https://doi.org/10.4081/ejh.2024.4063
Activation of Hedgehog pathway by circEEF2/miR-625-5p/TRPM2 axis promotes prostate cancer cell proliferation through mitochondrial stress
Submitted: 20 May 2024
Accepted: 29 August 2024
Published: 11 November 2024
Accepted: 29 August 2024
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
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The purpose of this study was to identify the role played by circEEF2 (has-circ-0048559) in prostate cancer (PCa) development and to determine the potential mechanism involved. circEEF2, miR-625-5p, and the transient receptor potential M2 channel protein (TRPM2) were determined using RT-qPCR in PCa. Cell proliferation was determined by CCK-8 assay and colony formation assay, whereas migration and invasion were assessed by Transwell assay, and apoptosis was evaluated by flow cytometry after annexin V-FITC and propidium iodide staining. The interactions between circEEF2 and miRNAs were investigated through the Circular RNA Interactome database, and the downstream targets of miR-625-5p were forecasted using TargetScan. The interaction was confirmed using both the dual luciferase reporter gene assay and RNA pull-down assay. TRPM2, Hedgehog signaling pathway proteins (GLI1 and GLI2), ubiquinone oxidase subunit B8, and cytochrome C oxidase subunit IV (COX4) were analyzed by protein blotting. JC-1 fluorescence detection was applied for mitochondrial membrane potential changes, fluorescent probe assay for intracellular ROS levels, and immunofluorescence staining for γ-H2AX expression. The role of circEEF2 in PCa tumor growth was tested by xenograft experiments. CircEEF2 expression was upregulated in PCa (p<0.05). Cells of PCa were inhibited in proliferation, migration, invasion, and enhanced in apoptosis by depleting circEEF2 (p<0.05). circEEF2 directly targeted adsorbed miR-625-5p. TRPM2 bound to miR-625-5p. Upregulating TRPM2 likewise reversed the therapeutic effect of depleting circEEF2 on cancer development in PCa cells. circEEF2 activated the Hedgehog pathway through the miR-625-5p/TRPM2 axis, promotes mitochondrial stress, and promotes PCa development in vivo. circEEF2 upregulates mitochondrial stress to promote PCa by activating the Hedgehog pathway through the miR-625-5p/TRPM2 axis.
1. Feng H, Deng Z, Peng W, Wei X, Liu J, Wang T. Circular RNA EPHA3 suppresses progression and metastasis in prostate cancer through the miR-513a-3p/BMP2 axis. J Transl Med 2023;21:288.
DOI: https://doi.org/10.1186/s12967-023-04132-4
2. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin 2022;72:7-33.
DOI: https://doi.org/10.3322/caac.21708
3. Nuhn P, De Bono JS, Fizazi K, Freedland SJ, Grilli M, Kantoff PW, et al. Update on Systemic Prostate Cancer Therapies: Management of Metastatic Castration-resistant Prostate Cancer in the Era of Precision Oncology. Eur Urol 2019;75:88-99.
DOI: https://doi.org/10.1016/j.eururo.2018.03.028
4. He H, Li J, Luo M, Wei Q. Inhibitory role of circRNA_100395 in the proliferation and metastasis of prostate cancer cells. J Int Med Res 2021;49:300060521992215.
DOI: https://doi.org/10.1177/0300060521992215
5. Hussain M, Fizazi K, Saad F, Rathenborg P, Shore N, Ferreira U, et al. Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med 2018;378:2465-74.
DOI: https://doi.org/10.1056/NEJMoa1800536
6. Rajappa A, Banerjee S, Sharma V, Khandelia P. Circular RNAs: Emerging Role in Cancer Diagnostics and Therapeutics. Front Mol Biosci 2020;7:577938.
DOI: https://doi.org/10.3389/fmolb.2020.577938
7. Chen LL. The biogenesis and emerging roles of circular RNAs. Nat Rev Mol Cell Biol 2016;17:205-11.
DOI: https://doi.org/10.1038/nrm.2015.32
8. Salzman J. Circular RNA Expression: Its Potential Regulation and Function. Trends Genet 2016;32:309-16.
DOI: https://doi.org/10.1016/j.tig.2016.03.002
9. Chen S, Huang V, Xu X, Livingstone J, Soares F, Jeon J, et al. Widespread and Functional RNA Circularization in Localized Prostate Cancer. Cell 2019;176:831-43.e22.
10. Hua JT, Chen S, He HH. Landscape of Noncoding RNA in Prostate Cancer. Trends Genet 2019;35:840-51.
DOI: https://doi.org/10.1016/j.tig.2019.08.004
11. Vo JN, Cieslik M, Zhang Y, Shukla S, Xiao L, Zhang Y, et al. The Landscape of Circular RNA in Cancer. Cell 2019;176:869-81.e13.
DOI: https://doi.org/10.1016/j.cell.2018.12.021
12. Li P, Wang Z, Li S, Wang L. Circ_0006404 Accelerates Prostate Cancer Progression Through Regulating miR-1299/CFL2 Signaling. Onco Targets Ther 2021;14:83-95.
DOI: https://doi.org/10.2147/OTT.S277831
13. Shen Z, Zhou L, Zhang C, Xu J. Reduction of circular RNA Foxo3 promotes prostate cancer progression and chemoresistance to docetaxel. Cancer Lett 2020;468:88-101.
DOI: https://doi.org/10.1016/j.canlet.2019.10.006
14. Xu S, Lian Z, Zhang S, Xu Y, Zhang H. CircGNG4 Promotes the Progression of Prostate Cancer by Sponging miR-223 to Enhance EYA3/c-myc Expression. Front Cell Dev Biol 2021;9:684125.
DOI: https://doi.org/10.3389/fcell.2021.684125
15. Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov 2017;16:203-22.
DOI: https://doi.org/10.1038/nrd.2016.246
16. Yong M, Hu J, Zhu H, Jiang X, Gan X, Hu L. Circ-EEF2 facilitated autophagy via interaction with mir-6881-3p and ANXA2 in EOC. Am J Cancer Res 2020;10:3737-51.
17. Rishabh K, Khadilkar S, Kumar A, Kalra I, Kumar AP, Kunnumakkara AB. MicroRNAs as Modulators of Oral Tumorigenesis-A Focused Review. Int J Mol Sci. 2021;22:2561.
DOI: https://doi.org/10.3390/ijms22052561
18. Maleki M, Golchin A, Javadi S, et al. Role of exosomal miRNA in chemotherapy resistance of Colorectal cancer: A systematic review. Chem Biol Drug Des. 2023;101:1096-1112.
DOI: https://doi.org/10.1111/cbdd.13947
19. Mok ETY, Chitty JL, Cox TR. miRNAs in pancreatic cancer progression and metastasis. Clin Exp Metastasis. 2024;41:163-186.
DOI: https://doi.org/10.1007/s10585-023-10256-0
20. Aktan Ç, Çal Ç, Kaymaz B, Selvi Günel N, Kıpçak S, Özel B, et al. Functional roles of miR-625-5p and miR-874-3p in the progression of castration resistant prostate cancer. Life Sci. 2022;301:120603.
DOI: https://doi.org/10.1016/j.lfs.2022.120603
21. Shang T, Zhou X, Chen W. LINC01123 Promotes the Progression of Colorectal Cancer via miR-625-5p/LASP1 Axis. Cancer Biother Radiopharm. 2021;36:765-773.
DOI: https://doi.org/10.1089/cbr.2020.3740
22. Chen Z, Wu H, Zhang Z, Li G, Liu B. LINC00511 accelerated the process of gastric cancer by targeting miR-625-5p/NFIX axis. Cancer Cell Int. 2019;19:351.
DOI: https://doi.org/10.1186/s12935-019-1070-0
23. Li H, Zheng S, Wan T, Yang X, Ouyang Y, Xia H, Wang X. Circular RNA circ_0000212 accelerates cervical cancer progression by acting as a miR-625-5p sponge to upregulate PTP4A1. Anticancer Drugs. 2023;34:659-668.
DOI: https://doi.org/10.1097/CAD.0000000000001435
24. Tektemur A, Ozaydin S, Etem Onalan E, Kaya N, Kuloglu T, Hanifi Ozercan I et al. TRPM2 mediates distruption of autophagy machinery and correlates with the grade level in prostate cancer. J Cancer Res Clin Oncol. 2019;145:1297-1311.
25. Gonnissen A, Isebaert S, Haustermans K. Hedgehog signaling in prostate cancer and its therapeutic implication. Int J Mol Sci 2013;14:13979-4007.
DOI: https://doi.org/10.3390/ijms140713979
26. Karhadkar SS, Bova GS, Abdallah N, Dhara S, Gardner D, Maitra A, et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 2004;431:707-12.
DOI: https://doi.org/10.1038/nature02962
27. O'Malley J, Kumar R, Inigo J, Yadava N, Chandra D. Mitochondrial Stress Response and Cancer. Trends Cancer 2020;6:688-701.
DOI: https://doi.org/10.1016/j.trecan.2020.04.009
28. Civenni G, Bosotti R, Timpanaro A, Vàzquez R, Merulla J, Pandit S, et al. Epigenetic Control of Mitochondrial Fission Enables Self-Renewal of Stem-like Tumor Cells in Human Prostate Cancer. Cell Metab 2019;30:303-18.e6.
DOI: https://doi.org/10.1016/j.cmet.2019.05.004
29. Zhang Y,Li J,Cui Q, Hu P, Hu S, Qian Y. Circular RNA hsa_circ_0006091 as a novel biomarker for hepatocellular carcinoma. Bioengineered,2022,13:1988-2003.
DOI: https://doi.org/10.1080/21655979.2021.2006952
30. Li M,Liu M,Bin Y, Xia J. Prediction of circRNA-disease associations based on inductive matrix completion. BMC Med Genomics,2020,13(Suppl 5):42.
DOI: https://doi.org/10.1186/s12920-020-0679-0
31. Zheng H, Cao Z, Lv Y, Cai X. WTAP-mediated N6-methyladenine Modification of circEEF2 Promotes Lung Adenocarcinoma Tumorigenesis by Stabilizing CANT1 in an IGF2BP2-dependent Manner. Mol Biotechnol. Published online April 15, 2024.
DOI: https://doi.org/10.1007/s12033-024-01134-5
32. Yang R,Chen H,Xing L, Wang B, Hu M, Ou X, et al. Hypoxia-induced circWSB1 promotes breast cancer progression through destabilizing p53 by interacting with USP10. Mol Cancer,2022, 21:88.
DOI: https://doi.org/10.1186/s12943-022-01567-z
33. Najafi S Circular RNAs as emerging players in cervical cancer tumorigenesis;A review to roles and biomarker potentials. Int J Biol Macromol,2022,206:939-953.
DOI: https://doi.org/10.1016/j.ijbiomac.2022.03.103
34. Zhang P, Gao H, Yan R, Yu L, Xia C, Yang D. has_circ_0070512 promotes prostate cancer progression by regulating the miR-338-3p/hedgehog signaling pathway. Cancer Sci 2023;114:1491-506.
DOI: https://doi.org/10.1111/cas.15672
35. Qi JC, Yang Z, Lin T, Ma L, Wang YX, Zhang Y, et al. CDK13 upregulation-induced formation of the positive feedback loop among circCDK13, miR-212-5p/miR-449a and E2F5 contributes to prostate carcinogenesis. J Exp Clin Cancer Res 2021;40:2.
DOI: https://doi.org/10.1186/s13046-020-01814-5
36. Shi J, Liu C, Chen C, Guo K, Tang Z, Luo Y, et al. Circular RNA circMBOAT2 promotes prostate cancer progression via a miR-1271-5p/mTOR axis. Aging (Albany NY) 2020;12:13255-80.
DOI: https://doi.org/10.18632/aging.103432
37. Esteller M. Non-coding RNAs in human disease. Nat Rev Genet 2011;12:861-74.
DOI: https://doi.org/10.1038/nrg3074
38. Li J,Sun D,Pu W, Wang J, Peng Y. Circular RNAs in Cancer:Biogenesis, Function, and Clinical Significance. Trends Cancer,2020,6:319-336.
DOI: https://doi.org/10.1016/j.trecan.2020.01.012
39. Anastasiadou E,Faggioni A,Trivedi P, Slack FJ. The Nefarious Nexus of Noncoding RNAs in Cancer. Int J Mol Sci,2018,19:2072.
DOI: https://doi.org/10.3390/ijms19072072
40. Samieyan Dehkordi S, Mousavi SH, Ebrahimi M, Alizadeh SH, Hedayati Asl AA, Mohammad M, et al. Upregulation of hsa-miR-625-5p Inhibits Invasion of Acute Myeloid Leukemia Cancer Cells through ILK/AKT Pathway. Cell J 2022;24:76-84.
41. Qi L, Sun B, Yang B, Lu S. CircMMP11 regulates proliferation, migration, invasion, and apoptosis of breast cancer cells through miR-625-5p/ZEB2 axis. Cancer Cell Int. 2021;21:133.
DOI: https://doi.org/10.1186/s12935-021-01816-z
42. Tektemur A, Ozaydin S, Etem Onalan E, Kaya N, Kuloglu T, Ozercan İ H, et al. TRPM2 mediates distruption of autophagy machinery and correlates with the grade level in prostate cancer. J Cancer Res Clin Oncol 2019;145:1297-311.
DOI: https://doi.org/10.1007/s00432-019-02898-z
43. Cheung JY, Miller BA. Transient Receptor Potential-Melastatin Channel Family Member 2: Friend or Foe. Trans Am Clin Climatol Assoc 2017;128:308-29.
44. Orfanelli U, Jachetti E, Chiacchiera F, Grioni M, Brambilla P, Briganti A, et al. Antisense transcription at the TRPM2 locus as a novel prognostic marker and therapeutic target in prostate cancer. Oncogene 2015;34:2094-102.
DOI: https://doi.org/10.1038/onc.2014.144
45. Almasi S, Kennedy BE, El-Aghil M, Sterea AM, Gujar S, Partida-Sánchez S, et al. TRPM2 channel-mediated regulation of autophagy maintains mitochondrial function and promotes gastric cancer cell survival via the JNK-signaling pathway. J Biol Chem 2018;293:3637-50.
DOI: https://doi.org/10.1074/jbc.M117.817635
46. Almasi S, Long CY, Sterea A, Clements DR, Gujar S, El Hiani Y. TRPM2 Silencing Causes G2/M Arrest and Apoptosis in Lung Cancer Cells via Increasing Intracellular ROS and RNS Levels and Activating the JNK Pathway. Cell Physiol Biochem 2019;52:742-57.
DOI: https://doi.org/10.33594/000000052
47. Zeng X, Sikka SC, Huang L, Sun C, Xu C, Jia D, et al. Novel role for the transient receptor potential channel TRPM2 in prostate cancer cell proliferation. Prostate Cancer Prostatic Dis. 2010;13:195-201.
DOI: https://doi.org/10.1038/pcan.2009.55
48. Hanna A, Shevde LA. Hedgehog signaling: modulation of cancer properies and tumor mircroenvironment. Mol Cancer 2016;15:24.
DOI: https://doi.org/10.1186/s12943-016-0509-3
49. Shemorry A, Harnoss JM, Guttman O, Marsters SA, Kőműves LG, Lawrence DA, et al. Caspase-mediated cleavage of IRE1 controls apoptotic cell commitment during endoplasmic reticulum stress. Elife 2019;8:e47084.
DOI: https://doi.org/10.7554/eLife.47084
50. Gu Y, Wang Y, He L, Zhang J, Zhu X, Liu N, et al. Circular RNA circIPO11 drives self-renewal of liver cancer initiating cells via Hedgehog signaling. Mol Cancer. 2021;20:132.
DOI: https://doi.org/10.1186/s12943-021-01435-2
Ethics Approval
the present study was approved by the Ethics Committee of Central People's Hospital of Zhanjiang, The animal experiments were approved by the Institutional Animal Care and Use Committee of Central People's Hospital of ZhanjiangHow to Cite
Zhu, C., Lin, L., Huang, C., & Wu, Z. (2024). Activation of Hedgehog pathway by circEEF2/miR-625-5p/TRPM2 axis promotes prostate cancer cell proliferation through mitochondrial stress. European Journal of Histochemistry, 68(4). https://doi.org/10.4081/ejh.2024.4063
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