular RNA FOXO3 in non small cell lung cancer through sponging miR 155. Mol Med Rep. 17:7692–7700. 2018.PubMed/NCBI
14	Smolle E, Leko P, Stacher-Priehse E, Brcic L, El-Heliebi A, Hofmann L, Quehenberger F, Hrzenjak A, Popper HH, Olschewski H, et al: Distribution and prognostic significance of gluconeogenesis and glycolysis in lung cancer. Mol Oncol. 14:2853–2867. 2020. View Article : Google Scholar : PubMed/NCBI
15	Haque MM and Desai KV: Pathways to endocrine therapy resistance in breast cancer. Front Endocrinol (Lausanne). 10:5732019. View Article : Google Scholar : PubMed/NCBI
16	Xiong Z, Fu Z, Shi J, Jiang X and Wan H: HtrA1 Down-regulation induces cisplatin resistance in colon cancer by increasing XIAP and Activating PI3K/Akt pathway. Ann Clin Lab Sci. 47:264–270. 2017.PubMed/NCBI
17	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
18	Yin D, Hua L, Wang J, Liu Y and Li X: Long non-coding RNA DUXAP8 facilitates cell viability, migration, and glycolysis in non-small-cell lung cancer via regulating HK2 and LDHA by inhibition of miR-409-3p. OncoTargets Ther. 13:7111–7123. 2020. View Article : Google Scholar : PubMed/NCBI
19	Wang L, Tong X, Zhou Z, Wang S, Lei Z, Zhang T, Liu Z, Zeng Y, Li C, Zhao J, et al: Circular RNA hsa_circ_0008305 (circPTK2) inhibits TGF-β-induced epithelial-mesenchymal transition and metastasis by controlling TIF1γ in non-small cell lung cancer. Mol Cancer. 17:1402018. View Article : Google Scholar : PubMed/NCBI
20	Guo C, Wang H, Jiang H, Qiao L and Wang X: Circ_0011292 enhances paclitaxel resistance in non-small cell lung cancer by regulating miR-379-5p/TRIM65 axis. Cancer Biother Radiopharm. Aug 20–2020.(Epub ahead of print). View Article : Google Scholar
21	Lu M, Xiong H, Xia ZK, Liu B, Wu F, Zhang HX, Hu CH and Liu P: circRACGAP1 promotes non small cell lung cancer proliferation by regulating miR 144 5p/CDKL1 signaling pathway. Cancer Gene Ther. 28:197–211. 2021. View Article : Google Scholar : PubMed/NCBI
22	Song L, Cui Z and Guo X: Comprehensive analysis of circular RNA expression profiles in cisplatin-resistant non-small cell lung cancer cell lines. Acta Biochim Biophys Sin (Shanghai). 52:944–953. 2020. View Article : Google Scholar : PubMed/NCBI
23	Zhao Y, Zheng R, Chen J and Ning D: circRNA CDR1as/miR-641/HOXA9 pathway regulated stemness contributes to cisplatin resistance in non-small cell lung cancer (NSCLC). Cancer Cell Int. 20:2892020. View Article : Google Scholar : PubMed/NCBI
24	Akins NS, Nielson TC and Le HV: Inhibition of glycolysis and glutaminolysis: An emerging drug discovery approach to combat cancer. Curr Top Med Chem. 18:494–504. 2018. View Article : Google Scholar : PubMed/NCBI
25	Guo J, Su Y and Zhang M: Circ_0000140 restrains the proliferation, metastasis and glycolysis metabolism of oral squamous cell carcinoma through upregulating CDC73 via sponging miR-182-5p. Cancer Cell Int. 20:4072020. View Article : Google Scholar : PubMed/NCBI
26	Xu Y, Jiang T, Wu C and Zhang Y: circAKT3 inhibits glycolysis balance in lung cancer cells by regulating miR-516b-5p/STAT3 to inhibit cisplatin sensitivity. Biotechnol Lett. 42:1123–1135. 2020. View Article : Google Scholar : PubMed/NCBI
27	Zhou C, Zhao X and Duan S: The role of miR 543 in human cancerous and noncancerous diseases. J Cell Physiol. 236:15–26. 2021. View Article : Google Scholar : PubMed/NCBI
28	Hu J, Chen Y, Li X, Miao H, Li R, Chen D and Wen Z: THUMPD3-AS1 is correlated with non-small cell lung cancer and regulates self-renewal through miR-543 and ONECUT₂. OncoTargets Ther. 12:9849–9860. 2019. View Article : Google Scholar : PubMed/NCBI
29	Wang D, Cai L, Tian X and Li W: miR-543 promotes tumorigenesis and angiogenesis in non-small cell lung cancer via modulating metastasis associated protein 1. Mol Med. 26:442020. View Article : Google Scholar : PubMed/NCBI
30	Liu G, Zhou J and Dong M: Down regulation of miR 543 expression increases the sensitivity of colorectal cancer cells to 5 Fluorouracil through the PTEN/PI3K/AKT pathway. Biosci Rep. 39:BSR201902492019. View Article : Google Scholar : PubMed/NCBI
31	Ma Z, Gu G, Pan W and Chen X: LncRNA PCAT6 accelerates the progression and chemoresistance of cervical cancer through up-regulating ZEB1 by sponging miR-543. OncoTargets Ther. 13:1159–1170. 2020. View Article : Google Scholar : PubMed/NCBI
32	Khatri S, Yepiskoposyan H, Gallo CA, Tandon P and Plas DR: FOXO3a regulates glycolysis via transcriptional control of tumor suppressor TSC1. J Biol Chem. 285:15960–15965. 2010. View Article : Google Scholar : PubMed/NCBI
33	Bodur C, Karakas B, Timucin AC, Tezil T and Basaga H: AMP-activated protein kinase couples 3-bromopyruvate-induced energy depletion to apoptosis via activation of FoxO3a and upregulation of proapoptotic Bcl-2 proteins. Mol Carcinog. 55:1584–1597. 2016. View Article : Google Scholar : PubMed/NCBI
34	Aldonza MB, Hong JY and Lee SK: Paclitaxel-resistant cancer cell-derived secretomes elicit ABCB1-associated docetaxel cross-resistance and escape from apoptosis through FOXO3a-driven glycolytic regulation. Exp Mol Med. 49:e2862017. View Article : Google Scholar : PubMed/NCBI