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CircRNA_OTUD7A upregulates FOXP1 expression to facilitate the progression of diffuse large B-cell lymphoma via acting as a sponge of miR-431-5p

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Abstract

Background

A growing number of studies have shown that circular RNA (circRNA) is an important regulator molecule in cancer progression, but it has been poorly studied in diffuse large b-cell lymphoma (DLBCL).

Objective

This study aimed to explore the role of circ_OTUD7A in DLBCL.

Methods

Relative expression levels of circ_OTUD7A, microRNA (miR)-431-5p and forkhead box P1 (FOXP1) were determined by quantitative real-time PCR (qRT-PCR). The proliferation of cells was elevated by colony formation assay and MTT assay. Western blot (WB) analysis was employed to measure the protein levels of proliferation marker, epithelial-mesenchymal transition (EMT) markers, cyclin marker, apoptosis markers and FOXP1. Moreover, the apoptosis, cell cycle process, migration and invasion of cells were detected using flow cytometry and transwell assay, respectively. In addition, the interaction between miR-431-5p and circ_OTUD7A or FOXP1 was confirmed by dual-luciferase reporter assay.

Results

Circ_OTUD7A was highly expressed in DLBCL, and its knockdown could inhibit DLBCL cell proliferation and metastasis, while promote cell cycle arrest and apoptosis. Similarly, FOXP1 also was upregulated in DLBCL, and its silencing could restrain the progression of DLBCL cells. Further experiments revealed that circ_OTUD7A could sponge miR-431-5p and miR-431-5p could target FOXP1. MiR-431-5p inhibitor could reverse the suppressive effect of circ_OTUD7A silencing on DLBCL progression, and FOXP1 overexpression also could reverse the inhibitory effect of miR-431-5p mimic on DLBCL progression.

Conclusion

Circ_OTUD7A promoted the progression of DLBCL by regulating the miR-431-5p/FOXP1 axis, which suggested that circ_OTUD7A might function as an oncogene in DLBCL.

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Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  • Barrans SL, Fenton JA, Banham A, Owen RG, Jack AS (2004) Strong expression of FOXP1 identifies a distinct subset of diffuse large B-cell lymphoma (DLBCL) patients with poor outcome. Blood 104:2933–2935

    Article  CAS  Google Scholar 

  • Belousova EA, Filipenko ML, Kushlinskii NE (2018) Circular RNA: new regulatory molecules. Bull Exp Biol Med 164:803–815

    Article  CAS  Google Scholar 

  • Braccioli L, Nijboer CH, Coffer PJ (2018) Forkhead box protein P1, a key player in neuronal development? Neural Regen Res 13:801–802

    Article  Google Scholar 

  • Chen B, Huang S (2018) Circular RNA: An emerging non-coding RNA as a regulator and biomarker in cancer. Cancer Lett 418:41–50

    Article  CAS  Google Scholar 

  • Chen H, Xiao Z, Yu R, Wang Y, Xu R, Zhu X (2018) miR-181d-5p-FOXP1 feedback loop modulates the progression of osteosarcoma. Biochem Biophys Res Commun 503:1434–1441

    Article  CAS  Google Scholar 

  • Craig VJ, Cogliatti SB, Imig J, Renner C, Neuenschwander S, Rehrauer H, Schlapbach R, Dirnhofer S, Tzankov A, Muller A (2011) Myc-mediated repression of microRNA-34a promotes high-grade transformation of B-cell lymphoma by dysregulation of FoxP1. Blood 117:6227–6236

    Article  CAS  Google Scholar 

  • Dudekula DB, Panda AC, Grammatikakis I, De S, Abdelmohsen K, Gorospe M (2016) CircInteractome: a web tool for exploring circular RNAs and their interacting proteins and microRNAs. RNA Biol 13:34–42

    Article  Google Scholar 

  • Ebbesen KK, Hansen TB, Kjems J (2017) Insights into circular RNA biology. RNA Biol 14:1035–1045

    Article  Google Scholar 

  • Eger N, Schoppe L, Schuster S, Laufs U, Boeckel JN (2018) Circular RNA splicing. Adv Exp Med Biol 1087:41–52

    Article  CAS  Google Scholar 

  • Flori M, Schmid CA, Sumrall ET, Tzankov A, Law CW, Robinson MD, Muller A (2016) The hematopoietic oncoprotein FOXP1 promotes tumor cell survival in diffuse large B-cell lymphoma by repressing S1PR2 signaling. Blood 127:1438–1448

    Article  CAS  Google Scholar 

  • Gascoyne DM, Banham AH (2017) The significance of FOXP1 in diffuse large B-cell lymphoma. Leuk Lymphoma 58:1037–1051

    Article  CAS  Google Scholar 

  • Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, Muller-Hermelink HK, Campo E, Braziel RM, Jaffe ES et al (2004) Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 103:275–282

    Article  CAS  Google Scholar 

  • Hoeller S, Schneider A, Haralambieva E, Dirnhofer S, Tzankov A (2010) FOXP1 protein overexpression is associated with inferior outcome in nodal diffuse large B-cell lymphomas with non-germinal centre phenotype, independent of gains and structural aberrations at 3p14.1. Histopathology 57:73–80

    Article  Google Scholar 

  • Hsiao KY, Sun HS, Tsai SJ (2017) Circular RNA—new member of noncoding RNA with novel functions. Exp Biol Med (Maywood) 242:1136–1141

    Article  CAS  Google Scholar 

  • Hu Y, Zhao Y, Shi C, Ren P, Wei B, Guo Y, Ma J (2019a) A circular RNA from APC inhibits the proliferation of diffuse large B-cell lymphoma by inactivating Wnt/beta-catenin signaling via interacting with TET1 and miR-888. Aging (Albany NY) 11:8068–8084

    Article  CAS  Google Scholar 

  • Hu YT, Li XX, Zeng LW (2019b) Circ_0001742 promotes tongue squamous cell carcinoma progression via miR-431-5p/ATF3 axis. Eur Rev Med Pharmacol Sci 23:10300–10312

    PubMed  Google Scholar 

  • Huang A, Zheng H, Wu Z, Chen M, Huang Y (2020) Circular RNA-protein interactions: functions, mechanisms, and identification. Theranostics 10:3503–3517

    Article  CAS  Google Scholar 

  • Jiang Q, Cheng L, Ma D, Zhao Y (2019) FBXL19-AS1 exerts oncogenic function by sponging miR-431–5p to regulate RAF1 expression in lung cancer. Biosci Rep 39:BSR20181804

    Article  CAS  Google Scholar 

  • Katoh M, Igarashi M, Fukuda H, Nakagama H, Katoh M (2013) Cancer genetics and genomics of human FOX family genes. Cancer Lett 328:198–206

    Article  CAS  Google Scholar 

  • Kim JH, Hwang J, Jung JH, Lee HJ, Lee DY, Kim SH (2019) Molecular networks of FOXP family: dual biologic functions, interplay with other molecules and clinical implications in cancer progression. Mol Cancer 18:180

    Article  Google Scholar 

  • Kong Q, Han J, Deng H, Wu F, Guo S, Ye Z (2018) miR-431-5p alters the epithelial-to-mesenchymal transition markers by targeting UROC28 in hepatoma cells. Onco Targets Ther 11:6489–6503

    Article  CAS  Google Scholar 

  • Lagunas-Rangel FA (2020) Circular RNAs and their participation in stemness of cancer. Med Oncol 37:42

    Article  CAS  Google Scholar 

  • Li JH, Liu S, Zhou H, Qu LH, Yang JH (2014) starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res 42:D92-97

    Article  CAS  Google Scholar 

  • Li S, Young KH, Medeiros LJ (2018) Diffuse large B-cell lymphoma. Pathology 50:74–87

    Article  Google Scholar 

  • Liu AN, Qu HJ, Yu CY, Sun P (2018a) Knockdown of LINC01614 inhibits lung adenocarcinoma cell progression by up-regulating miR-217 and down-regulating FOXP1. J Cell Mol Med 22:4034–4044

    Article  CAS  Google Scholar 

  • Liu W, Ma W, Yuan Y, Zhang Y, Sun S (2018b) Circular RNA hsa_circRNA_103809 promotes lung cancer progression via facilitating ZNF121-dependent MYC expression by sequestering miR-4302. Biochem Biophys Res Commun 500:846–851

    Article  CAS  Google Scholar 

  • Liu Y, Gonzalez Y, Amengual JE (2019) Chromatin-remodeled state in lymphoma. Curr Hematol Malig Rep 14:439–450

    Article  Google Scholar 

  • Meng Y, Quan L, Liu A (2018) Identification of key microRNAs associated with diffuse large B-cell lymphoma by analyzing serum microRNA expressions. Gene 642:205–211

    Article  CAS  Google Scholar 

  • Qin W, Xie W, He Q, Sun T, Meng C, Yang K, Luo Y, Yang D (2018) MicroRNA-152 inhibits ovarian cancer cell proliferation and migration and may infer improved outcomes in ovarian cancer through targeting FOXP1. Exp Ther Med 15:1672–1679

    CAS  PubMed  Google Scholar 

  • Qu S, Yang X, Li X, Wang J, Gao Y, Shang R, Sun W, Dou K, Li H (2015) Circular RNA: a new star of noncoding RNAs. Cancer Lett 365:141–148

    Article  CAS  Google Scholar 

  • Rosenwald A, Staudt LM (2003) Gene expression profiling of diffuse large B-cell lymphoma. Leuk Lymphoma 44(Suppl 3):S41-47

    Article  CAS  Google Scholar 

  • Wang X, Sun J, Cui M, Zhao F, Ge C, Chen T, Yao M, Li J (2016) Downregulation of FOXP1 inhibits cell proliferation in hepatocellular carcinoma by inducing G1/S phase cell cycle arrest. Int J Mol Sci 17:1501

    Article  Google Scholar 

  • Wang H, Xiao Y, Wu L, Ma D (2018) Comprehensive circular RNA profiling reveals the regulatory role of the circRNA-000911/miR-449a pathway in breast carcinogenesis. Int J Oncol 52:743–754

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao ZJ, Shen J (2017) Circular RNA participates in the carcinogenesis and the malignant behavior of cancer. RNA Biol 14:514–521

    Article  Google Scholar 

  • Zhao Y, Cui WL, Feng ZY, Xue J, Gulinaer A, Zhang W (2020) Expression of Foxp3 and interleukin-7 receptor and clinicopathological characteristics of patients with diffuse large B-cell lymphoma. Oncol Lett 19:2755–2764

    CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Hematology, The First Hospital of Yulin, Yulin, Shaanxi, China

    Wei Liu

  2. Clinical Laboratory, The First Hospital of Yulin, No. 59 Yuxi Avenue, Yulin, 719000, Shaanxi, China

    Lei Lei, Xiaoying Liu & Suiyan Ye

Authors
  1. Wei Liu
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  2. Lei Lei
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  3. Xiaoying Liu
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  4. Suiyan Ye
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Contributions

WL was principal investigator, designed the study. LL supervised experiments. SY wrote the manuscript. XL. All authors agreed and approved the manuscript to be published.

Corresponding author

Correspondence to Suiyan Ye.

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Conflict of interest

Wei Liu, Lei Lei, Xiaoying Liu and Suiyan Ye declare that they have no conflict of interest.

Ethical approval

Enrolled patients signed informed consent, and this study was approved by the Ethics Committee of The First Hospital of Yulin.

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Supplementary Information

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13258_2021_1094_MOESM1_ESM.tif

Supplementary Fig. 1 The protein levels of CyclinD1, Bcl-2 and Bax in each treatment group. (A-C) WB analysis was used to detect the protein levels of CyclinD1, Bcl-2 and Bax in U2932 and TMD8 cells transfected with si-circ_OTUD7A or si-NC. (D-F) The protein levels of CyclinD1, Bcl-2 and Bax in U2932 and TMD8 cells transfected with sh-FOXP1 or sh-NC were measured by WB analysis. (G-I) U2932 and TMD8 cells were transfected with si-NC, si-circ_OTUD7A, si-circ_OTUD7A + anti-miR-NC or si-circ_OTUD7A + anti-miR-431-5p. WB analysis was performed to examine the protein levels of CyclinD1, Bcl-2 and Bax. (J-L) U2932 and TMD8 cells were transfected with miR-NC, miR-431-5p, miR-431-5p + pcDNA or miR-431-5p + FOXP1. The protein levels of CyclinD1, Bcl-2 and Bax were determined using WB analysis. *P < 0.05

13258_2021_1094_MOESM2_ESM.tif

Supplementary Fig. 2 The expression of candidate miRNAs for circ_OTUD7A. U2932 and TMD8 cells were transfected with si-circ_OTUD7A or si-NC. The expression of miR-431-5p and miR-324-5p in U2932 cells (A) and TMD8 cells (B) was detected by qRT-PCR. *P < 0.05

13258_2021_1094_MOESM3_ESM.tif

Supplementary Fig. 3 The representative image for Fig. 6. (A) The images of colony formation assay for Fig. 6B. (B) The images of cell cycle for Fig. 6F-G. (C) The image of cell apoptosis for Fig. 6H. (D) The image of cell migration for Fig. 6I. (E) The images of cell invasion for Fig. 6J

13258_2021_1094_MOESM4_ESM.tif

Supplementary Fig. 4 The representative image for Fig. 7. (A) The images of colony formation assay for Fig. 7C. (B) The images of cell cycle for Fig. 7G-H. (C) The image of cell apoptosis for Fig. 7I. (D) The image of cell migration for Fig. 7J. (E) The images of cell invasion for Fig. 7K

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Liu, W., Lei, L., Liu, X. et al. CircRNA_OTUD7A upregulates FOXP1 expression to facilitate the progression of diffuse large B-cell lymphoma via acting as a sponge of miR-431-5p. Genes Genom 43, 653–667 (2021). https://doi.org/10.1007/s13258-021-01094-z

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  • DOI: https://doi.org/10.1007/s13258-021-01094-z

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