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Circ_0012152 Accelerates Acute Myeloid Leukemia Progression through the miR-652-3p/SOX4 Axis

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Abstract

Objective

Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by abnormal myeloid blast expansion. Recent studies have demonstrated that circular RNAs play a role in AML pathogenesis. In this study, we aimed to investigate the clinical significance of circ_0012152 in AML and elucidate its underlying molecular mechanism in the pathogenesis of this condition.

Methods

Circ_0012152 expression was detected by quantitative real-time polymerase chain reaction in samples obtained from 247 patients with AML and 40 healthy controls. A systematic analysis of clinical characteristics and prognostic factors was also conducted. Cell growth was assessed using the Cell Counting Kit-8 (CCK-8) assay, and apoptosis and cell cycle progression were evaluated by flow cytometry. Moreover, RNA pull-down was performed to identify target microRNAs, and transcriptome RNA sequencing and bioinformatics analyses were utilized to identify downstream mRNA targets.

Results

Circ_0012152 was significantly upregulated in samples from patients with AML and served as an independent adverse prognostic factor for overall survival (OS) (hazard ratio: 2.357; 95% confidence interval 1.258–4.415). The circ_0012152 knockdown reduced cell growth, increased apoptosis, and inhibited cell cycle progression in AML cell lines. RNA pull-down and sequencing identified miR-652-3p as a target microRNA of circ_0012152. Cell growth inhibition by circ_0012152 knockdown was significantly relieved by miR-652-3p inhibitors. We suggested that miR-652-3p targeted SOX4, as the decrease in SOX4 expression resulting from circ_0012152 knockdown was upregulated by miR-652-3p inhibitors in AML cells.

Conclusion

Circ_0012152 is an independent poor prognostic factor for OS in AML, and it promotes AML cell growth by upregulating SOX4 through miR-652-3p.

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References

  1. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. N Engl J Med, 2016,374(23):2209–2221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Burnett A, Stone R. AML: New Drugs but New Challenges. Clin Lymphoma Myeloma Leuk, 2020,20(6):341–350

    Article  PubMed  Google Scholar 

  3. Thol F, Ganser A. Treatment of Relapsed Acute Myeloid Leukemia. Curr Treat Options Oncol, 2020,21(8):66

    Article  PubMed  PubMed Central  Google Scholar 

  4. Cummins KD, Gill S. Will CAR T-cell therapy have a role in AML? Promises and pitfalls. Seminars in hematol, 2019,56(2):155–163

    Article  Google Scholar 

  5. Fennell KA, Bell CC, Dawson MA. Epigenetic therapies in acute myeloid leukemia: where to from here? Blood, 2019,134(22):1891–1901

    Article  PubMed  Google Scholar 

  6. Kumar S, Gonzalez EA, Rameshwar P, et al. Non-Coding RNAs as Mediators of Epigenetic Changes in Malignancies. Cancers (Basel), 2020,12(12):3657

    Article  CAS  PubMed  Google Scholar 

  7. Jeck WR, Sorrentino JA, Wang K, et al. Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA, 2013,19(2):141–157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Verduci L, Strano S, Yarden Y, et al. The circRNA-microRNA code: emerging implications for cancer diagnosis and treatment. Mol Oncol, 2019,13(4):669–680

    Article  PubMed  PubMed Central  Google Scholar 

  9. Li A, Wang WC, McAlister V, et al. Circular RNA in colorectal cancer. J Cell Mol Med, 2021, 25(8):3667–3679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lei B, Tian Z, Fan W, et al. Circular RNA: a novel biomarker and therapeutic target for human cancers. Int J Med Sci, 2019,16(2):292–301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fu L, Tang D, Sun A, et al. Recent progress in study of circRNAs and its role in leukemia. J Leukoc Biol, 2021,109(4):731–739

    Article  CAS  PubMed  Google Scholar 

  12. Ding Y, Dong Y, Lu H, et al. Circular RNA profile of acute myeloid leukemia indicates circular RNA annexin A2 as a potential biomarker and therapeutic target for acute myeloid leukemia. Am J Transl Res, 2020,12(5):1683–1699

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Hu Q, Gu Y, Chen S, et al. Hsa_circ_0079480 promotes tumor progression in acute myeloid leukemia via miR-654-3p/HDGF axis. Aging (Albany NY), 2020,13(1):1120–1131

    Article  PubMed  Google Scholar 

  14. Zhou X, Zhan L, Huang K, et al. The functions and clinical significance of circRNAs in hematological malignancies. J Hematol Oncol, 2020,13(1):138

    Article  PubMed  PubMed Central  Google Scholar 

  15. Li W, Zhong C, Jiao J, et al. Characterization of hsa_circ_0004277 as a New Biomarker for Acute Myeloid Leukemia via Circular RNA Profile and Bioinformatics Analysis. Int J Mol Sci, 2017,18(3):597

    Article  PubMed  PubMed Central  Google Scholar 

  16. Rybak-Wolf A, Stottmeister C, Glažar P, et al. Circular RNAs in the Mammalian Brain Are Highly Abundant, Conserved, and Dynamically Expressed. Mol Cell, 2015,58(5):870–885

    Article  CAS  PubMed  Google Scholar 

  17. Kristensen LS, Hansen TB, Venø MT, et al. Circular RNAs in cancer: opportunities and challenges in the field. Oncogene, 2018,37(5):555–565

    Article  CAS  PubMed  Google Scholar 

  18. Li Z, Huang C, Bao C, et al. Exon–intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol, 2015,22(3):256–264

    Article  PubMed  Google Scholar 

  19. Guo S, Li B, Chen Y, et al. Hsa_circ_0012152 and Hsa_circ_0001857 Accurately Discriminate Acute Lymphoblastic Leukemia From Acute Myeloid Leukemia. Front Oncol, 2020,10(1655):1–13

    Google Scholar 

  20. Shang Z, Ming X, Wu J, et al. Downregulation of circ_0012152 inhibits proliferation and induces apoptosis in acute myeloid leukemia cells through the miR-625-5p/SOX12 axis. Hematol Oncol, 2021,39(4):539–548

    Article  CAS  PubMed  Google Scholar 

  21. Liu X, Liu X, Cai M, et al. CircRNF220, not its linear cognate gene RNF220, regulates cell growth and is associated with relapse in pediatric acute myeloid leukemia. Mol Cancer, 2021,20(1):139

    Article  PubMed  PubMed Central  Google Scholar 

  22. Zhang Z, Lin S, Yin J, et al. CircRNF220 plays a pathogenic role to facilitate cell progression of AML in vitro by sponging miR-330-5p to induce upregulation of SOX4. Histol Histopathol, 2022,37(10):1019–1030

    CAS  PubMed  Google Scholar 

  23. Bataller A, Garrido A, Guijarro F, et al. European LeukemiaNet 2017 risk stratification for acute myeloid leukemia: validation in a risk-adapted protocol. Blood Adv, 2022,6(4):1193–1206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. De Kouchkovsky I, Abdul-Hay M. Acute myeloid leukemia: a comprehensive review and 2016 update. Blood Cancer J, 2016,6(7):e441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Levis M. FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013? Hematology Am Soc Hematol Educ Program, 2013,2013:220–226

    Article  PubMed  Google Scholar 

  26. Nicolet BP, Engels S, Aglialoro F, et al. Circular RNA expression in human hematopoietic cells is widespread and cell-type specific. Nucleic Acids Res, 2018,46(16):8168–8180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang F, Jiang J, Qian H, et al. Exosomal circRNA: emerging insights into cancer progression and clinical application potential. J Hematol Oncol, 2023,16(1):67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhou B, Mo Z, Lai G, et al. Targeting tumor exosomal circular RNA cSERPINE2 suppresses breast cancer progression by modulating MALT1-NF-κB-IL-6 axis of tumor-associated macrophages. J Exp Clin Cancer Res, 2023,42(1):48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sun X, Dongol S, Qiu C, et al. miR-652 Promotes Tumor Proliferation and Metastasis by Targeting RORA in Endometrial Cancer. Mol Cancer Res, 2018,16(12):1927–1939

    Article  CAS  PubMed  Google Scholar 

  30. Chao Y, Yang C, **ong W, et al. miR-652 Inhibits the Proliferation, Migration, and Invasion of Osteosarcoma Cells by Targeting HOXA9 and Regulating the PI3K/Akt Signaling Pathway. J Oncol, 2022,2022:4809312

    Google Scholar 

  31. Jiang Q, Lu X, Huang P, et al. Expression of miR-652-3p and Effect on Apoptosis and Drug Sensitivity in Pediatric Acute Lymphoblastic Leukemia. Biomed Res Int, 2018,2018:5724686

    Article  PubMed  PubMed Central  Google Scholar 

  32. Zhang J, **ao C, Feng Z, et al. SOX4 promotes the growth and metastasis of breast cancer. Cancer Cell Int, 2020,20:468

    Article  PubMed  PubMed Central  Google Scholar 

  33. Lu JW, Hsieh MS, Hou HA, et al. Overexpression of SOX4 correlates with poor prognosis of acute myeloid leukemia and is leukemogenic in zebrafish. Blood Cancer J, 2017,7(8):e593

    Article  PubMed  PubMed Central  Google Scholar 

  34. Gruszka AM, Valli D, Alcalay M. Wnt Signaling in Acute Myeloid Leukemia. Cells, 2019, 8(11):1403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tickenbrock L, Schwäble J, Wiedehage M, et al. Flt3 tandem duplication mutations cooperate with Wnt signaling in leukemic signal transduction. Blood, 2005,105(9):3699–3706

    Article  CAS  PubMed  Google Scholar 

  36. Moreno CS. SOX4: The unappreciated oncogene. Semin Cancer Biol 2020,67(Pt 1):57–64

    Article  CAS  PubMed  Google Scholar 

  37. Qu Y, Wang Y, Wang P, et al. Overexpression of long noncoding RNA HOXA-AS2 predicts an adverse prognosis and promotes tumorigenesis via SOX4/PI3K/AKT pathway in acute myeloid leukemia. Cell Biol Int, 2020,44(8):1745–1759

    Article  CAS  PubMed  Google Scholar 

  38. Mehta GA, Parker JS, Silva GO, et al. Amplification of SOX4 promotes PI3K/Akt signaling in human breast cancer. Breast Cancer Res Treat, 2017,162(3):439–450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ramezani-Rad P, Geng H, Hurtz C, et al. SOX4 enables oncogenic survival signals in acute lymphoblastic leukemia. Blood, 2013,121(1):148–155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Author notes

  1. The authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Stem Cell Transplantation, The First Affiliated Hospital of Ningbo University, Ningbo, 315300, China

    Ying Chen, Ting-ting Niu, Duo-bing Zou, Ning-ning Wu & Qi-tian Mu

  2. Ningbo Clinical Research Center For Hematologic Malignancies, Ningbo, 315300, China

    Ying Chen, Bi-xia Li, Ting-ting Niu, Shu-jun Yang, Le-huai Shi, Duo-bing Zou, Ning-ning Wu, Li-xia Sheng, **ao Yan, Gui-fang Ouyang & Qi-tian Mu

  3. Department of Hematology, The First Affiliated Hospital of Ningbo University, Ningbo, 315300, China

    Bi-xia Li, Shu-jun Yang, Li-xia Sheng, **ao Yan & Gui-fang Ouyang

  4. School of Medicine, Hangzhou City University, Zhejiang University, Hangzhou, 310000, China

    Li-chao Wu

  5. Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang Province, Ningbo, 315300, China

    Qi-tian Mu

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  1. Ying Chen
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Corresponding authors

Correspondence to **ao Yan, Gui-fang Ouyang or Qi-tian Mu.

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The authors declare no competing interests.

Additional information

This research was supported by grants from the Natural Science Foundation of Zhejiang Province (No. LY20H080001), and Medical and Health Science and Technology Projects of Zhejiang Province (No. 2021KY997, No. 2022KY306, No. 2022KY316, No. 2023KY263).

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Chen, Y., Li, Bx., Niu, Tt. et al. Circ_0012152 Accelerates Acute Myeloid Leukemia Progression through the miR-652-3p/SOX4 Axis. CURR MED SCI 44, 611–622 (2024). https://doi.org/10.1007/s11596-024-2878-y

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  • DOI: https://doi.org/10.1007/s11596-024-2878-y

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