Skip to main content
Erschienen in: Tumor Biology 2/2014

01.02.2014 | Research Article

CIP2A is overexpressed in osteosarcoma and regulates cell proliferation and invasion

verfasst von: Mo Zhai, Lin Cong, Yaxin Han, Guanjun Tu

Erschienen in: Tumor Biology | Ausgabe 2/2014

Einloggen, um Zugang zu erhalten

Abstract

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.
Literatur
1.
2.
Zurück zum Zitat Heare T, Hensley MA, Dell’Orfano S. Bone tumors: osteosarcoma and Ewing’s sarcoma. Curr Opin Pediatr. 2009;21:365–72.PubMedCrossRef Heare T, Hensley MA, Dell’Orfano S. Bone tumors: osteosarcoma and Ewing’s sarcoma. Curr Opin Pediatr. 2009;21:365–72.PubMedCrossRef
3.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
4.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
5.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
6.
Zurück zum Zitat 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.CrossRef 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.CrossRef
7.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
8.
Zurück zum Zitat Junttila MR, Puustinen P, Niemela M, Ahola R, et al. CIP2A inhibits PP2A in human malignancies. Cell. 2007;130:51–62.PubMedCrossRef Junttila MR, Puustinen P, Niemela M, Ahola R, et al. CIP2A inhibits PP2A in human malignancies. Cell. 2007;130:51–62.PubMedCrossRef
9.
Zurück zum Zitat Basile JR, Czerninski R. The role of CIP2A in oral squamous cell carcinoma. Canc Biol Ther. 2010;10:700–2.CrossRef Basile JR, Czerninski R. The role of CIP2A in oral squamous cell carcinoma. Canc Biol Ther. 2010;10:700–2.CrossRef
10.
Zurück zum Zitat 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.CrossRef 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.CrossRef
11.
Zurück zum Zitat 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.CrossRef 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.CrossRef
12.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
13.
Zurück zum Zitat Huang LP, Adelson ME, Mordechai E, Trama JP. CIP2A expression is elevated in cervical cancer. Cancer Biomark. 2011;8:309–17. Huang LP, Adelson ME, Mordechai E, Trama JP. CIP2A expression is elevated in cervical cancer. Cancer Biomark. 2011;8:309–17.
14.
Zurück zum Zitat 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.CrossRef 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.CrossRef
15.
Zurück zum Zitat Qu W, Li W, Wei L, Xing L, et al. CIP2A is overexpressed in esophageal squamous cell carcinoma. Med Oncol. 2012;29:113–8.PubMedCrossRef Qu W, Li W, Wei L, Xing L, et al. CIP2A is overexpressed in esophageal squamous cell carcinoma. Med Oncol. 2012;29:113–8.PubMedCrossRef
16.
Zurück zum Zitat 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.CrossRef 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.CrossRef
17.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
18.
Zurück zum Zitat Vaarala MH, Vaisanen MR, Ristimaki A. CIP2A expression is increased in prostate cancer. J Exp Clin Canc Res. 2010;29:136.CrossRef Vaarala MH, Vaisanen MR, Ristimaki A. CIP2A expression is increased in prostate cancer. J Exp Clin Canc Res. 2010;29:136.CrossRef
19.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
20.
Zurück zum Zitat 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.CrossRef 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.CrossRef
21.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
22.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
23.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
24.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
25.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
26.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
27.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
28.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
29.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
30.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
31.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
32.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
33.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
34.
Zurück zum Zitat 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.CrossRef 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.CrossRef
35.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
36.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
37.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
38.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
39.
Zurück zum Zitat 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.PubMed 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.PubMed
40.
Zurück zum Zitat 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.PubMed 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.PubMed
41.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
Metadaten
Titel
CIP2A is overexpressed in osteosarcoma and regulates cell proliferation and invasion
verfasst von
Mo Zhai
Lin Cong
Yaxin Han
Guanjun Tu
Publikationsdatum
01.02.2014
Verlag
Springer Netherlands
Erschienen in
Tumor Biology / Ausgabe 2/2014
Print ISSN: 1010-4283
Elektronische ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-013-1150-z

Weitere Artikel der Ausgabe 2/2014

Tumor Biology 2/2014 Zur Ausgabe

Adjuvante Immuntherapie verlängert Leben bei RCC

25.04.2024 Nierenkarzinom Nachrichten

Nun gibt es auch Resultate zum Gesamtüberleben: Eine adjuvante Pembrolizumab-Therapie konnte in einer Phase-3-Studie das Leben von Menschen mit Nierenzellkarzinom deutlich verlängern. Die Sterberate war im Vergleich zu Placebo um 38% geringer.

Alectinib verbessert krankheitsfreies Überleben bei ALK-positivem NSCLC

25.04.2024 NSCLC Nachrichten

Das Risiko für Rezidiv oder Tod von Patienten und Patientinnen mit reseziertem ALK-positivem NSCLC ist unter einer adjuvanten Therapie mit dem Tyrosinkinase-Inhibitor Alectinib signifikant geringer als unter platinbasierter Chemotherapie.

Bei Senioren mit Prostatakarzinom auf Anämie achten!

24.04.2024 DGIM 2024 Nachrichten

Patienten, die zur Behandlung ihres Prostatakarzinoms eine Androgendeprivationstherapie erhalten, entwickeln nicht selten eine Anämie. Wer ältere Patienten internistisch mitbetreut, sollte auf diese Nebenwirkung achten.

ICI-Therapie in der Schwangerschaft wird gut toleriert

Müssen sich Schwangere einer Krebstherapie unterziehen, rufen Immuncheckpointinhibitoren offenbar nicht mehr unerwünschte Wirkungen hervor als andere Mittel gegen Krebs.

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.