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Medical Oncology

, 36:86 | Cite as

Circular RNA expression and circPTPRM promotes proliferation and migration in hepatocellular carcinoma

  • Zhun Luo
  • Xuelan Mao
  • Wei CuiEmail author
Original Paper
  • 86 Downloads

Abstract

Circular RNAs (circRNAs) play a critical role during hepatocellular carcinoma (HCC) development. CircRNA PTPRM (circPTPRM) has not been reported to cause disease and its role in HCC is unclear. This study explored circRNA expression and the function of circPTPRM in HCC. RNA sequencing (RNA-seq) was performed on 3 randomly selected pairs of HCC tissues and their corresponding adjacent non-tumor tissues. Three differentially expressed circRNAs, circPTPRM, circSMAD2 and circPTBP3 were selected and verified by real-time quantitative reverse transcription-polymerase chain reactions in 30 pairs of tissue samples, In vitro cultured hepatoma cells, and normal liver cells. Clinical data analysis was performed to select target circRNAs. Anti-target circRNA siRNAs were transfected into hepatoma cell lines, and the biological behavior of hepatoma cells following silencing of the target circRNA were detected by cell proliferation, plate cloning, and transwell assays. There were 86 differentially expressed circRNAs from RNA-seq, of which 53 were significantly upregulated and 33 were significantly downregulated in HCC. CircPTPRM expression was significantly upregulated in HCC tissue (p = 0.023) based on the analysis of 30 paired samples. CircPTPRM expression positively correlated with HCC recurrence and metastasis (p = 0.039). CircPTPRM silencing reduced HCC cell proliferation, migration and invasion. CircRNAs were differentially expressed in HCC samples. CircPTPRM was significantly upregulated in HCC and may function during the tumorigenesis and metastasis of HCC.

Keywords

Hepatocellular carcinoma Circular RNA RNA sequencing circPTPRM 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Tu K, Dong Q, Tao J. Role of ncRNAs in hepatocellular carcinoma. Biomed Res Int. 2018;2018:3014543.  https://doi.org/10.1155/2018/3014543.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Heo MJ, Yun J, Kim SG. Role of non-coding RNAs in liver disease progression to hepatocellular carcinoma. Arch Pharm Res. 2019;42(1):48–62.  https://doi.org/10.1007/s12272-018-01104-x.CrossRefPubMedGoogle Scholar
  3. 3.
    Aravalli RN. Development of MicroRNA therapeutics for hepatocellular carcinoma. Diagnostics (Basel). 2013;3(1):170–91.  https://doi.org/10.3390/diagnostics3010170.CrossRefGoogle Scholar
  4. 4.
    Drakaki A, Hatziapostolou M, Iliopoulos D. Therapeutically targeting microRNAs in liver cancer. Curr Pharm Des. 2013;19(7):1180–91.PubMedGoogle Scholar
  5. 5.
    D’Anzeo M, Faloppi L, Scartozzi M, Giampieri R, Bianconi M, Del Prete M, et al. The role of micro-RNAs in hepatocellular carcinoma: from molecular biology to treatment. Molecules. 2014;19(5):6393–406.  https://doi.org/10.3390/molecules19056393.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Song Y, Wang F, Huang Q, Cao Y, Zhao Y, Yang C. MicroRNAs contribute to hepatocellular carcinoma. Mini Rev Med Chem. 2015;15(6):459–66.CrossRefGoogle Scholar
  7. 7.
    Jain R, Frederick JP, Huang EY, Burke KE, Mauger DM, Andrianova EA, et al. MicroRNAs enable mRNA therapeutics to selectively program cancer cells to self-destruct. Nucl Acid Ther. 2018;28(5):285–96.  https://doi.org/10.1089/nat.2018.0734.CrossRefGoogle Scholar
  8. 8.
    Abbastabar M, Sarfi M, Golestani A, Khalili E. lncRNA involvement in hepatocellular carcinoma metastasis and prognosis. EXCLI J. 2018;17:900–13.  https://doi.org/10.17179/excli2018-1541.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Lanzafame M, Bianco G, Terracciano LM, Ng CKY, Piscuoglio S. The role of long non-coding RNAs in hepatocarcinogenesis. Int J Mol Sci. 2018.  https://doi.org/10.3390/ijms19030682.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Chen S, Zhang Y, Wu X, Zhang C, Li G. Diagnostic value of lncRNAs as biomarker in hepatocellular carcinoma: an updated meta-analysis. Can J Gastroenterol Hepatol. 2018;2018:8410195.  https://doi.org/10.1155/2018/8410195.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Ding B, Lou W, Xu L, Fan W. Non-coding RNA in drug resistance of hepatocellular carcinoma. Biosci Rep. 2018.  https://doi.org/10.1042/bsr20180915.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Reuter JA, Spacek DV, Snyder MP. High-throughput sequencing technologies. Mol Cell. 2015;58(4):586–97.  https://doi.org/10.1016/j.molcel.2015.05.004.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Luscombe NM, Greenbaum D, Gerstein M. What is bioinformatics? A proposed definition and overview of the field. Methods Inf Med. 2001;40(4):346–58.CrossRefGoogle Scholar
  14. 14.
    Foulkes AC, Watson DS, Griffiths CEM, Warren RB, Huber W, Barnes MR. Research techniques made simple: bioinformatics for genome-scale biology. J Invest Dermatol. 2017;137(9):e163–8.  https://doi.org/10.1016/j.jid.2017.07.095.CrossRefPubMedGoogle Scholar
  15. 15.
    Qiu LP, Wu YH, Yu XF, Tang Q, Chen L, Chen KP. The emerging role of circular RNAs in hepatocellular carcinoma. J Cancer. 2018;9(9):1548–59.  https://doi.org/10.7150/jca.24566.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Hu J, Li P, Song Y, Ge YX, Meng XM, Huang C, et al. Progress and prospects of circular RNAs in hepatocellular carcinoma: novel insights into their function. J Cell Physiol. 2018;233(6):4408–22.  https://doi.org/10.1002/jcp.26154.CrossRefPubMedGoogle Scholar
  17. 17.
    Wang M, Yu F, Li P. Circular RNAs: characteristics, function and clinical significance in hepatocellular carcinoma. Cancers (Basel). 2018.  https://doi.org/10.3390/cancers10080258.CrossRefPubMedCentralGoogle Scholar
  18. 18.
    Qiu L, Huang Y, Li Z, Dong X, Chen G, Xu H, et al. Circular RNA profiling identifies circADAMTS13 as a miR-484 sponge which suppresses cell proliferation in hepatocellular carcinoma. Mol Oncol. 2019;13(2):441–55.  https://doi.org/10.1002/1878-0261.12424.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Zhang J, Chang Y, Xu L, Qin L. Elevated expression of circular RNA circ_0008450 predicts dismal prognosis in hepatocellular carcinoma and regulates cell proliferation, apoptosis, and invasion via sponging miR-548p. J Cell Biochem. 2018.  https://doi.org/10.1002/jcb.28224.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Xie B, Zhao Z, Liu Q, Wang X, Ma Z, Li H. CircRNA has_circ_0078710 acts as the sponge of microRNA-31 involved in hepatocellular carcinoma progression. Gene. 2019;683:253–61.  https://doi.org/10.1016/j.gene.2018.10.043.CrossRefPubMedGoogle Scholar
  21. 21.
    Xiong DD, Dang YW, Lin P, Wen DY, He RQ, Luo DZ, et al. A circRNA-miRNA-mRNA network identification for exploring underlying pathogenesis and therapy strategy of hepatocellular carcinoma. J Transl Med. 2018;16(1):220.  https://doi.org/10.1186/s12967-018-1593-5.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Pamudurti NR, Bartok O, Jens M, Ashwal-Fluss R, Stottmeister C, Ruhe L, et al. Translation of CircRNAs. Mol Cell. 2017;66(1):9–21.  https://doi.org/10.1016/j.molcel.2017.02.021.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Wesselhoeft RA, Kowalski PS, Anderson DG. Engineering circular RNA for potent and stable translation in eukaryotic cells. Nat Commun. 2018;9(1):2629.  https://doi.org/10.1038/s41467-018-05096-6.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Dong R, Zhang XO, Zhang Y, Ma XK, Chen LL, Yang L. CircRNA-derived pseudogenes. Cell Res. 2016;26(6):747–50.  https://doi.org/10.1038/cr.2016.42.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Zhang XO, Dong R, Zhang Y, Zhang JL, Luo Z, Zhang J, et al. Diverse alternative back-splicing and alternative splicing landscape of circular RNAs. Genome Res. 2016;26(9):1277–87.  https://doi.org/10.1101/gr.202895.115.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Zhang M, Huang N, Yang X, Luo J, Yan S, Xiao F, et al. A novel protein encoded by the circular form of the SHPRH gene suppresses glioma tumorigenesis. Oncogene. 2018;37(13):1805–14.  https://doi.org/10.1038/s41388-017-0019-9.CrossRefGoogle Scholar
  27. 27.
    Holdt LM, Stahringer A, Sass K, Pichler G, Kulak NA, Wilfert W, et al. Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans. Nat Commun. 2016;7:12429.  https://doi.org/10.1038/ncomms12429.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Glazar P, Papavasileiou P, Rajewsky N. circBase: a database for circular RNAs. RNA. 2014;20(11):1666–70.  https://doi.org/10.1261/rna.043687.113.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Tautz L, Critton DA, Grotegut S. Protein tyrosine phosphatases: structure, function, and implication in human disease. Methods Mol Biol. 2013;1053:179–221.  https://doi.org/10.1007/978-1-62703-562-0_13.CrossRefPubMedGoogle Scholar
  30. 30.
    Bouyain S. Protein tyrosine phosphatases. Semin Cell Dev Biol. 2015;37:56–7.  https://doi.org/10.1016/j.semcdb.2015.01.004.CrossRefPubMedGoogle Scholar
  31. 31.
    Bollu LR, Mazumdar A, Savage MI, Brown PH. Molecular pathways: targeting protein tyrosine phosphatases in cancer. Clin Cancer Res. 2017;23(9):2136–42.  https://doi.org/10.1158/1078-0432.CCR-16-0934.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Hellberg CB, Burden-Gulley SM, Pietz GE, Brady-Kalnay SM. Expression of the receptor protein-tyrosine phosphatase, PTPmu, restores E-cadherin-dependent adhesion in human prostate carcinoma cells. J Biol Chem. 2002;277(13):11165–73.  https://doi.org/10.1074/jbc.M112157200.CrossRefPubMedGoogle Scholar
  33. 33.
    Sun PH, Ye L, Mason MD, Jiang WG. Protein tyrosine phosphatase micro (PTP micro or PTPRM), a negative regulator of proliferation and invasion of breast cancer cells, is associated with disease prognosis. PLoS ONE. 2012;7(11):e50183.  https://doi.org/10.1371/journal.pone.0050183.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Laczmanska I, Karpinski P, Bebenek M, Sedziak T, Ramsey D, Szmida E, et al. Protein tyrosine phosphatase receptor-like genes are frequently hypermethylated in sporadic colorectal cancer. J Hum Genet. 2013;58(1):11–5.  https://doi.org/10.1038/jhg.2012.119.CrossRefPubMedGoogle Scholar
  35. 35.
    Han D, Li J, Wang H, Su X, Hou J, Gu Y, et al. Circular RNA circMTO1 acts as the sponge of microRNA-9 to suppress hepatocellular carcinoma progression. Hepatology. 2017;66(4):1151–64.  https://doi.org/10.1002/hep.29270.CrossRefPubMedGoogle Scholar
  36. 36.
    Shi L, Yan P, Liang Y, Sun Y, Shen J, Zhou S, et al. Circular RNA expression is suppressed by androgen receptor (AR)-regulated adenosine deaminase that acts on RNA (ADAR1) in human hepatocellular carcinoma. Cell Death Dis. 2017;8(11):e3171.  https://doi.org/10.1038/cddis.2017.556.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Zhu Q, Lu G, Luo Z, Gui F, Wu J, Zhang D, et al. CircRNA circ_0067934 promotes tumor growth and metastasis in hepatocellular carcinoma through regulation of miR-1324/FZD5/Wnt/beta-catenin axis. Biochem Biophys Res Commun. 2018;497(2):626–32.  https://doi.org/10.1016/j.bbrc.2018.02.119.CrossRefPubMedGoogle Scholar
  38. 38.
    Zhang X, Xu Y, Qian Z, Zheng W, Wu Q, Chen Y, et al. circRNA_104075 stimulates YAP-dependent tumorigenesis through the regulation of HNF4a and may serve as a diagnostic marker in hepatocellular carcinoma. Cell Death Dis. 2018;9(11):1091.  https://doi.org/10.1038/s41419-018-1132-6.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Zhang X, Luo P, Jing W, Zhou H, Liang C, Tu J. circSMAD2 inhibits the epithelial-mesenchymal transition by targeting miR-629 in hepatocellular carcinoma. Onco Targets Ther. 2018;11:2853–63.  https://doi.org/10.2147/OTT.S158008.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Li Z, Huang C, Bao C, Chen L, Lin M, Wang X, et al. Exon-intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol. 2015;22(3):256–64.  https://doi.org/10.1038/nsmb.2959.CrossRefPubMedGoogle Scholar
  41. 41.
    Li F, Zhang L, Li W, Deng J, Zheng J, An M, et al. Circular RNA ITCH has inhibitory effect on ESCC by suppressing the Wnt/beta-catenin pathway. Oncotarget. 2015;6(8):6001–13.  https://doi.org/10.18632/oncotarget.3469.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Wang J, Huang F, Huang J, Kong J, Liu S, Jin J. Epigenetic analysis of FHL1 tumor suppressor gene in human liver cancer. Oncol Lett. 2017;14(5):6109–16.  https://doi.org/10.3892/ol.2017.6950.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Wu J, Du C, Lv Z, Ding C, Cheng J, Xie H, et al. The up-regulation of histone deacetylase 8 promotes proliferation and inhibits apoptosis in hepatocellular carcinoma. Dig Dis Sci. 2013;58(12):3545–53.  https://doi.org/10.1007/s10620-013-2867-7.CrossRefPubMedGoogle Scholar
  44. 44.
    Wang LT, Chiou SS, Chai CY, Hsi E, Wang SN, Huang SK, et al. Aryl hydrocarbon receptor regulates histone deacetylase 8 expression to repress tumor suppressive activity in hepatocellular carcinoma. Oncotarget. 2017;8(5):7489–501.  https://doi.org/10.18632/oncotarget.9841.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Infectious Diseases, The First Affiliated HospitalChina Medical UniversityShenyangChina
  2. 2.Department of Infectious DiseasesYueyang Second People’s HospitalYueyangChina

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