Middle East Journal of Cancer

Clinical and Bioinformatic Characterization of the Mitochondrial-Encoded Circular RNA hsa_circ_0002363 in Triple-Negative Breast Cancer

Articles in Press

Document Type : Original Article(s)

Authors

Zahra Firoozi 1
Yaser Mansoori 2
Mohammadreza Sharifi 3
Abbas Shahi 4, 5
Abdolreza Daraei 6, 7
Behnam Mansoori 4
Rasoul Salehi 1, 8

1 Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

2 Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

3 Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

4 Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran

5 Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman

6 Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran

7 Department of Medical Genetics, School of Medicine, Babol University of Medical Sciences, Babol, Iran

8 Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran

10.30476/mejc.2026.112242.2454
Abstract
Background: Mitochondrial-encoded circular RNAs have recently emerged as novel regulators of mitochondrial homeostasis and cancer progression. However, the expression pattern and biological significance of hsa_circ_0002363 in triple-negative breast cancer (TNBC) remain unknown. The present study aimed to evaluate the expression and potential clinical and biological significance of the hsa_circ_0002363 in TNBC.
Method: In a case-control study, expression of hsa_circ_0002363 was evaluated by real-time quantitative reverse transcription polymerase chain reaction in 20 paired TNBC and adjacent normal tissues. Associations with clinicopathological characteristics were assessed using Wilcoxon, Mann–Whitney, Kruskal–Wallis, and Spearman’s correlation tests. Diagnostic performance was evaluated using receiver operating characteristic curve analysis. Statistical analyses were performed using IBM SPSS Statistics version 21, with P < 0.05 considered statistically significant. Bioinformatic analyses were performed to construct a competing endogenous RNA (ceRNA) network and identify enriched pathways and hub genes.
Results: hsa_circ_0002363 was significantly upregulated in TNBC tissues (P = 0.001), positively correlated with tumor size (r = 0.466, P = 0.038), and exhibited good diagnostic performance (area under the curve = 0.890). Bioinformatic analyses identified hsa-miR-384 and hsa-miR-668 as interacting miRNAs and highlighted HSPA5, YY1, and AGO1 as key hub genes. Enrichment analysis suggested the involvement of cancer-related pathways, including breast cancer, mTOR signaling, and RNA degradation.
Conclusion: Our study provides the first evidence that the mecciRNA hsa_circ_0002363 is aberrantly expressed in TNBC and may participate in tumor progression through a putative ceRNA regulatory network. These findings introduce hsa_circ_0002363 as a promising biomarker and provide a basis for future mechanistic investigations.

Highlights

Zahra Firoozi (google scholar)

Rasoul Salehi (google scholar)

Keywords

RNA
Circular
Mitochondria
MicroRNAs
Triple negative breast neoplasms
Biomarkers
Subjects

Please cite this article as:

 Firoozi Z, Mansoori Y, Sharifi M, Shahi A, Daraei A, Mansoori B, et al. Clinical and bioinformatic characterization of the mitochondrial-encoded circular RNA hsa_circ_0002363 in triple-negative breast cancer. Middle East J Cancer. 2026: in press. doi: 10.30476/mejc.2026.112242.2454.

1.         Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-49. doi: 10.3322/caac.21660. PMID: 33538338.
2.         Garrido-Castro AC, Lin NU, Polyak K. Insights into molecular classifications of triple-negative breast cancer: Improving patient selection for treatment. Cancer Discov. 2019;9(2):176-98. doi: 10.1158/2159-8290.CD-18-1177. PMID: 30679171; PMCID: PMC6387871.
3.         Bianchini G, Balko JM, Mayer IA, Sanders ME, Gianni L. Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease. Nat Rev Clin Oncol. 2016;13(11):674-90. doi: 10.1038/nrclinonc.2016.66. PMID: 27184417; PMCID: PMC5461122.
4.         Waks AG, Winer EP. Breast cancer treatment: A review. JAMA. 2019;321(3):288-300. doi: 10.1001/jama.2018.19323. PMID: 30667505.
5.         Vyas S, Zaganjor E, Haigis MC. Mitochondria and cancer. Cell. 2016;166(3):555-66. doi: 10.1016/j.cell.2016.07.002. PMID: 27471965; PMCID: PMC5036969.
6.         Ashton TM, McKenna WG, Kunz-Schughart LA, Higgins GS. Oxidative phosphorylation as an emerging target in cancer therapy. Clin Cancer Res. 2018;24(11):2482-90. doi: 10.1158/1078-0432.CCR-17-3070. PMID: 29420223.
7.         Ren B, Guan M-X, Zhou T, Cai X, Shan G. Emerging functions of mitochondria-encoded noncoding RNAs. Trends Genet. 2023;39(2):125-39. doi: 10.1016/j.tig.2022.08.004. PMID: 36137834.
8.         Liu X, Wang X, Li J, Hu S, Deng Y, Yin H, et al. Identification of mecciRNAs and their roles in the mitochondrial entry of proteins. Sci China Life Sci. 2020;63(10):1429-49. doi: 10.1007/s11427-020-1631-9. PMID: 32048164.
9.         Wu Z, Sun H, Wang C, Liu W, Liu M, Zhu Y, et al. Mitochondrial genome-derived circRNA mc-COX2 functions as an oncogene in chronic lymphocytic leukemia. Mol Ther Nucleic Acids. 2020;20:801-11. doi: 10.1016/j.omtn.2020.04.017. PMID: 32438315; PMCID: PMC7240210.
10.       Nourbakhsh ST, Mirzaei SA, Mohamadhashem F, Naghizadeh MM, Razavi AN, Mansoori Y, et al. Pathological expression of mitochondrial genome-derived circRNA SCAR/mc-COX2 and its ceRNA network in colorectal cancer: implications for clinical significance. BMC Cancer. 2025;25:466. doi: 10.1186/s12885-025-13886-7. PMID: 40082804; PMCID: PMC11907809.
11.       Darbeheshti F, Mahdiannasser M, Noroozi Z, Firoozi Z, Mansoori B, Daraei A, et al. Circular RNA-associated ceRNA network involved in HIF-1 signalling in triple-negative breast cancer: circ_0047303 as a potential key regulator. J Cell Mol Med. 2021;25(24):11322-32. doi: 10.1111/jcmm.17066. PMID: 34791795; PMCID: PMC8650046.
12.       Firoozi Z, Mohammadisoleimani E, Shahi A, Mansoori H, Naghizadeh MM, Bastami M, et al. Potential roles of hsa_circ_000839 and hsa_circ_0005986 in breast cancer. J Clin Lab Anal. 2022;36(3):e24263. doi: 10.1002/jcla.24263. PMID: 35098570; PMCID: PMC8906031.
13.       Li X, Ren Z, Yao Y, Bao J, Yu Q. The circular RNA circEIF3M promotes breast cancer progression by promoting cyclin D1 expression. Aging (Albany NY). 2020;12(14):14775-90. doi: 10.18632/aging.103539. PMID: 32652519; PMCID: PMC7425499.
14.       Dudekula DB, Panda AC, Grammatikakis I, De S, Abdelmohsen K, Gorospe M. CircInteractome: a web tool for exploring circular RNAs and their interacting proteins and microRNAs. RNA Biol. 2016;13(1):34-42. doi: 10.1080/15476286.2015.1128065. PMID: 26669964; PMCID: PMC4829301.
15.       Hashimoto Y, Akiyama Y, Yuasa Y. Multiple-to-multiple relationships between microRNAs and target genes in gastric cancer. PLoS One. 2013;8(5):e62589. doi: 10.1371/journal.pone.0062589. PMID: 23667495. PMCID: PMC3648557.
16.       Kern F, Aparicio-Puerta E, Li Y, Fehlmann T, Kehl T, Wagner V, et al. miRTargetLink 2.0-interactive miRNA target gene and target pathway networks. Nucleic Acids Res. 2021;49(W1):W409-16. doi: 10.1093/nar/gkab297. PMID: 34009375; PMCID: PMC8262750.
17.       Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q, Wang Z, et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 2016;44(W1):W90-7. doi: 10.1093/nar/gkw377. PMID: 27141961; PMCID: PMC4987924.
18.       Kanehisa M, Goto S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28(1):27-30. doi: 10.1093/nar/28.1.27. PMID: 10592173; PMCID: PMC102409.
19.       Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Mehryary F, Hachilif R, et al. The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 2023;51(D1):D638-46. doi: 10.1093/nar/gkac1000. PMID: 36370105; PMCID: PMC9825434.
20.       Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498-504. doi: 10.1101/gr.1239303. PMID: 14597658; PMCID: PMC403769.
21.       Collignon J, Lousberg L, Schroeder H, Jerusalem G. Triple-negative breast cancer: treatment challenges and solutions. Breast Cancer (Dove Med Press). 2016;8:93-107. doi: 10.2147/BCTT.S69488. PMID: 27284266; PMCID: PMC4881925.
22.       Elwan A, Abdelrahman AE, Alnagar AA, Abdelhamid MI, Nawar N. Clinicopathological features and treatment challenges in triple negative breast cancer patients: a retrospective cohort study. Turk J Pathol. 2021;37(2):121-29. doi: 10.5146/tjpath.2020.01516. PMID: 33432555; PMCID: PMC10512684.
23.       Liu X, Shan G. Mitochondria encoded non-coding RNAs in cell physiology. Front Cell Dev Biol. 2021;9:713729. doi: 10.3389/fcell.2021.713729. PMID: 34395442; PMCID: PMC8362354.
24.       Clemente-Suarez VJ, Martin-Rodriguez A, Redondo-Florez L, Ruisoto P, Navarro-Jimenez E, Ramos-Campo DJ, et al. Metabolic health, mitochondrial fitness, physical activity, and cancer. Cancers (Basel). 2023;15(3):814. doi: 10.3390/cancers15030814. PMID: 36765772; PMCID: PMC9913323.
25.       Pelicano H, Zhang W, Liu J, Hammoudi N, Dai J, Xu RH, et al. Mitochondrial dysfunction in some triple-negative breast cancer cell lines: role of mTOR pathway and therapeutic potential. Breast Cancer Res. 2014;16(5):434. doi: 10.1186/s13058-014-0434-6. PMID: 25209360; PMCID: PMC4303115.
26.       Baek ML, Lee J, Pendleton KE, Berner MJ, Goff EB, Tan L, et al. Mitochondrial structure and function adaptation in residual triple negative breast cancer cells surviving chemotherapy treatment. Oncogene. 2023;42(14):1117-31. doi: 10.1038/s41388-023-02596-8. PMID: 36813854; PMCID: PMC10069007.
27.       Fan L, Yao L, Li Z, Wan Z, Sun W, Qiu S, et al. Exosome-based mitochondrial delivery of circRNA mSCAR alleviates sepsis by orchestrating macrophage activation. Adv Sci (Weinh). 2023;10(14):e2205692. doi: 10.1002/advs.202205692. PMID: 36965082; PMCID: PMC10190648.
28.       Greene J, Baird AM, Brady L, Lim M, Gray SG, McDermott R, et al. Circular RNAs: biogenesis, function and role in human diseases. Front Mol Biosci. 2017;4:38. doi: 10.3389/fmolb.2017.00038. PMID: 28634583; PMCID: PMC5459888.
29.       Mohammadisoleimani E, Firoozi Z, Naghizadeh MM, Asad AG, Jafari A, Pourjafarian MH, et al. Expression analysis of hsa_circ_0020397, hsa_circ_0005986, hsa_circ_0003028, and hsa_circ_0006990 in renal cell carcinoma. Exp Mol Pathol. 2023;129:104848. doi: 10.1016/j.yexmp.2022.104848. PMID: 36496205.
30.       Wang Y, Zhang Z, Wang J. MicroRNA-384 inhibits the progression of breast cancer by targeting ACVR1. Oncol Rep. 2018;39(6):2563-74. doi: 10.3892/or.2018.6385. PMID: 29693185; PMCID: PMC5983929.
31.       Luo M, Ding L, Li Q, Yao H. miR-668 enhances the radioresistance of human breast cancer cell by targeting IκBα. Breast Cancer. 2017;24(5):673-82. doi: 10.1007/s12282-017-0756-1. PMID: 28138801.
32.       Costa RLB, Han HS, Gradishar WJ. Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: a review. Breast Cancer Res Treat. 2018;169(3):397-406. doi: 10.1007/s10549-018-4697-y. PMID: 29417298.
33.       Hutvagner G, Simard MJ. Argonaute proteins: key players in RNA silencing. Nat Rev Mol Cell Biol. 2008;9(1):22-32. doi: 10.1038/nrm2321. PMID: 18073770.
34.       Sadeghipour MM, Torabizadeh SA, Karimabad MN. The glucose-regulated protein78 (GRP78) in the unfolded protein response (UPR) pathway: a potential therapeutic target for breast cancer. Anticancer Agents Med Chem. 2023;23(5):505-24. doi: 10.2174/1871520622666220823094350. PMID: 36017846.
35.       Lin Y, Li Y, Chen X, Jin X, Jiang M, Xiao H, et al. YY1 mediated DCUN1D5 transcriptional activation promotes triple-negative breast cancer progression by targeting FN1/PI3K/AKT pathway. Biol Direct. 2024;19(1):42. doi: 10.1186/s13062-024-00481-2. PMID: 38831379; PMCID: PMC11145835.
Middle East Journal of Cancer

Articles in Press, Accepted Manuscript
Available Online from 01 July 2027

Home

Guide for Authors

Submit Manuscript

Guide for Reviewers

Contact Us