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Yumurtalık Kanseri Hücre Soylarında CIP2A Onkogeni Mutasyonlarının Taranması

Year 2019, Volume: 5 Issue: 1, 55 - 59, 01.01.2019

Abstract

Amaç: Kanserle ilişkili genetik değişimlerin belirlenmesi erken tanı, hastalığın takibi ve hedefe yönelik tedavi yaklaşımlarının geliştirilmesi açısından önem taşımaktadır. CIP2A, birçok insan kanserleri ile ilişkilendirilmiş yeni tanımlanmış bir onkoproteindir. Birçok kanserde CIP2A gen ekspresyonunun artışı gösterilmiştir ancak bu güne kadar AGS, HeLa, HT1080 kanser hücre soylarında CIP2A promotor bölge mutasyonlarının araştırıldığı ve tarafımızdan yapılmış olan bir çalışma dışında herhangi bir kanser tipinde CIP2A geninin kodlayan dizilerindeki mutasyonlarını araştıran bir çalışma yapılmamıştır. Bu çalışmamızda CIP2A gen ekspresyonunun kanserdeki artışına ilişkin moleküler mekanizmaların aydınlatılmasına katkıda bulunmak amacı ile bu genin onkogenik etkisinin oluşmasında rolü olması muhtemel regülatör bölge ve gen içi mutasyonlar araştırılmıştır. Gereç ve Yöntemler: CIP2A geninin kodlayan dizileri, ekzon-intron bağlantı bölgeleri ve promotor bölgesi DNA dizi analizi yöntemiyle SK-OV-3, Ov-CAR3 ve Caov-3 insan yumurtalık kanseri hücre soylarında taranmıştır. Bulgular: Ov-CAR3 hücre soyunda ekson 3, intron 6 ve intron 8’de, Caov-3 hücre soyunda ise sadece intron 6 ve intron 8’de genomik değişimler saptanmıştır. Sonuç: Bulgularımız, yumurtalık kanseri için CIP2A ekspresyonundaki artışta CIP2A’daki genomik değişimlerin etkisini dışlamaktadır. CIP2A onkoproteinini yüksek düzeylerde ekspresyon eden hücrelerde bu duruma neden olabilecek diğer mekanizmaların da araştırıldığı fonksiyonel çalışmalara gereksinim vardır

References

  • 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(32):5006-15.
  • Junttila MR, Puustinen P, Niemela M, Ahola R, Arnold H, Böttzauw T, Ala-aho R, Nielsen C, Ivaska J, Taya Y, Lu SL, Lin S, Chan EK, Wang XJ, Grenman R, Kast J, Kallunki T, Sears R, Kähäri VM, Westermarck J. CIP2A inhibits PP2A in human malignancies. Cell 2007; 130(1):51-62.
  • Khanna A, Bockelman C, Hemmes A, Junttila MR, Wiksten JP, Lundin M, Junnila S, Murphy DJ, Evan GI, Haglund C, Westermarck J, Ristimaki A. MYC- dependent regulation and prognostic role of CIP2A in gastric cancer. J Natl Cancer Inst 2009;101(11):793-805.
  • Li W, Ge Z, Liu C, Liu Z, Björkholm M, Jia J, Xu D. 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.
  • Routila J, Bilgen T, Saramaki O, Grenman R, Visakorpi T, Westermarck J, Ventela S. Copy number increase of oncoprotein CIP2A is associated with poor patient survival in human head and neck squamous cell carcinoma. Journal of Oral Pathology & Medicine 2016; 45(5):329- 37.
  • Come C, Laine A, Chanrion M, Edgren H, Mattila E, Liu X, Jonkers J, Ivaska J, Isola J, Darbon JM, Kallioniemi O, Thezenas S, Westermarck J. CIP2A is associated with human breast cancer aggressivity. Clin Cancer Res 2009; 15(16):5092-100.
  • Dong QZ, Wang Y, Dong XJ, Li ZX, Tang ZP, Cui QZ, Wanget EH. CIP2A is overexpressed in non-small cell lung cancer and correlates with poor prognosis. Ann Surg Oncol 2011; 18(3):857-65.
  • Qu W, Li W, Wei L, Xing L, Wang X, Yu J. CIP2A is overexpressed in esophageal squamous cell carcinoma. Med Oncol 2012; 29(1):113-8.
  • Vaarala MH, Vaisanen MR, Ristimaki A. CIP2A expression is increased in prostate cancer. J Exp Clin Cancer Res 2010; 29(1):136.
  • Fang Y, Li Z, Wang X, Zhang S. CIP2A is overexpressed in human ovarian cancer and regulates cell proliferation and apoptosis. Tumour Biology 2012; 33(6):2299-306.
  • Ma T, Zhang L, Xiao P, Liu Y, Li Y, Shi P, Zhou Y. Clinical significance of CIP2A expression in bladder cancer. Zhonghua Yi Xue Za Zhi 2014; 94(34):2681-3.
  • Coenen EA, Zwaan CM, Meyer C, Marschalek R, Pieters R, van der Veken LT, Beverloo HB, van den Heuvel- Eibrink MM. KIAA1524: A novel MLL translocation partner in acute myeloid leukemia. Leuk Res 2011; 35(1):133-5.
  • Chen KF, Liu CY, Lin YC, Yu HC, Liu TH, Hou DR, Chen PJ, Cheng AL. CIP2A mediates effects of bortezomib on phospho-Akt and apoptosis in hepatocellular carcinoma cells. Oncogene 2010; 29(47):6257-66.
  • Zhang X, Xu B, Sun C, Wang L, Miao X. Knockdown of CIP2A sensitizes ovarian cancer cells to cisplatin: an in vitro study. International journal of clinical and experimental medicine 2015; 8(9):16941-7.
  • Zhao D, Liu Z, Ding J, Wenjuan Li, Sun Y, Yu H, Zhou Y, Zeng J, Chen C, Jia J. Helicobacter pylori CagA upregulation of CIP2A is dependent on the Src and MEK/ERK pathways. J Med Microbiol 2010; 59(Pt 3):259-65.
  • Khanna A, Okkeri J, Bilgen T, Tiirikka T, Vihinen M, Visakorpi T, Westermarck J. ETS1 Mediates MEK1/2- dependent overexpression of cancerous inhibitor of protein phosphatase 2A (CIP2A) in human cancer cells. PLoS One 2011; 6(3):e17979.
  • Bockelman C, Lassus H, Hemmes A, Leminen A, Westermarck J, Haglund C, Butzow R, Ristimaki A. Prognostic role of CIP2A expression in serous ovarian cancer. British Journal of Cancer 2011; 105:989-95.
  • Li Y, Wang K, Dai L, Wang P, Song C, Shı J, Ren P, Ye H, Zhang J. HapMap-based study of CIP2A gene polymorphisms and HCC susceptibility. Oncol Lett 2012; 4(2):358-64.

Screening of CIP2A Oncogene Mutations in Ovarian

Year 2019, Volume: 5 Issue: 1, 55 - 59, 01.01.2019

Abstract

Objective: Determination of genetic changes associated with cancer is important for early diagnosis, follow-up of the disease and development of targeted therapeutic approaches. CIP2A is a newly identified oncoprotein associated with many human cancers. In many cancers, an increase in the CIP2A gene expression has been shown, but until now there has been no study investigating CIP2A promoter region mutations except our previous study about the mutations in the coding sequence of the CIP2A gene in AGS, HeLa, HT1080 cancer cell lines. The aim of this study was to contribute to the elucidation of the molecular mechanisms of CIP2A over expression in cancer and investigate the possible regulatory regions and intra-genic mutations that may play a role in the oncogenic effect of this gene.Material and Methods: The sequences encoding the CIP2A gene, exon-intron linkage regions, and the promoter region were screened in the SK-OV-3, Ov-CAR3, and Caov-3 human ovarian cancer cell lines by DNA sequence analysis. Results: Genomic changes were detected at exon 3, intron 6 and intron 8 in the Ov-CAR3 cell line and at intron 6 and intron 8 in the Caov-3 cell line. Conclusion: Our findings exclude the effect of genomic alterations in CIP2A in the increase in CIP2A expression for ovarian cancer. For cells expressing CIP2A oncoprotein at high levels, there is a need for functional studies to examine the underlying mechanisms

References

  • 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(32):5006-15.
  • Junttila MR, Puustinen P, Niemela M, Ahola R, Arnold H, Böttzauw T, Ala-aho R, Nielsen C, Ivaska J, Taya Y, Lu SL, Lin S, Chan EK, Wang XJ, Grenman R, Kast J, Kallunki T, Sears R, Kähäri VM, Westermarck J. CIP2A inhibits PP2A in human malignancies. Cell 2007; 130(1):51-62.
  • Khanna A, Bockelman C, Hemmes A, Junttila MR, Wiksten JP, Lundin M, Junnila S, Murphy DJ, Evan GI, Haglund C, Westermarck J, Ristimaki A. MYC- dependent regulation and prognostic role of CIP2A in gastric cancer. J Natl Cancer Inst 2009;101(11):793-805.
  • Li W, Ge Z, Liu C, Liu Z, Björkholm M, Jia J, Xu D. 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.
  • Routila J, Bilgen T, Saramaki O, Grenman R, Visakorpi T, Westermarck J, Ventela S. Copy number increase of oncoprotein CIP2A is associated with poor patient survival in human head and neck squamous cell carcinoma. Journal of Oral Pathology & Medicine 2016; 45(5):329- 37.
  • Come C, Laine A, Chanrion M, Edgren H, Mattila E, Liu X, Jonkers J, Ivaska J, Isola J, Darbon JM, Kallioniemi O, Thezenas S, Westermarck J. CIP2A is associated with human breast cancer aggressivity. Clin Cancer Res 2009; 15(16):5092-100.
  • Dong QZ, Wang Y, Dong XJ, Li ZX, Tang ZP, Cui QZ, Wanget EH. CIP2A is overexpressed in non-small cell lung cancer and correlates with poor prognosis. Ann Surg Oncol 2011; 18(3):857-65.
  • Qu W, Li W, Wei L, Xing L, Wang X, Yu J. CIP2A is overexpressed in esophageal squamous cell carcinoma. Med Oncol 2012; 29(1):113-8.
  • Vaarala MH, Vaisanen MR, Ristimaki A. CIP2A expression is increased in prostate cancer. J Exp Clin Cancer Res 2010; 29(1):136.
  • Fang Y, Li Z, Wang X, Zhang S. CIP2A is overexpressed in human ovarian cancer and regulates cell proliferation and apoptosis. Tumour Biology 2012; 33(6):2299-306.
  • Ma T, Zhang L, Xiao P, Liu Y, Li Y, Shi P, Zhou Y. Clinical significance of CIP2A expression in bladder cancer. Zhonghua Yi Xue Za Zhi 2014; 94(34):2681-3.
  • Coenen EA, Zwaan CM, Meyer C, Marschalek R, Pieters R, van der Veken LT, Beverloo HB, van den Heuvel- Eibrink MM. KIAA1524: A novel MLL translocation partner in acute myeloid leukemia. Leuk Res 2011; 35(1):133-5.
  • Chen KF, Liu CY, Lin YC, Yu HC, Liu TH, Hou DR, Chen PJ, Cheng AL. CIP2A mediates effects of bortezomib on phospho-Akt and apoptosis in hepatocellular carcinoma cells. Oncogene 2010; 29(47):6257-66.
  • Zhang X, Xu B, Sun C, Wang L, Miao X. Knockdown of CIP2A sensitizes ovarian cancer cells to cisplatin: an in vitro study. International journal of clinical and experimental medicine 2015; 8(9):16941-7.
  • Zhao D, Liu Z, Ding J, Wenjuan Li, Sun Y, Yu H, Zhou Y, Zeng J, Chen C, Jia J. Helicobacter pylori CagA upregulation of CIP2A is dependent on the Src and MEK/ERK pathways. J Med Microbiol 2010; 59(Pt 3):259-65.
  • Khanna A, Okkeri J, Bilgen T, Tiirikka T, Vihinen M, Visakorpi T, Westermarck J. ETS1 Mediates MEK1/2- dependent overexpression of cancerous inhibitor of protein phosphatase 2A (CIP2A) in human cancer cells. PLoS One 2011; 6(3):e17979.
  • Bockelman C, Lassus H, Hemmes A, Leminen A, Westermarck J, Haglund C, Butzow R, Ristimaki A. Prognostic role of CIP2A expression in serous ovarian cancer. British Journal of Cancer 2011; 105:989-95.
  • Li Y, Wang K, Dai L, Wang P, Song C, Shı J, Ren P, Ye H, Zhang J. HapMap-based study of CIP2A gene polymorphisms and HCC susceptibility. Oncol Lett 2012; 4(2):358-64.
There are 18 citations in total.

Details

Primary Language Turkish
Journal Section Research Article
Authors

Duygu Yaşar Şirin This is me

Türker Bilgen This is me

Publication Date January 1, 2019
Published in Issue Year 2019 Volume: 5 Issue: 1

Cite

APA Yaşar Şirin, D., & Bilgen, T. (2019). Yumurtalık Kanseri Hücre Soylarında CIP2A Onkogeni Mutasyonlarının Taranması. Akdeniz Tıp Dergisi, 5(1), 55-59.