Abstract
Circular RNAs (circRNAs) play critical roles in the initiation and progression of various cancers. However, the potential functional roles of circSNX14 in hepatocellular carcinoma (HCC) remain largely unknown. CircSNX14 expression pattern was analyzed in HCC tissues and cell lines via qRT-PCR. The effects of circSNX14 on cell proliferation, invasion, angiogenesis, and Epithelial-mesenchymal transition (EMT) were investigated by overexpression experiments. The role of circSNX14 in the tumorigenesis of HCC cells was examined using in vivo xenograft mouse model. The interaction between circSNX14, miR-562, and Large Tumor Suppressor Kinase 2 (LATS2) mRNA was confirmed by Luciferase reporter assay and RNA immunoprecipitation (RIP) analysis. CircSNX14 was significantly down-regulated in HCC tissues and cell lines, and its down-regulation was correlated with a poor prognosis in HCC patients. In the following functional experiments, circSNX14 overexpression remarkably suppressed the proliferation and invasion of HCC cells, and attenuated the mesenchymall status. circSNX14 overexpression also suppressed the tumorigenesis of HCC cells in the mouse model. We further revealed the interaction of circSNX14 and miR-562, and miR-562 could suppress the expression of LATS2 by interacting with its mRNA. The negative correlation of circSNX14 and miR-562, negative correlation of miR-562 and LATS2, and positive correlation of circSNX14 and LATS2 have been confirmed by Pearson correlation in the HCC samples. Collectively, these results reveal a novel role of circSNX14/miR-562/LATS2 axis in regulating the malignant progression of HCC cancer progression, indicating the tumor suppressor role of circSNX14 and its potential as a prognostic biomarker.
Similar content being viewed by others
Data availability
The data will be available from corresponding author by reasonable request.
References
Bruix J, Sherman M, American Association for the Study of Liver, D (2011) Management of hepatocellular carcinoma: an update. Hepatology 53(3):1020–1022. https://doi.org/10.1002/hep.24199
Chen Y, Lei Y, Lin J, Huang Y, Zhang J, Chen K, Sun S, Lin X (2020) The LINC01260 functions as a tumor suppressor via the miR-562/CYLD/NF-kappaB Pathway in non-small cell lung cancer. Onco Targets Ther 13:10707–10719. https://doi.org/10.2147/OTT.S253730
Chidambaranathan-Reghupaty S, Fisher PB, Sarkar D (2021) Hepatocellular carcinoma (HCC): epidemiology, etiology and molecular classification. Adv Cancer Res 149:1–61. https://doi.org/10.1016/bs.acr.2020.10.001
Drake KM, Ruteshouser EC, Natrajan R, Harbor P, Wegert J, Gessler M, Pritchard-Jones K, Grundy P, Dome J, Huff V, Jones C, Aldred MA (2009) Loss of heterozygosity at 2q37 in sporadic Wilms’ tumor: putative role for miR-562. Clin Cancer Res 15(19):5985–5992. https://doi.org/10.1158/1078-0432.CCR-09-1065
Farazi PA, DePinho RA (2006) Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 6(9):674–687. https://doi.org/10.1038/nrc1934
Furth N, Aylon Y (2017) The LATS1 and LATS2 tumor suppressors: beyond the Hippo pathway. Cell Death Differ 24(9):1488–1501. https://doi.org/10.1038/cdd.2017.99
Han LL, Yin XR, Zhang SQ (2018) miR-103 promotes the metastasis and EMT of hepatocellular carcinoma by directly inhibiting LATS2. Int J Oncol 53(6):2433–2444. https://doi.org/10.3892/ijo.2018.4580
Huang XY, Huang ZL, Xu YH, Zheng Q, Chen Z, Song W, Zhou J, Tang ZY, Huang XY (2017) Comprehensive circular RNA profiling reveals the regulatory role of the circRNA-100338/miR-141-3p pathway in hepatitis B-related hepatocellular carcinoma. Sci Rep 7(1):5428. https://doi.org/10.1038/s41598-017-05432-8
Josson S, Gururajan M, Sung SY, Hu P, Shao C, Zhau HE, Liu C, Lichterman J, Duan P, Li Q, Rogatko A, Posadas EM, Haga CL, Chung LW (2015) Stromal fibroblast-derived miR-409 promotes epithelial-to-mesenchymal transition and prostate tumorigenesis. Oncogene 34(21):2690–2699. https://doi.org/10.1038/onc.2014.212
Lee Y, Kim NH, Cho ES, Yang JH, Cha YH, Kang HE, Yun JS, Cho SB, Lee SH, Paclikova P, Radaszkiewicz TW, Bryja V, Kang CG, Yuk YS, Cha SY, Kim SY, Kim HS, Yook JI (2018) Dishevelled has a YAP nuclear export function in a tumor suppressor context-dependent manner. Nat Commun 9(1):2301. https://doi.org/10.1038/s41467-018-04757-w
Li SP, Xu HX, Yu Y, He JD, Wang Z, Xu YJ, Wang CY, Zhang HM, Zhang RX, Zhang JJ, Yao Z, Shen ZY (2016) LncRNA HULC enhances epithelial-mesenchymal transition to promote tumorigenesis and metastasis of hepatocellular carcinoma via the miR-200a-3p/ZEB1 signaling pathway. Oncotarget 7(27):42431–42446. https://doi.org/10.18632/oncotarget.9883
Lin Y, Peng S, Yu H, Teng H, Cui M (2012) RNAi-mediated downregulation of NOB1 suppresses the growth and colony-formation ability of human ovarian cancer cells. Med Oncol 29(1):311–317. https://doi.org/10.1007/s12032-010-9808-5
Liu YC, Yeh CT, Lin KH (2020) Cancer stem cell functions in hepatocellular carcinoma and comprehensive therapeutic strategies. Cells. https://doi.org/10.3390/cells9061331
Loh C-Y, Chai JY, Tang TF, Wong WF, Sethi G, Shanmugam MK, Chong PP, Looi CYJC (2019) The E-cadherin and N-cadherin switch in epithelial-to-mesenchymal transition: signaling, therapeutic implications, and challenges. Cells 8(10):1118
Mittal V (2018) Epithelial mesenchymal transition in tumor metastasis. Annu Rev Pathol 13:395–412. https://doi.org/10.1146/annurev-pathol-020117-043854
Parasramka MA, Maji S, Matsuda A, Yan IK, Patel T (2016) Long non-coding RNAs as novel targets for therapy in hepatocellular carcinoma. Pharmacol Ther 161:67–78. https://doi.org/10.1016/j.pharmthera.2016.03.004
Powell EE, Wong VW, Rinella M (2021) Non-alcoholic fatty liver disease. Lancet 397(10290):2212–2224. https://doi.org/10.1016/S0140-6736(20)32511-3
Rusnak L, Tang C, Qi Q, Mo X, Fu H (2018) Large tumor suppressor 2, LATS2, activates JNK in a kinase-independent mechanism through ASK1. J Mol Cell Biol 10(6):549–558. https://doi.org/10.1093/jmcb/mjy061
Saliminejad K, Khorram Khorshid HR, Soleymani Fard S, Ghaffari SH (2019) An overview of microRNAs: Biology, functions, therapeutics, and analysis methods. J Cell Physiol 234(5):5451–5465. https://doi.org/10.1002/jcp.27486
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(19):8183–8203. https://doi.org/10.18632/aging.102312
Tan Y, Ouyang H, Xiao X, Zhong J, Dong M (2019) Irisin ameliorates septic cardiomyopathy via inhibiting DRP1-related mitochondrial fission and normalizing the JNK-LATS2 signaling pathway. Cell Stress Chaperones 24(3):595–608. https://doi.org/10.1007/s12192-019-00992-2
Tian Y, Lv W, Lu C, Zhao X, Zhang C, Song H (2019) LATS2 promotes cardiomyocyte H9C2 cells apoptosis via the Prx3-Mfn2-mitophagy pathways. J Recept Signal Transduct Res 39(5–6):470–478. https://doi.org/10.1080/10799893.2019.1701031
Wong CM, Tsang FH, Ng IO (2018) Non-coding RNAs in hepatocellular carcinoma: molecular functions and pathological implications. Nat Rev Gastroenterol Hepatol 15(3):137–151. https://doi.org/10.1038/nrgastro.2017.169
Wu Y, Zhang Y, Qin X, Geng H, Zuo D, Zhao Q (2020) PI3K/AKT/mTOR pathway-related long non-coding RNAs: roles and mechanisms in hepatocellular carcinoma. Pharmacol Res 160:105195. https://doi.org/10.1016/j.phrs.2020.105195
Xie Y, Lv Y, Zhang Y, Liang Z, Han L, Xie Y (2019) LATS2 promotes apoptosis in non-small cell lung cancer A549 cells via triggering Mff-dependent mitochondrial fission and activating the JNK signaling pathway. Biomed Pharmacother 109:679–689. https://doi.org/10.1016/j.biopha.2018.10.097
Xie C, Li SY, Fang JH, Zhu Y, Yang JE (2021) Functional long non-coding RNAs in hepatocellular carcinoma. Cancer Lett 500:281–291. https://doi.org/10.1016/j.canlet.2020.10.042
Xin T, Lv W, Liu D, Jing Y, Hu F (2020) ROCK1 knockdown inhibits non-small-cell lung cancer progression by activating the LATS2-JNK signaling pathway. Aging (albany NY) 12(12):12160–12174. https://doi.org/10.18632/aging.103386
Xu J, Ji L, Liang Y, Wan Z, Zheng W, Song X, Gorshkov K, Sun Q, Lin H, Zheng X, Chen J, Jin RA, Liang X, Cai X (2020) CircRNA-SORE mediates sorafenib resistance in hepatocellular carcinoma by stabilizing YBX1. Signal Transduct Target Ther 5(1):298. https://doi.org/10.1038/s41392-020-00375-5
Yang Y, Chen L, Gu J, Zhang H, Yuan J, Lian Q, Lv G, Wang S, Wu Y, Yang YT, Wang D, Liu Y, Tang J, Luo G, Li Y, Hu L, Sun X, Wang D, Guo M, Xi Q, Xi J, Wang H, Zhang MQ, Lu ZJ (2017) Recurrently deregulated lncRNAs in hepatocellular carcinoma. Nat Commun 8:14421. https://doi.org/10.1038/ncomms14421
Yang L, Zhang C, Bai X, Xiao C, Dang E, Wang G (2020) hsa_circ_0003738 inhibits the suppressive function of tregs by targeting miR-562/IL-17A and miR-490-5p/IFN-gamma signaling pathway. Mol Ther Nucleic Acids 21:1111–1119. https://doi.org/10.1016/j.omtn.2020.08.001
Ye J, Li TS, Xu G, Zhao YM, Zhang NP, Fan J, Wu J (2017) JCAD Promotes progression of nonalcoholic steatohepatitis to liver cancer by inhibiting LATS2 kinase activity. Cancer Res 77(19):5287–5300. https://doi.org/10.1158/0008-5472.CAN-17-0229
Zhang J, Ma L (2012) MicroRNA control of epithelial-mesenchymal transition and metastasis. Cancer Metastasis Rev 31(3–4):653–662. https://doi.org/10.1007/s10555-012-9368-6
Zheng Q, Zhao Y, Guo J, Zhao S, Fei C, Xiao C, Wu D, Wu L, Li X, Chang C (2018) Iron overload promotes mitochondrial fragmentation in mesenchymal stromal cells from myelodysplastic syndrome patients through activation of the AMPK/MFF/Drp1 pathway. Cell Death Dis 9(5):515. https://doi.org/10.1038/s41419-018-0552-7
Acknowledgements
Not applicable.
Funding
Not applicable.
Author information
Authors and Affiliations
Contributions
YW: conceptualization, formal analysis, data curation, writing-original draft. YY and XY: methodology, investigation, software. LS: conceptualization, resources, writing-review & editing.
Corresponding author
Ethics declarations
Competing interests
The authors declare no potential conflicts of interest.
Ethical approval
Written informed consent was obtained from each patient included in the study and the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the Ethics Committee of University-Town Hospital of Chongqing Medical University (APPROVAL NUMBER: 201903–16).
Consent for publication
All patients have signed the informed consent in writing before participation.
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
Wu, Y., Yang, Y., Yi, X. et al. The circSNX14 functions as a tumor suppressor via the miR-562/ LATS2 pathway in hepatocellular carcinoma cells. J Mol Histol 54, 593–607 (2023). https://doi.org/10.1007/s10735-023-10157-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10735-023-10157-2