Tumor Biology

, Volume 35, Issue 2, pp 1123–1128 | Cite as

CIP2A is overexpressed in osteosarcoma and regulates cell proliferation and invasion

  • Mo Zhai
  • Lin Cong
  • Yaxin Han
  • Guanjun Tu
Research Article


Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a newly characterized oncoprotein involved in a variety of malignant tumors. However, its expression pattern and biological functions in osteosarcoma remain unclear. In the present study, CIP2A expression was analyzed in 51 human osteosarcoma specimens using immunohistochemistry. CIP2A siRNA was used in the MG-63 cell line, and the effect of CIP2A depletion on cell proliferation and invasion was evaluated. We found that CIP2A was overexpressed in 76.5 % (39/51) of osteosarcoma tissues, while normal bone tissues showed negative CIP2A expression. In addition, the positive rate of CIP2A expression was higher in stage IIB osteosarcoma than stage IIA cases. Knockdown of the CIP2A expression significantly reduced osteosarcoma cell proliferation and invasion, with decreased c-Myc expression and p-AKT expression. CIP2A depletion also facilitated apoptosis and inhibited MMP9 mRNA expression. Taken together, our data identified CIP2A as a critical oncoprotein involved in cell proliferation and invasion, which could serve as a therapeutic target in osteosarcoma.


CIP2A Osteosarcoma Proliferation Invasion c-Myc 


Conflicts of interest



  1. 1.
    Ottaviani G, Jaffe N. The epidemiology of osteosarcoma. Cancer Treat Res. 2009;152:3–13.PubMedCrossRefGoogle Scholar
  2. 2.
    Heare T, Hensley MA, Dell’Orfano S. Bone tumors: osteosarcoma and Ewing’s sarcoma. Curr Opin Pediatr. 2009;21:365–72.PubMedCrossRefGoogle Scholar
  3. 3.
    Levings PP, McGarry SV, Currie TP, Nickerson DM, et al. Expression of an exogenous human Oct-4 promoter identifies tumor-initiating cells in osteosarcoma. Cancer Res. 2009;69:5648–55.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Fujiwara M, Kashima TG, Kunita A, Kii I, et al. Stable knockdown of S100A4 suppresses cell migration and metastasis of osteosarcoma. Tumour Biol. 2011;32:611–22.PubMedCrossRefGoogle Scholar
  5. 5.
    Hua Y, Jia X, Sun M, Zheng L, et al. Plasma membrane proteomic analysis of human osteosarcoma and osteoblastic cells: revealing NDRG1 as a marker for osteosarcoma. Tumour Biol. 2011;32:1013–21.PubMedCrossRefGoogle Scholar
  6. 6.
    Sharili AS, Allen S, Smith K, Hargreaves J, et al. Expression of Snail2 in long bone osteosarcomas correlates with tumour malignancy. Tumour Biol. 2012;32:515–26.CrossRefGoogle Scholar
  7. 7.
    Soo Hoo L, Zhang JY, Chan EK. Cloning and characterization of a novel 90 kDa “companion” auto-antigen of p62 overexpressed in cancer. Oncogene. 2002;21:5006–15.PubMedCrossRefGoogle Scholar
  8. 8.
    Junttila MR, Puustinen P, Niemela M, Ahola R, et al. CIP2A inhibits PP2A in human malignancies. Cell. 2007;130:51–62.PubMedCrossRefGoogle Scholar
  9. 9.
    Basile JR, Czerninski R. The role of CIP2A in oral squamous cell carcinoma. Canc Biol Ther. 2010;10:700–2.CrossRefGoogle Scholar
  10. 10.
    Bockelman C, Koskensalo S, Hagstrom J, Lundin M, et al. CIP2A overexpression is associated with c-Myc expression in colorectal cancer. Cancer Biol Ther. 2010;13:289–95.CrossRefGoogle Scholar
  11. 11.
    Bockelman C, Lassus H, Hemmes A, Leminen A, et al. Prognostic role of CIP2A expression in serous ovarian cancer. Br J Canc. 2011;105:989–95.CrossRefGoogle Scholar
  12. 12.
    Dong QZ, Wang Y, Dong XJ, Li ZX, et al. CIP2A is overexpressed in non-small cell lung cancer and correlates with poor prognosis. Ann Surg Oncol. 2011;18:857–65.PubMedCrossRefGoogle Scholar
  13. 13.
    Huang LP, Adelson ME, Mordechai E, Trama JP. CIP2A expression is elevated in cervical cancer. Cancer Biomark. 2011;8:309–17.Google Scholar
  14. 14.
    Katz J, Jakymiw A, Ducksworth MK, Stewart CM, et al. CIP2A expression and localization in oral carcinoma and dysplasia. Canc Biol Ther. 2010;10:694–9.CrossRefGoogle Scholar
  15. 15.
    Qu W, Li W, Wei L, Xing L, et al. CIP2A is overexpressed in esophageal squamous cell carcinoma. Med Oncol. 2012;29:113–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Ren J, Li W, Yan L, Jiao W, et al. Expression of CIP2A in renal cell carcinomas correlates with tumour invasion, metastasis and patients’ survival. Br J Canc. 2011;105:1905–11.CrossRefGoogle Scholar
  17. 17.
    Teng HW, Yang SH, Lin JK, Chen WS, et al. CIP2A is a predictor of poor prognosis in colon cancer. J Gastrointest Surg. 2012;16:1037–47.PubMedCrossRefGoogle Scholar
  18. 18.
    Vaarala MH, Vaisanen MR, Ristimaki A. CIP2A expression is increased in prostate cancer. J Exp Clin Canc Res. 2010;29:136.CrossRefGoogle Scholar
  19. 19.
    Li W, Ge Z, Liu C, Liu Z, et al. CIP2A is overexpressed in gastric cancer and its depletion leads to impaired clonogenicity, senescence, or differentiation of tumor cells. Clin Cancer Res. 2008;14:3722–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Come C, Laine A, Chanrion M, Edgren H, et al. CIP2A is associated with human breast cancer aggressivity. Clin Canc Res. 2009;15:5092–100.CrossRefGoogle Scholar
  21. 21.
    Fang Y, Li Z, Wang X, Zhang S. CIP2A is overexpressed in human ovarian cancer and regulates cell proliferation and apoptosis. Tumour Biol. 2012;33:2299–306.PubMedCrossRefGoogle Scholar
  22. 22.
    Ren J, Li W, Yan L, Jiao W, et al. Expression of CIP2A in renal cell carcinomas correlates with tumour invasion, metastasis and patients’ survival. Br J Cancer. 2011;105:1905–11.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Lee J, Park EJ, Hwang JW, Oh JM, et al. CIP2A expression is associated with synovial hyperplasia and invasive function of fibroblast-like synoviocytes in rheumatoid arthritis. Rheumatol Int. 2012;32:2023–30.PubMedCrossRefGoogle Scholar
  24. 24.
    Chen KF, Liu CY, Lin YC, Yu HC, et al. CIP2A mediates effects of bortezomib on phospho-Akt and apoptosis in hepatocellular carcinoma cells. Oncogene. 2010;29:6257–66.PubMedCrossRefGoogle Scholar
  25. 25.
    Lin YC, Chen KC, Chen CC, Cheng AL, et al. CIP2A-mediated Akt activation plays a role in bortezomib-induced apoptosis in head and neck squamous cell carcinoma cells. Oral Oncol. 2012;48:585–93.PubMedCrossRefGoogle Scholar
  26. 26.
    Wang L, Gu F, Ma N, Zhang L, et al. CIP2A expression is associated with altered expression of epithelial-mesenchymal transition markers and predictive of poor prognosis in pancreatic ductal adenocarcinoma. Tumour Biol. 2013;34:2309–13.PubMedCrossRefGoogle Scholar
  27. 27.
    Gordan JD, Bertout JA, Hu CJ, Diehl JA, et al. HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell. 2007;11:335–47.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Laurenti E, Varnum-Finney B, Wilson A, Ferrero I, et al. Hematopoietic stem cell function and survival depend on c-Myc and N-Myc activity. Cell Stem Cell. 2008;3:611–24.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Hu S, Xu-Monette ZY, Tzankov A, Green T, et al. MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program. Blood. 2013;121:4021–31.PubMedCrossRefGoogle Scholar
  30. 30.
    Chuan YC, Iglesias-Gato D, Fernandez-Perez L, Cedazo-Minguez A, et al. Ezrin mediates c-Myc actions in prostate cancer cell invasion. Oncogene. 2010;29:1531–42.PubMedCrossRefGoogle Scholar
  31. 31.
    Cho KB, Cho MK, Lee WY, Kang KW. Overexpression of c-myc induces epithelial mesenchymal transition in mammary epithelial cells. Cancer Lett. 2010;293:230–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Baudino TA, McKay C, Pendeville-Samain H, Nilsson JA, et al. c-Myc is essential for vasculogenesis and angiogenesis during development and tumor progression. Genes Dev. 2002;16:2530–43.PubMedCrossRefGoogle Scholar
  33. 33.
    Robanus-Maandag EC, Bosch CA, Kristel PM, Hart AA, et al. Association of C-MYC amplification with progression from the in situ to the invasive stage in C-MYC-amplified breast carcinomas. J Pathol. 2003;201:75–82.PubMedCrossRefGoogle Scholar
  34. 34.
    Liu Y, Chen LH, Yuan YW, Li QS, et al. Activation of AKT is associated with metastasis of nasopharyngeal carcinoma. Tumor Biol. 2012;33:241–5.CrossRefGoogle Scholar
  35. 35.
    Wang X, Deng Y, Mao Z, Ma X, et al. CCN1 promotes tumorigenicity through Rac1/Akt/NF-kappaB signaling pathway in pancreatic cancer. Tumour Biol. 2012;33:1745–58.PubMedCrossRefGoogle Scholar
  36. 36.
    Chen JS, Wang Q, Fu XH, Huang XH, et al. Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: association with MMP-9. Hepatol Res. 2009;39:177–86.PubMedCrossRefGoogle Scholar
  37. 37.
    Kaomongkolgit R, Cheepsunthorn P, Pavasant P, Sanchavanakit N. Iron increases MMP-9 expression through activation of AP-1 via ERK/Akt pathway in human head and neck squamous carcinoma cells. Oral Oncol. 2008;44:587–94.PubMedCrossRefGoogle Scholar
  38. 38.
    Diaz-Montero CM, Wygant JN, McIntyre BW. PI3-K/Akt-mediated anoikis resistance of human osteosarcoma cells requires Src activation. Eur J Cancer. 2006;42:1491–500.PubMedCrossRefGoogle Scholar
  39. 39.
    Miwa S, Sugimoto N, Shirai T, Hayashi K, et al. Caffeine activates tumor suppressor PTEN in sarcoma cells. Int J Oncol. 2011;39:465–72.PubMedGoogle Scholar
  40. 40.
    Cenni V, Maraldi NM, Ruggeri A, Secchiero P, et al. Sensitization of multidrug resistant human osteosarcoma cells to Apo2 Ligand/TRAIL-induced apoptosis by inhibition of the Akt/PKB kinase. Int J Oncol. 2004;25:1599–608.PubMedGoogle Scholar
  41. 41.
    Inoue R, Matsuki NA, Jing G, Kanematsu T, et al. The inhibitory effect of alendronate, a nitrogen-containing bisphosphonate on the PI3K-Akt-NFkappaB pathway in osteosarcoma cells. Br J Pharmacol. 2005;146:633–41.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  1. 1.Department of OrthopaedicsThe First Hospital of China Medical UniversityShenyangChina

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