Long non-coding RNA CCAT2 as a potential serum biomarker for diagnosis and prognosis of multiple myeloma


Increasing knowledge of long non-coding RNAs (lncRNAs) has shown that they can be used as circulating tumor markers. Also, considerable evidences have revealed that lncRNAs have important roles in tumor diagnosis and prognosis. The lncRNA CCAT2 has manifested its carcinogenic effect in a variety of tumors, but the serum expression level and clinical value in multiple myeloma (MM) remain to be explored. In our study, the expression of lncRNA CCAT2 is upregulated in the serum and bone marrow of MM patients by using quantitative real-time polymerase chain reaction (qRT-PCR). The high expression level of CCAT2 in the serum of MM patients correlated with International Scoring System (ISS) stages, renal dysfunction, serum β2-microglobulin (β2-MG) concentration, and light chain (κ and λ) concentrations. Area under the curve (AUC) of CCAT2 in serum is 0.899. Besides, the sensitivity and specificity were 85.80% and 83%, respectively. Furthermore, combination of CCAT2, IgA, HGB, and β2-MG significantly improved the MM diagnostic sensitivity and AUC. Here, our present investigation indicates that serum circulating CCAT2 may serve as a potential tumor marker for diagnosis and prognosis of MM.

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  1. 1.

    Ronchetti D, Agnelli L, Pietrelli A, Todoerti K, Manzoni M, Taiana E, Neri A (2018) A compendium of long non-coding RNAs transcriptional fingerprint in multiple myeloma. Sci Rep 8(1):6557. https://doi.org/10.1038/s41598-018-24701-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Amodio N, Stamato MA, Juli G, Morelli E, Fulciniti M, Manzoni M, Taiana E, Agnelli L, Cantafio MEG, Romeo E, Raimondi L, Caracciolo D, Zuccala V, Rossi M, Neri A, Munshi NC, Tagliaferri P, Tassone P (2018) Drugging the lncRNA MALAT1 via LNA gapmeR ASO inhibits gene expression of proteasome subunits and triggers anti-multiple myeloma activity. Leukemia. 32:1948–1957. https://doi.org/10.1038/s41375-018-0067-3

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Zhao L, Ji G, Le X, Wang C, Xu L, Feng M, Zhang Y, Yang H, Xuan Y, Yang Y, Lei L, Yang Q, Lau WB, Lau B, Chen Y, Deng X, Yao S, Yi T, Zhao X, Wei Y, Zhou S (2017) Long noncoding RNA LINC00092 acts in cancer-associated fibroblasts to drive glycolysis and progression of ovarian cancer. Cancer Res 77(6):1369–1382. https://doi.org/10.1158/0008-5472.CAN-16-1615

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Waldvogel Abramowski S, Tirefort D, Lau P, Guichebaron A, Taleb S, Modoux C, Lemoine Chaduc C, Bruyere Cerdan P, Roux Lombard P, Lecompte T, Preynat-Seauve O (2018) Cell-free nucleic acids are present in blood products and regulate genes of innate immune response. Transfusion. 58:1671–1681. https://doi.org/10.1111/trf.14613

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Li Z, Yu X, Shen J (2016) ANRIL: a pivotal tumor suppressor long non-coding RNA in human cancers. Tumour Biol 37(5):5657–5661. https://doi.org/10.1007/s13277-016-4808-5

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Backes C, Meese E, Keller A (2016) Specific miRNA disease biomarkers in blood, serum and plasma: challenges and prospects. Mol Diagn Ther 20(6):509–518. https://doi.org/10.1007/s40291-016-0221-4

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Tzimagiorgis G, Michailidou EZ, Kritis A, Markopoulos AK, Kouidou S (2011) Recovering circulating extracellular or cell-free RNA from bodily fluids. Cancer Epidemiol 35(6):580–589. https://doi.org/10.1016/j.canep.2011.02.016

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Pos O, Biro O, Szemes T, Nagy B (2018) Circulating cell-free nucleic acids: characteristics and applications. Eur J Hum Genet 26:937–945. https://doi.org/10.1038/s41431-018-0132-4

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Schwarzenbach H (2013) Circulating nucleic acids as biomarkers in breast cancer. Breast Cancer Res 15(5):211. https://doi.org/10.1186/bcr3446

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Bellassai N, Spoto G (2016) Biosensors for liquid biopsy: circulating nucleic acids to diagnose and treat cancer. Anal Bioanal Chem 408(26):7255–7264. https://doi.org/10.1007/s00216-016-9806-3

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Das J, Ivanov I, Montermini L, Rak J, Sargent EH, Kelley SO (2015) An electrochemical clamp assay for direct, rapid analysis of circulating nucleic acids in serum. Nat Chem 7(7):569–575. https://doi.org/10.1038/nchem.2270

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Ling H, Spizzo R, Atlasi Y, Nicoloso M, Shimizu M, Redis RS, Nishida N, Gafa R, Song J, Guo Z, Ivan C, Barbarotto E, De Vries I, Zhang X, Ferracin M, Churchman M, van Galen JF, Beverloo BH, Shariati M, Haderk F, Estecio MR, Garcia-Manero G, Patijn GA, Gotley DC, Bhardwaj V, Shureiqi I, Sen S, Multani AS, Welsh J, Yamamoto K, Taniguchi I, Song MA, Gallinger S, Casey G, Thibodeau SN, Le Marchand L, Tiirikainen M, Mani SA, Zhang W, Davuluri RV, Mimori K, Mori M, Sieuwerts AM, Martens JW, Tomlinson I, Negrini M, Berindan-Neagoe I, Foekens JA, Hamilton SR, Lanza G, Kopetz S, Fodde R, Calin GA (2013) CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer. Genome Res 23(9):1446–1461. https://doi.org/10.1101/gr.152942.112

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Zhang J, Jiang Y, Zhu J, Wu T, Ma J, Du C, Chen S, Li T, Han J, Wang X (2017) Overexpression of long non-coding RNA colon cancer-associated transcript 2 is associated with advanced tumor progression and poor prognosis in patients with colorectal cancer. Oncol Lett 14(6):6907–6914. https://doi.org/10.3892/ol.2017.7049

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Kasagi Y, Oki E, Ando K, Ito S, Iguchi T, Sugiyama M, Nakashima Y, Ohgaki K, Saeki H, Mimori K, Maehara Y (2017) The expression of CCAT2, a novel long noncoding RNA transcript, and rs6983267 single-nucleotide polymorphism genotypes in colorectal cancers. Oncology 92(1):48–54. https://doi.org/10.1159/000452143

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Chen S, Wu H, Lv N, Wang H, Wang Y, Tang Q, Shao H, Sun C (2016) LncRNA CCAT2 predicts poor prognosis and regulates growth and metastasis in small cell lung cancer. Biomed Pharmacother 82:583–588. https://doi.org/10.1016/j.biopha.2016.05.017

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Wu SW, Hao YP, Qiu JH, Zhang DB, Yu CG, Li WH (2017) High expression of long non-coding RNA CCAT2 indicates poor prognosis of gastric cancer and promotes cell proliferation and invasion. Minerva Med 108(4):317–323. https://doi.org/10.23736/S0026-4806.17.04703-6

    Article  PubMed  Google Scholar 

  17. 17.

    Chen F, Bai G, Li Y, Feng Y, Wang L (2017) A positive feedback loop of long noncoding RNA CCAT2 and FOXM1 promotes hepatocellular carcinoma growth. Am J Cancer Res 7(7):1423–1434

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Sarrafzadeh S, Geranpayeh L, Tasharrofi B, Soudyab M, Nikpayam E, Iranpour M, Mirfakhraie R, Gharesouran J, Ghafouri-Fard S, Ghafouri-Fard S (2017) Expression study and clinical correlations of MYC and CCAT2 in breast cancer patients. Iran Biomed J 21(5):303–311

    Article  Google Scholar 

  19. 19.

    Geng W, Guo X, Zhang L, Ma Y, Wang L, Liu Z, Ji H, Xiong Y (2018) Resveratrol inhibits proliferation, migration and invasion of multiple myeloma cells via NEAT1-mediated Wnt/beta-catenin signaling pathway. Biomed Pharmacother 107:484–494. https://doi.org/10.1016/j.biopha.2018.08.003

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Sedlarikova L, Gromesova B, Kubaczkova V, Radova L, Filipova J, Jarkovsky J, Brozova L, Velichova R, Almasi M, Penka M, Bezdekova R, Stork M, Adam Z, Pour L, Krejci M, Kuglik P, Hajek R, Sevcikova S (2017) Deregulated expression of long non-coding RNA UCA1 in multiple myeloma. Eur J Haematol 99(3):223–233. https://doi.org/10.1111/ejh.12908

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Zhang ZS, Wang J, Zhu BQ, Ge L (2018) Long noncoding RNA UCA1 promotes multiple myeloma cell growth by targeting TGF-beta. Eur Rev Med Pharmacol Sci 22(5):1374–1379. https://doi.org/10.26355/eurrev_201803_14481

    Article  PubMed  Google Scholar 

  22. 22.

    Yang N, Chen J, Zhang H, Wang X, Yao H, Peng Y, Zhang W (2017) LncRNA OIP5-AS1 loss-induced microRNA-410 accumulation regulates cell proliferation and apoptosis by targeting KLF10 via activating PTEN/PI3K/AKT pathway in multiple myeloma. Cell Death Dis 8(8):e2975. https://doi.org/10.1038/cddis.2017.358

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Li B, Chen P, Qu J, Shi L, Zhuang W, Fu J, Li J, Zhang X, Sun Y, Zhuang W (2014) Activation of LTBP3 gene by a long noncoding RNA (lncRNA) MALAT1 transcript in mesenchymal stem cells from multiple myeloma. J Biol Chem 289(42):29365–29375. https://doi.org/10.1074/jbc.M114.572693

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Gu Y, Xiao X, Yang S (2017) LncRNA MALAT1 acts as an oncogene in multiple myeloma through sponging miR-509-5p to modulate FOXP1 expression. Oncotarget 8(60):101984–101993. https://doi.org/10.18632/oncotarget.21957

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Cho SF, Chang YC, Chang CS, Lin SF, Liu YC, Hsiao HH, Chang JG, Liu TC (2014) MALAT1 long non-coding RNA is overexpressed in multiple myeloma and may serve as a marker to predict disease progression. BMC Cancer 14:809. https://doi.org/10.1186/1471-2407-14-809

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Handa H, Kuroda Y, Kimura K, Masuda Y, Hattori H, Alkebsi L, Matsumoto M, Kasamatsu T, Kobayashi N, Tahara KI, Takizawa M, Koiso H, Ishizaki T, Shimizu H, Yokohama A, Tsukamoto N, Saito T, Murakami H (2017) Long non-coding RNA MALAT1 is an inducible stress response gene associated with extramedullary spread and poor prognosis of multiple myeloma. Br J Haematol 179(3):449–460. https://doi.org/10.1111/bjh.14882

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Liu H, Wang H, Wu B, Yao K, Liao A, Miao M, Li Y, Yang W (2017) Down-regulation of long non-coding RNA MALAT1 by RNA interference inhibits proliferation and induces apoptosis in multiple myeloma. Clin Exp Pharmacol Physiol 44(10):1032–1041. https://doi.org/10.1111/1440-1681.12804

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Hu Y, Lin J, Fang H, Fang J, Li C, Chen W, Liu S, Ondrejka S, Gong Z, Reu F, Maciejewski J, Yi Q, Zhao JJ (2018) Targeting the MALAT1/PARP1/LIG3 complex induces DNA damage and apoptosis in multiple myeloma. Leukemia. 32:2250–2262. https://doi.org/10.1038/s41375-018-0104-2

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Meng YB, He X, Huang YF, Wu QN, Zhou YC, Hao DJ (2017) Long noncoding RNA CRNDE promotes multiple myeloma cell growth by suppressing miR-451. Oncol Res 25(7):1207–1214. https://doi.org/10.3727/096504017X14886679715637

    Article  PubMed  Google Scholar 

  30. 30.

    Zhuang W, Ge X, Yang S, Huang M, Zhuang W, Chen P, Zhang X, Fu J, Qu J, Li B (2015) Upregulation of lncRNA MEG3 promotes osteogenic differentiation of mesenchymal stem cells from multiple myeloma patients by targeting BMP4 transcription. Stem Cells 33(6):1985–1997. https://doi.org/10.1002/stem.1989

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Benetatos L, Dasoula A, Hatzimichael E, Georgiou I, Syrrou M, Bourantas KL (2008) Promoter hypermethylation of the MEG3 (DLK1/MEG3) imprinted gene in multiple myeloma. Clin Lymphoma Myeloma 8(3):171–175. https://doi.org/10.3816/CLM.2008.n.021

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Wong KY, Li Z, Zhang X, Leung GK, Chan GC, Chim CS (2015) Epigenetic silencing of a long non-coding RNA KIAA0495 in multiple myeloma. Mol Cancer 14:175. https://doi.org/10.1186/s12943-015-0444-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Yang X, Ye H, He M, Zhou X, Sun N, Guo W, Lin X, Huang H, Lin Y, Yao R, Wang H (2018) LncRNA PDIA3P interacts with c-Myc to regulate cell proliferation via induction of pentose phosphate pathway in multiple myeloma. Biochem Biophys Res Commun 498(1):207–213. https://doi.org/10.1016/j.bbrc.2018.02.211

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Pan Y, Chen H, Shen X, Wang X, Ju S, Lu M, Cong H (2018) Serum level of long noncoding RNA H19 as a diagnostic biomarker of multiple myeloma. Clin Chim Acta 480:199–205. https://doi.org/10.1016/j.cca.2018.02.019

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    (2017) The guidelines for the diagnosis and management of multiple myeloma in China (2017 revision). Zhonghua Nei Ke Za Zhi 56(11):866–870. https://doi.org/10.3760/cma.j.issn.0578-1426.2017.11.021

  36. 36.

    Shen X, Zhang Y, Wu X, Guo Y, Shi W, Qi J, Cong H, Wang X, Wu X, Ju S (2017) Upregulated lncRNA-PCAT1 is closely related to clinical diagnosis of multiple myeloma as a predictive biomarker in serum. Cancer Biomark 18(3):257–263. https://doi.org/10.3233/cbm-160158

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Hampel H, Toschi N, Baldacci F, Zetterberg H, Blennow K, Kilimann I, Teipel SJ, Cavedo E, Melo Dos Santos A, Epelbaum S, Lamari F, Genthon R, Dubois B, Floris R, Garaci F, Lista S (2018) Alzheimer's disease biomarker-guided diagnostic workflow using the added value of six combined cerebrospinal fluid candidates: Abeta1-42, total-tau, phosphorylated-tau, NFL, neurogranin, and YKL-40. Alzheimers Dement 14(4):492–501. https://doi.org/10.1016/j.jalz.2017.11.015

    Article  PubMed  Google Scholar 

  38. 38.

    Chen L, Hu N, Wang C, Zhao H, Gu Y (2018) Long non-coding RNA CCAT1 promotes multiple myeloma progression by acting as a molecular sponge of miR-181a-5p to modulate HOXA1 expression. Cell Cycle 17(3):319–329. https://doi.org/10.1080/15384101.2017.1407893

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Yang Y, Wang S, Li J, Qi S, Zhang D (2017) CUL4A as a marker and potential therapeutic target in multiple myeloma. Tumour Biol 39(7):1010428317703923. https://doi.org/10.1177/1010428317703923

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Gonzalez-Masia JA, Garcia-Olmo D, Garcia-Olmo DC (2013) Circulating nucleic acids in plasma and serum (CNAPS): applications in oncology. Onco Targets Ther 6:819–832. https://doi.org/10.2147/OTT.S44668

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Rinn JL, Chang HY (2012) Genome regulation by long noncoding RNAs. Annu Rev Biochem 81:145–166. https://doi.org/10.1146/annurev-biochem-051410-092902

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Su W, Feng S, Chen X, Yang X, Mao R, Guo C, Wang Z, Thomas DG, Lin J, Reddy RM, Orringer MB, Chang AC, Yang Z, Beer DG, Chen G (2018) Silencing of long non-coding RNA MIR22HG triggers cell survival/death signaling via oncogenes YBX1, MET, and p21 in lung cancer. Cancer Res:canres.0222.2018. https://doi.org/10.1158/0008-5472.CAN-18-0222

  43. 43.

    Thi Ngoc PC, Tan SH, Tan TK, Chan MM, Li Z, Yeoh AEJ, Tenen DG, Sanda T (2018) Identification of novel lncRNAs regulated by the TAL1 complex in T-cell acute lymphoblastic leukemia. Leukemia. 32:2138–2151. https://doi.org/10.1038/s41375-018-0110-4

    CAS  Article  Google Scholar 

  44. 44.

    Zhang R, Xia Y, Wang Z, Zheng J, Chen Y, Li X, Wang Y, Ming H (2017) Serum long non coding RNA MALAT-1 protected by exosomes is up-regulated and promotes cell proliferation and migration in non-small cell lung cancer. Biochem Biophys Res Commun 490(2):406–414. https://doi.org/10.1016/j.bbrc.2017.06.055

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Zheng ZK, Pang C, Yang Y, Duan Q, Zhang J, Liu WC (2018) Serum long noncoding RNA urothelial carcinoma-associated 1: a novel biomarker for diagnosis and prognosis of hepatocellular carcinoma. J Int Med Res 46(1):348–356. https://doi.org/10.1177/0300060517726441

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Shen J, Hodges TR, Song R, Gong Y, Calin GA, Heimberger AB, Zhao H (2018) Serum HOTAIR and GAS5 levels as predictors of survival in patients with glioblastoma. Mol Carcinog 57(1):137–141. https://doi.org/10.1002/mc.22739

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Gong W, Tian M, Qiu H, Yang Z (2017) Elevated serum level of lncRNA-HIF1A-AS1 as a novel diagnostic predictor for worse prognosis in colorectal carcinoma. Cancer biomarkers : section A of Disease markers 20(4):417–424. https://doi.org/10.3233/cbm-170179

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Zheng J, Zhao S, He X, Zheng Z, Bai W, Duan Y, Cheng S, Wang J, Liu X, Zhang G (2016) The up-regulation of long non-coding RNA CCAT2 indicates a poor prognosis for prostate cancer and promotes metastasis by affecting epithelial-mesenchymal transition. Biochem Biophys Res Commun 480(4):508–514. https://doi.org/10.1016/j.bbrc.2016.08.120

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Zeng J, Du T, Song Y, Gao Y, Li F, Wu R, Chen Y, Li W, Zhou H, Yang Y, Pei Z (2017) Knockdown of long noncoding RNA CCAT2 inhibits cellular proliferation, invasion, and epithelial-mesenchymal transition in glioma cells. Oncol Res 25(6):913–921. https://doi.org/10.3727/096504016X14792098307036

    Article  PubMed  Google Scholar 

  50. 50.

    Fu D, Zhang Y, Cui H (2018) Long noncoding RNA CCAT2 is activated by E2F1 and exerts oncogenic properties by interacting with PTTG1 in pituitary adenomas. Am J Cancer Res 8(2):245–255

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Yan L, Wu X, Yin X, Du F, Liu Y, Ding X (2018) LncRNA CCAT2 promoted osteosarcoma cell proliferation and invasion. J Cell Mol Med 22(5):2592–2599. https://doi.org/10.1111/jcmm.13518

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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This project was supported by grants from National Natural Science Foundation of China (81672099), Key Social Development Project of Jiangsu Province (BE2015654), and Construction Project of Clinical Laboratory Diagnosis Center of Nantong (HS2015002).

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Correspondence to Shaoqing Ju.

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Figure S1

Ct values of 5 candidate reference genes. (PNG 724 kb).

Figure S2

Sanger sequencing of amplified products. (a) CCAT2 and (b) 18S rRNA. (PNG 818 kb).

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Table S1

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Table S2

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Xu, H., Yin, Q., Shen, X. et al. Long non-coding RNA CCAT2 as a potential serum biomarker for diagnosis and prognosis of multiple myeloma. Ann Hematol (2020). https://doi.org/10.1007/s00277-020-04161-9

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  • lncRNA CCAT2
  • Multiple myeloma
  • Serum
  • Biomarker
  • Clinical value