Skip to main content
Top
Published in: Tumor Biology 6/2012

01-12-2012 | Research Article

CIP2A is overexpressed in human ovarian cancer and regulates cell proliferation and apoptosis

Authors: Yuanyuan Fang, Zhengtao Li, Xiuxia Wang, Shulan Zhang

Published in: Tumor Biology | Issue 6/2012

Login to get access

Abstract

CIP2A is a recently characterized oncoprotein which involves in the progression of several human malignancies. This study aimed to investigate its clinical significance and biological function in ovarian cancer. CIP2A expression was analyzed in 152 archived ovarian cancer specimens using immunohistochemistry. One hundred cases (65.79 %) showed CIP2A overexpression, including 63 of 92 serous carcinomas (68.48 %), 21 of 33 endometrioid carcinomas (63.64 %), 12 of 23 mucinous carcinomas (52.17 %), and 4 of 4 clear cell carcinomas (100 %). There is no significant difference of CIP2A expression between serous tumors and all other morphologies combined. CIP2A overexpression positively correlated with advanced FIGO stage (p = 0.0336) and tumor grade (p = 0.0213). siRNA knockdown was performed in A2780 and SKOV3 cell lines. MTT, colony formation assay, and flow cytometry were carried out to assess the role of CIP2A in proliferation, cell cycle, and apoptosis. CIP2A depletion in ovarian cancer cell lines inhibited proliferation, blocked cell cycle progression, and increased paclitaxel-induced apoptosis. Futhermore, CIP2A depletion downregulated cyclin D1, c-myc, phospho-Rb, Bcl-2, and phospho-AKT expression. These results validate the role of CIP2A as a clinically relevant oncoprotein and establish CIP2A as a promising therapeutic target of ovarian cancer.
Literature
1.
2.
3.
go back to reference Darcy KM and Birrer MJ. 2010.Translational research in the Gynecologic Oncology Group: evaluation of ovarian cancer markers, profiles, and novel therapies. Gynecol Oncol. 117(3): p. 429–39. Darcy KM and Birrer MJ. 2010.Translational research in the Gynecologic Oncology Group: evaluation of ovarian cancer markers, profiles, and novel therapies. Gynecol Oncol. 117(3): p. 429–39.
4.
go back to reference Despierre E, Lambrechts D, Neven P, Amant F, Lambrechts S and Vergote I. 2010. The molecular genetic basis of ovarian cancer and its roadmap towards a better treatment. Gynecol Oncol. 117(2): p. 358-65 Despierre E, Lambrechts D, Neven P, Amant F, Lambrechts S and Vergote I. 2010. The molecular genetic basis of ovarian cancer and its roadmap towards a better treatment. Gynecol Oncol. 117(2): p. 358-65
5.
go back to reference Junttila MR, Puustinen P, Niemela M, Ahola R, Arnold H, Bottzauw T, et al. CIP2A inhibits PP2A in human malignancies. Cell. 2007;130(1):51–62.PubMedCrossRef Junttila MR, Puustinen P, Niemela M, Ahola R, Arnold H, Bottzauw T, et al. CIP2A inhibits PP2A in human malignancies. Cell. 2007;130(1):51–62.PubMedCrossRef
6.
go back to reference Tseng LM, Liu CY, Chang KC, Chu PY, Shiau CW and Chen KF. 2012. CIP2A is a target of bortezomib in human triple negative breast cancer cells. Breast Cancer Res. 14(2): p. R68. Tseng LM, Liu CY, Chang KC, Chu PY, Shiau CW and Chen KF. 2012. CIP2A is a target of bortezomib in human triple negative breast cancer cells. Breast Cancer Res. 14(2): p. R68.
7.
go back to reference Chen KF, Liu CY, Lin YC, Yu HC, Liu TH, Hou DR, et al. 2010. CIP2A mediates effects of bortezomib on phospho-Akt and apoptosis in hepatocellular carcinoma cells. Oncogene. 29(47): p. 6257-66. Chen KF, Liu CY, Lin YC, Yu HC, Liu TH, Hou DR, et al. 2010. CIP2A mediates effects of bortezomib on phospho-Akt and apoptosis in hepatocellular carcinoma cells. Oncogene. 29(47): p. 6257-66.
8.
go back to reference Lin YC, Chen KC, Chen CC, Cheng AL and Chen KF. 2012. CIP2A-mediated Akt activation plays a role in bortezomib-induced apoptosis in head and neck squamous cell carcinoma cells. Oral Oncol 48(7):585-93 Lin YC, Chen KC, Chen CC, Cheng AL and Chen KF. 2012. CIP2A-mediated Akt activation plays a role in bortezomib-induced apoptosis in head and neck squamous cell carcinoma cells. Oral Oncol 48(7):585-93
9.
go back to reference Come C, Laine A, Chanrion M, Edgren H, Mattila E, Liu X, et al. CIP2A is associated with human breast cancer aggressivity. Clin Cancer Res. 2009;15(16):5092–100.PubMedCrossRef Come C, Laine A, Chanrion M, Edgren H, Mattila E, Liu X, et al. CIP2A is associated with human breast cancer aggressivity. Clin Cancer Res. 2009;15(16):5092–100.PubMedCrossRef
10.
go back to reference Niemela M, Kauko O, Sihto H, Mpindi JP, Nicorici D, Pernila P, et al. 2012. CIP2A signature reveals the MYC dependency of CIP2A-regulated phenotypes and its clinical association with breast cancer subtypes. Oncogene (in press) Niemela M, Kauko O, Sihto H, Mpindi JP, Nicorici D, Pernila P, et al. 2012. CIP2A signature reveals the MYC dependency of CIP2A-regulated phenotypes and its clinical association with breast cancer subtypes. Oncogene (in press)
11.
go back to reference Li W, Ge Z, Liu C, Liu Z, Bjorkholm M, Jia J, 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(12):3722–8.PubMedCrossRef Li W, Ge Z, Liu C, Liu Z, Bjorkholm M, Jia J, 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(12):3722–8.PubMedCrossRef
12.
go back to reference Dong QZ, Wang Y, Dong XJ, Li ZX, Tang ZP, Cui QZ, et al. 2011. CIP2A is overexpressed in non-small cell lung cancer and correlates with poor prognosis. Ann Surg Oncol. 18(3): p. 857-65. Dong QZ, Wang Y, Dong XJ, Li ZX, Tang ZP, Cui QZ, et al. 2011. CIP2A is overexpressed in non-small cell lung cancer and correlates with poor prognosis. Ann Surg Oncol. 18(3): p. 857-65.
13.
go back to reference Vaarala MH, Vaisanen MR and Ristimaki A. 2010. CIP2A expression is increased in prostate cancer. J Exp Clin Cancer Res. 29: p. 136. Vaarala MH, Vaisanen MR and Ristimaki A. 2010. CIP2A expression is increased in prostate cancer. J Exp Clin Cancer Res. 29: p. 136.
14.
go back to reference Bockelman C, Koskensalo S, Hagstrom J, Lundin M, Ristimaki A and Haglund C. 2012. CIP2A overexpression is associated with c-Myc expression in colorectal cancer. Cancer Biol Ther. 13(5):289–95. Bockelman C, Koskensalo S, Hagstrom J, Lundin M, Ristimaki A and Haglund C. 2012. CIP2A overexpression is associated with c-Myc expression in colorectal cancer. Cancer Biol Ther. 13(5):289–95.
15.
go back to reference Ren J, Li W, Yan L, Jiao W, Tian S, Li D, et al. 2011. Expression of CIP2A in renal cell carcinomas correlates with tumour invasion, metastasis and patients' survival. Br J Cancer. 105(12): p. 1905-11. Ren J, Li W, Yan L, Jiao W, Tian S, Li D, et al. 2011. Expression of CIP2A in renal cell carcinomas correlates with tumour invasion, metastasis and patients' survival. Br J Cancer. 105(12): p. 1905-11.
16.
go back to reference Bockelman C, Lassus H, Hemmes A, Leminen A, Westermarck J, Haglund C, et al. 2011. Prognostic role of CIP2A expression in serous ovarian cancer. Br J Cancer. 105(7): p. 989-95. Bockelman C, Lassus H, Hemmes A, Leminen A, Westermarck J, Haglund C, et al. 2011. Prognostic role of CIP2A expression in serous ovarian cancer. Br J Cancer. 105(7): p. 989-95.
17.
go back to reference Schwartz DR, Kardia SL, Shedden KA, Kuick R, Michailidis G, Taylor JM, et al. Gene expression in ovarian cancer reflects both morphology and biological behavior, distinguishing clear cell from other poor-prognosis ovarian carcinomas. Cancer Res. 2002;62(16):4722–9.PubMed Schwartz DR, Kardia SL, Shedden KA, Kuick R, Michailidis G, Taylor JM, et al. Gene expression in ovarian cancer reflects both morphology and biological behavior, distinguishing clear cell from other poor-prognosis ovarian carcinomas. Cancer Res. 2002;62(16):4722–9.PubMed
18.
go back to reference Zorn KK, Bonome T, Gangi L, Chandramouli GV, Awtrey CS, Gardner GJ, et al. Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer. Clin Cancer Res. 2005;11(18):6422–30.PubMedCrossRef Zorn KK, Bonome T, Gangi L, Chandramouli GV, Awtrey CS, Gardner GJ, et al. Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer. Clin Cancer Res. 2005;11(18):6422–30.PubMedCrossRef
19.
go back to reference Kim A, Ueda Y, Naka T and Enomoto T. 2012. Therapeutic strategies in epithelial ovarian cancer. J Exp Clin Cancer Res. 31: p. 14. Kim A, Ueda Y, Naka T and Enomoto T. 2012. Therapeutic strategies in epithelial ovarian cancer. J Exp Clin Cancer Res. 31: p. 14.
20.
go back to reference Levanon K, Crum C, Drapkin R. New insights into the pathogenesis of serous ovarian cancer and its clinical impact. J Clin Oncol. 2008;26(32):5284–93.PubMedCrossRef Levanon K, Crum C, Drapkin R. New insights into the pathogenesis of serous ovarian cancer and its clinical impact. J Clin Oncol. 2008;26(32):5284–93.PubMedCrossRef
21.
go back to reference Knudsen KE, Diehl JA, Haiman CA, Knudsen ES. Cyclin D1: polymorphism, aberrant splicing and cancer risk. Oncogene. 2006;25(11):1620–8.PubMedCrossRef Knudsen KE, Diehl JA, Haiman CA, Knudsen ES. Cyclin D1: polymorphism, aberrant splicing and cancer risk. Oncogene. 2006;25(11):1620–8.PubMedCrossRef
23.
go back to reference Ratschiller D, Heighway J, Gugger M, Kappeler A, Pirnia F, Schmid RA, et al. Cyclin D1 overexpression in bronchial epithelia of patients with lung cancer is associated with smoking and predicts survival. J Clin Oncol. 2003;21(11):2085–93.PubMedCrossRef Ratschiller D, Heighway J, Gugger M, Kappeler A, Pirnia F, Schmid RA, et al. Cyclin D1 overexpression in bronchial epithelia of patients with lung cancer is associated with smoking and predicts survival. J Clin Oncol. 2003;21(11):2085–93.PubMedCrossRef
24.
go back to reference Keum JS, Kong G, Yang SC, Shin DH, Park SS, Lee JH, et al. Cyclin D1 overexpression is an indicator of poor prognosis in resectable non-small cell lung cancer. Br J Cancer. 1999;81(1):127–32.PubMedCrossRef Keum JS, Kong G, Yang SC, Shin DH, Park SS, Lee JH, et al. Cyclin D1 overexpression is an indicator of poor prognosis in resectable non-small cell lung cancer. Br J Cancer. 1999;81(1):127–32.PubMedCrossRef
25.
go back to reference Bali A, O'Brien PM, Edwards LS, Sutherland RL, Hacker NF, Henshall SM. Cyclin D1, p53, and p21Waf1/Cip1 expression is predictive of poor clinical outcome in serous epithelial ovarian cancer. Clin Cancer Res. 2004;10(15):5168–77.PubMedCrossRef Bali A, O'Brien PM, Edwards LS, Sutherland RL, Hacker NF, Henshall SM. Cyclin D1, p53, and p21Waf1/Cip1 expression is predictive of poor clinical outcome in serous epithelial ovarian cancer. Clin Cancer Res. 2004;10(15):5168–77.PubMedCrossRef
26.
go back to reference Masamha CP, Benbrook DM. Cyclin D1 degradation is sufficient to induce G1 cell cycle arrest despite constitutive expression of cyclin E2 in ovarian cancer cells. Cancer Res. 2009;69(16):6565–72.PubMedCrossRef Masamha CP, Benbrook DM. Cyclin D1 degradation is sufficient to induce G1 cell cycle arrest despite constitutive expression of cyclin E2 in ovarian cancer cells. Cancer Res. 2009;69(16):6565–72.PubMedCrossRef
27.
go back to reference Mateyak MK, Obaya AJ, Sedivy JM. c-Myc regulates cyclin D-Cdk4 and -Cdk6 activity but affects cell cycle progression at multiple independent points. Mol Cell Biol. 1999;19(7):4672–83.PubMed Mateyak MK, Obaya AJ, Sedivy JM. c-Myc regulates cyclin D-Cdk4 and -Cdk6 activity but affects cell cycle progression at multiple independent points. Mol Cell Biol. 1999;19(7):4672–83.PubMed
28.
go back to reference Pugazhenthi S, Nesterova A, Sable C, Heidenreich KA, Boxer LM, Heasley LE, et al. Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein. J Biol Chem. 2000;275(15):10761–6.PubMedCrossRef Pugazhenthi S, Nesterova A, Sable C, Heidenreich KA, Boxer LM, Heasley LE, et al. Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein. J Biol Chem. 2000;275(15):10761–6.PubMedCrossRef
Metadata
Title
CIP2A is overexpressed in human ovarian cancer and regulates cell proliferation and apoptosis
Authors
Yuanyuan Fang
Zhengtao Li
Xiuxia Wang
Shulan Zhang
Publication date
01-12-2012
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 6/2012
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-012-0492-2

Other articles of this Issue 6/2012

Tumor Biology 6/2012 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine