Abstract
A growing number of studies have indicated that circRNAs play an important role in the progression of malignant tumors, including hepatocellular carcinoma (HCC). In this study, we designed to explore the abnormal expression of hsa_circ_0091579 (circ_0091579) and its role in the pathogenesis of HCC. In this study, the mRNA levels of circ_0091579, miR-1270, and Yes-associated protein (YAP1) were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). RNase R and Actinomycin D were used to test the stability of circ_0091579. Cell Counting Kit-8 (CCK-8) was used to measure cell viability. Tubule formation assay was used to determine the effect of HCC cells on the number of tubes. Cell apoptosis was detected by flow cytometry. Western blot was used for the protein levels. Transwell and wound healing tests were used to measure the abilities of invasion and migration. The effect of circ_0091579 knockdown on tumor growth was verified in vivo by xenograft tumor assay and Immunohistochemistry (IHC) analysis. Dual-luciferase reporter or RIP assay was used to detect the relationship between miR-1270 and circ_0091579 or YAP1. Glutamine metabolism was determined by ELISA and western blot assays. In the present study, we found that circ_0091579 was upregulated in HCC tissues and cells. Inhibited circ_0091579 expression significantly suppressed proliferation and promoted apoptosis of HCC cells. Moreover, circ_0091579 knockdown inhibited tumor growth in vivo. Bioinformatic prediction and luciferase assay showed that circ_0091579 acted as a molecular sponge for miR-1270 and YAP1 was a target gene of miR-1270. MiR-1270 silencing could reverse the inhibitory effect of circ_0091579 knockdown on HCC progression, and YAP1 overexpression also could reverse the suppressive effect of circ_0091579 silencing on HCC progression. Meanwhile, miR-1270 inhibitor could invert the negative regulation effect of circ_0091579 silencing on YAP1 expression. Circ_0091579 promoted HCC progression by regulating the miR-1270/YAP1 axis, and our study might offer novel biomarkers and therapeutic targets for HCC.
Similar content being viewed by others
Data Availability
Not applicable.
References
Cao Y, Tao Q, Kao X, Zhu X (2021) Hsa-circRNA-103809 promotes hepatocellular carcinoma development via MicroRNA-1270/PLAG1 like zinc finger 2 axis. Dig Dis Sci 66:1524–1532. https://doi.org/10.1007/s10620-020-06416-x
Chen LL (2020) The expanding regulatory mechanisms and cellular functions of circular RNAs. Nat Rev Mol Cell Biol 21:475–490. https://doi.org/10.1038/s41580-020-0243-y
Chen F, Fang Y, Zhao R, Le J, Zhang B, Huang R, Chen Z, Shao J (2019a) Evolution in medicinal chemistry of sorafenib derivatives for hepatocellular carcinoma. Eur J Med Chem 179:916–935. https://doi.org/10.1016/j.ejmech.2019.06.070
Chen H, Liu S, Li M, Huang P, Li X (2019b) circ_0003418 Inhibits tumorigenesis and cisplatin chemoresistance through Wnt/beta-catenin pathway in hepatocellular carcinoma. Onco Targets Ther 12:9539–9549. https://doi.org/10.2147/OTT.S229507
Chen W, Quan Y, Fan S, Wang H, Liang J, Huang L, Chen L, Liu Q, He P, Ye Y (2020) Exosome-transmitted circular RNA hsa_circ_0051443 suppresses hepatocellular carcinoma progression. Cancer Lett 475:119–128. https://doi.org/10.1016/j.canlet.2020.01.022
Chen Y, Song S, Zhang L, Zhang Y (2021) Circular RNA hsa_circ_0091579 facilitates the Warburg effect and malignancy of hepatocellular carcinoma cells via the miR-624/H3F3B axis. Clin Transl Oncol 23:2280–2292. https://doi.org/10.1007/s12094-021-02627-4
Couri T, Pillai A (2019) Goals and targets for personalized therapy for HCC. Hepatol Int 13:125–137. https://doi.org/10.1007/s12072-018-9919-1
Craig AJ, von Felden J, Garcia-Lezana T, Sarcognato S, Villanueva A (2020) Tumour evolution in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 17:139–152. https://doi.org/10.1038/s41575-019-0229-4
Du WW, Zhang C, Yang W, Yong T, Awan FM, Yang BB (2017) Identifying and characterizing circRNA-protein interaction. Theranostics 7:4183–4191. https://doi.org/10.7150/thno.21299
Edwards DN, Ngwa VM, Wang S, Shiuan E, Brantley-Sieders DM, Kim LC, Reynolds AB, Chen J (2017) The receptor tyrosine kinase EphA2 promotes glutamine metabolism in tumors by activating the transcriptional coactivators YAP and TAZ. Sci Signal. https://doi.org/10.1126/scisignal.aan4667
Fujii T, Shimada K, Nakai T, Ohbayashi C (2018) MicroRNAs in smoking-related carcinogenesis: biomarkers functions and therapy. J Clin Med. https://doi.org/10.3390/jcm7050098
Gao N, Ye B (2020) Circ-SOX4 drives the tumorigenesis and development of lung adenocarcinoma via sponging miR-1270 and modulating PLAGL2 to activate WNT signaling pathway. Cancer Cell Int 20:2. https://doi.org/10.1186/s12935-019-1065-x
Hayes J, Peruzzi PP, Lawler S (2014) MicroRNAs in cancer: biomarkers, functions and therapy. Trends Mol Med 20:460–469. https://doi.org/10.1016/j.molmed.2014.06.005
Jeck WR, Sharpless NE (2014) Detecting and characterizing circular RNAs. Nat Biotechnol 32:453–461. https://doi.org/10.1038/nbt.2890
KhashkhashiMoghadam S, Bakhshinejad B, Khalafizadeh A, Mahmud Hussen B, Babashah S (2021) Non-coding RNA-associated competitive endogenous RNA regulatory networks: Novel diagnostic and therapeutic opportunities for hepatocellular carcinoma. J Cell Mol Med. https://doi.org/10.1111/jcmm.17126
Li Z, Liu Y, Yan J, Zeng Q, Hu Y, Wang H, Li H, Li J, Yu Z (2020) Circular RNA hsa_circ_0056836 functions an oncogenic gene in hepatocellular carcinoma through modulating miR-766–3p/FOSL2 axis. Aging (Albany NY) 12:2485–2497. https://doi.org/10.18632/aging.102756
Lin Y, Huang G, Jin H, Jian Z (2020) Circular RNA Gprc5a promotes HCC progression by activating YAP1/TEAD1 signalling pathway by sponging miR-1283. Onco Targets Ther 13:4509–4521. https://doi.org/10.2147/OTT.S240261
Liu J, Li D, Luo H, Zhu X (2019a) Circular RNAs: the star molecules in cancer. Mol Aspects Med 70:141–152. https://doi.org/10.1016/j.mam.2019.10.006
Liu Z, Yu Y, Huang Z, Kong Y, Hu X, Xiao W, Quan J, Fan X (2019b) CircRNA-5692 inhibits the progression of hepatocellular carcinoma by sponging miR-328-5p to enhance DAB2IP expression. Cell Death Dis 10:900. https://doi.org/10.1038/s41419-019-2089-9
Liu W, Yin C, Liu Y (2020) Circular RNA circ_0091579 promotes hepatocellular carcinoma proliferation, migration, invasion, and glycolysis through miR-490-5p/CASC3 Axis. Cancer Biother Radiopharm. https://doi.org/10.1089/cbr.2019.3472
Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M, Loewer A, Ziebold U, Landthaler M, Kocks C, le Noble F, Rajewsky N (2013) Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495:333–338. https://doi.org/10.1038/nature11928
Muehlich S, Rehm M, Ebenau A, Goppelt-Struebe M (2017) Synergistic induction of CTGF by cytochalasin D and TGFbeta-1 in primary human renal epithelial cells: Role of transcriptional regulators MKL1, YAP/TAZ and Smad2/3. Cell Signal 29:31–40. https://doi.org/10.1016/j.cellsig.2016.10.002
Niu WY, Chen L, Zhang P, Zang H, Zhu B, Shao WB (2019) Circ_0091579 promotes proliferative ability and metastasis of liver cancer cells by regulating microRNA-490–3p. Eur Rev Med Pharmacol Sci 23:10264–10273. https://doi.org/10.26355/eurrev_201912_19664
Patop IL, Wust S, Kadener S (2019) Past, present, and future of circRNAs. EMBO J 38:e100836. https://doi.org/10.15252/embj.2018100836
Prats AC, David F, Diallo LH, Roussel E, Tatin F, Garmy-Susini B, Lacazette E (2020) Circular RNA the key for translation. Int J Mol Sci. https://doi.org/10.3390/ijms21228591
Pu J, Wang J, Li W, Lu Y, Wu X, Long X, Luo C, Wei H (2020) hsa_circ_0000092 promotes hepatocellular carcinoma progression through up-regulating HN1 expression by binding to microRNA-338-3p. J Cell Mol Med. https://doi.org/10.1111/jcmm.15010
Qiu M, Xia W, Chen R, Wang S, Xu Y, Ma Z, Xu W, Zhang E, Wang J, Fang T, Hu J, Dong G, Yin R, Wang J, Xu L (2018) The circular RNA circPRKCI promotes tumor growth in lung adenocarcinoma. Cancer Res 78:2839–2851. https://doi.org/10.1158/0008-5472.CAN-17-2808
Ren K, Li T, Zhang W, Ren J, Li Z, Wu G (2016) miR-199a-3p inhibits cell proliferation and induces apoptosis by targeting YAP1, suppressing Jagged1-Notch signaling in human hepatocellular carcinoma. J Biomed Sci 23:79. https://doi.org/10.1186/s12929-016-0295-7
Sheng R, Li X, Wang Z, Wang X (2020) Circular RNAs and their emerging roles as diagnostic and prognostic biomarkers in ovarian cancer. Cancer Lett 473:139–147. https://doi.org/10.1016/j.canlet.2019.12.043
Shu J, Du J, Wang F, Cheng Y, Chen G, Xu B, Zhang D, Chen S (2021) Circ_0091579 enhances the malignancy of hepatocellular carcinoma via miR-1287/PDK2 axis. Open Life Sci 16:69–83. https://doi.org/10.1515/biol-2021-0009
Su X, Su J, He H, Zhan Y, Liu H (2019) Hsa_circ_0070269 inhibits hepatocellular carcinoma progression through modulating miR-182/NPTX1 axis. Biomed Pharmacother 120:109497. https://doi.org/10.1016/j.biopha.2019.109497
Su Y, Lv X, Yin W, Zhou L, Hu Y, Zhou A, Qi F (2019) CircRNA Cdr1as functions as a competitive endogenous RNA to promote hepatocellular carcinoma progression. Aging (Albany NY) 11:8183–8203. https://doi.org/10.18632/aging.102312
Sun Z, Ou C, Liu J, Chen C, Zhou Q, Yang S, Li G, Wang G, Song J, Li Z, Zhang Z, Yuan W, Li X (2019) YAP1-induced MALAT1 promotes epithelial-mesenchymal transition and angiogenesis by sponging miR-126-5p in colorectal cancer. Oncogene 38:2627–2644. https://doi.org/10.1038/s41388-018-0628-y
Sun K, Wang H, Zhang D, Li Y, Ren L (2021) Depleting circ_0088364 restrained cell growth and motility of human hepatocellular carcinoma via circ_0088364-miR-1270-COL4A1 ceRNA pathway. Cell Cycle. https://doi.org/10.1080/15384101.2021.2016196
Tan S, Gou Q, Pu W, Guo C, Yang Y, Wu K, Liu Y, Liu L, Wei YQ, Peng Y (2018) Circular RNA F-circEA produced from EML4-ALK fusion gene as a novel liquid biopsy biomarker for non-small cell lung cancer. Cell Res 28:693–695. https://doi.org/10.1038/s41422-018-0033-7
Wang X, Li H, Lu Y, Cheng L (2020) Circular RNAs in human cancer. Front Oncol 10:577118. https://doi.org/10.3389/fonc.2020.577118
Wang W, Xu A, Zhao M, Sun J, Gao L (2021) Circ_0001247 functions as a miR-1270 sponge to accelerate cervical cancer progression by up-regulating ZEB2 expression level. Biotechnol Lett 43:745–755. https://doi.org/10.1007/s10529-020-03059-w
Wei L, Li P, Zhao C, Wang N, Wei N (2019) Upregulation of microRNA-1270 suppressed human glioblastoma cancer cell proliferation migration and tumorigenesis by acting through WT1. Onco Targets Ther 12:4839–4848. https://doi.org/10.2147/OTT.S192521
Wei X, Zheng W, Tian P, He Y, Liu H, Peng M, Li X, Liu X (2020) Oncogenic hsa_circ_0091581 promotes the malignancy of HCC cell through blocking miR-526b from degrading c-MYC mRNA. Cell Cycle 19:817–824. https://doi.org/10.1080/15384101.2020.1731945
Xiao Y, Najeeb RM, Ma D, Yang K, Zhong Q, Liu Q (2019) Upregulation of CENPM promotes hepatocarcinogenesis through mutiple mechanisms. J Exp Clin Cancer Res 38:458. https://doi.org/10.1186/s13046-019-1444-0
Xu M, Gu M, Zhou J, Da J, Wang Z (2020) Interaction of YAP1 and mTOR promotes bladder cancer progression. Int J Oncol 56:232–242. https://doi.org/10.3892/ijo.2019.4922
Yao Z, Xu R, Yuan L, Xu M, Zhuang H, Li Y, Zhang Y, Lin N (2019) Circ_0001955 facilitates hepatocellular carcinoma (HCC) tumorigenesis by sponging miR-516a-5p to release TRAF6 and MAPK11. Cell Death Dis 10:945. https://doi.org/10.1038/s41419-019-2176-y
Zang J, Lu D, Xu A (2020) The interaction of circRNAs and RNA binding proteins: an important part of circRNA maintenance and function. J Neurosci Res 98:87–97. https://doi.org/10.1002/jnr.24356
Zhang H, Liu H, Bi H (2017) MicroRNA-345 inhibits hepatocellular carcinoma metastasis by inhibiting YAP1. Oncol Rep 38:843–849. https://doi.org/10.3892/or.2017.5772
Zhang C, Zhang C, Lin J, Wang H (2018) Circular RNA Hsa_Circ_0091579 serves as a diagnostic and prognostic marker for hepatocellular carcinoma. Cell Physiol Biochem 51:290–300. https://doi.org/10.1159/000495230
Zou H, Xu X, Luo L, Zhang Y, Luo L, Yao Y, Xiang G, Huang X, Wang G (2019) Hsa_circ_0101432 promotes the development of hepatocellular carcinoma (HCC) by adsorbing miR-1258 and miR-622. Cell Cycle 18:2398–2413. https://doi.org/10.1080/15384101.2019.1618120
Funding
None.
Author information
Authors and Affiliations
Contributions
ML designed and performed the research; BG, GZ, and HQ analyzed the data; and ML wrote the manuscript. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical Approval
Written informed consents were obtained from all participants and this study was permitted by the Ethics Committee of Taian City Central Hospital.
Consent for Publication
Not applicable.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Liu, M., Guo, B., Zhang, G. et al. Circ_0091579 Knockdown Inhibited HCC Proliferation and Glutamine Metabolism Through miR-1270/YAP1 Axis. Biochem Genet 62, 208–228 (2024). https://doi.org/10.1007/s10528-023-10386-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10528-023-10386-w