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Nrf2 expression participates in growth and differentiation of endometrial carcinoma cells in vitro and in vivo

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Abstract

The expression level of Nrf2 is increased in series of tumors and it plays a vital role in proliferation of cancer cells. However, little is known about the clinical implications and biological functions of Nrf2 in endometrial carcinoma. The aim of this study is to study whether up-regulation of Nrf2 expression can promote growth of endometrial carcinoma cells. Using immunohistochemistry, Nrf2 protein expression was analyzed in endometrial carcinoma patients. A series of assays was performed to elucidate the role of Nrf2 in growth of endometrial carcinoma. Positive rate of Nrf2 was 64.3 % (45/70) in endometrial carcinoma patients, and it was associated with FIGO stage and histological grade (P < 0.05). In addition, ectopic overexpression of Nrf2 promoted the growth of endometrial carcinoma cells in vitro and in vivo. Interestingly, Nrf2 protein translocation from cytoplasm to nucleus may influence differentiation of endometrial carcinoma cells. These results suggest that Nrf2 participates in progression of endometrial carcinoma by influencing the growth and differentiation of endometrial carcinoma cells, and it could be used as a novel and potential therapeutic target for endometrial carcinoma.

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References

  • Cho HY, Reddy SP, Yamamoto M, Kleeberger SR (2004) The transcription factor Nrf2 protects against pulmonary fibrosis. FASEB J 18(11):1258–1260

    CAS  PubMed  Google Scholar 

  • Dinkova-Kostova AT, Liby KT, Stephenson KK, Holtzclaw WD, Gao X, Suh N, Williams C, Risingsong R, Honda T, Sporn MB, Gribble GW, Talalay P (2005) Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc Natl Acad Sci USA 102(12):4584–4589

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Du W, Jiang Y, Zheng Z, Zhang Z, Chen N, Ma Z, Yao Z, Terada L, Liu Z (2013) Feedback loop between p66 (Shc) and Nrf2 promotes lung cancer progression. Cancer Lett 337(1):58–65

    Article  CAS  PubMed  Google Scholar 

  • Hayes JD, McMahon M (2009) Nrf2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem Sci 34(4):176–188

    Article  CAS  PubMed  Google Scholar 

  • Homma S, Ishii Y, Morishima Y, Yamadori T, Matsuno Y, Haraguchi N, Kikuchi N, Satoh H, Sakamoto T, Hizawa N, Itoh K, Yamamoto M (2009) Nrf2 enhances cell proliferation and resistance to anticancer drugs in human lung cancer. Clin Cancer Res 15(10):3423–3432

    Article  CAS  PubMed  Google Scholar 

  • Hu T, Yao Y, Yu S, Guo H, Han L, Wang W, Tian T, Hao Y, Liu Z, Nan K, Wang S (2013) Clinicopathologic significance of CXCR4 and Nrf2 in colorectal cancer. J Biomed Res 27(4):283–290

    Article  PubMed Central  PubMed  Google Scholar 

  • Khor TO, Huang MT, Prawan A, Liu Y, Hao X, Yu S, Cheung WK, Chan JY, Reddy BS, Yang CS, Kong AN (2008) Increased susceptibility of Nrf2 knockout mice to colitis-associated colorectal cancer. Cancer Prev Res 1(3):187–191

    Article  CAS  Google Scholar 

  • Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K, Yamamoto M (2004) Oxidative stress sensor Keap 1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol 24(16):7130–7139

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kuang X, Scofield VL, Yan M, Stoica G, Liu N, Wong PK (2009) Attenuation of oxidative stress, inflammation and apoptosis by minocycline prevents retrovirusinduced neurodegeneration in mice. Brain Res 1286:174–184

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lau A, Villeneuve NF, Sun Z, Wong PK, Zhang DD (2008) Dual roles of Nrf2 in cancer. Pharmacol Res 58(5–6):262–270

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lister A, Nedjadi T, Kitteringham NR, Campbell F, Costello E, Lloyd B, Copple IM, Williams S, Owen A, Neoptolemos JP, Goldring CE, Park BK (2011) Nrf2 is overexpressed in pancreatic cancer: implications for cell proliferation and therapy. Mol Cancer 10:37. doi:10.1186/1476-4598-10-37

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ma X, Zhang J, Liu S, Huang Y, Chen B, Wang D (2012) Nrf2 knockdown by shRNA inhibits tumor growth and increases efficacy of chemotherapy in cervical cancer. Cancer Chemother Pharmacol 69(2):485–494

    Article  CAS  PubMed  Google Scholar 

  • Reddy NM, Kleeberger SR, Cho HY, Yamamoto M, Kensler TW, Biswal S, Reddy SP (2007) Deficiency in Nrf2-GSH signaling impairs type II cell growth and enhances sensitivity to oxidants. Am J Respir Cell Mol Biol 37(1):3–8

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Shih AY, Li P, Murphy TH (2005) A small-molecule-inducible Nrf2-mediated antioxidant response provides effective prophylaxis against cerebral ischemia in vivo. J Neurosci 25(44):10321–10335

    Article  CAS  PubMed  Google Scholar 

  • Singh A, Misra V, Thimmulappa RK, Lee H, Ames S, Hoque MO, Herman JG, Baylin SB, Sidransky D, Gabrielson E, Brock MV, Biswal S (2006) Dysfunctional KEAP1-Nrf2 interaction in non-small-cell lung cancer. PLoS Med 3:e420

    Article  PubMed Central  PubMed  Google Scholar 

  • Singh A, Boldin-Adamsky S, Thimmulappa RK, Rath SK, Ashush H, Coulter J, Blackford A, Goodman SN, Bunz F, Watson WH, Gabrielson E, Feinstein E, Biswal S (2008) RNAi-mediated silencing of nuclear factor erythroid-2-related factor 2 gene expression in non-small cell lung cancer inhibits tumor growth and increases efficacy of chemotherapy. Cancer Res 68(19):7975–7984

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Stacy DR, Ely K, Massion PP, Yarbrough WG, Hallahan DE, Sekhar KR, Freeman ML (2006) Increased expression of nuclear factor E2 p45-related factor 2 (Nrf2) in head and neck squamous cell carcinomas. Head Neck 28:813–818

    Article  PubMed  Google Scholar 

  • Wang J, Fields J, Zhao C, Langer J, Thimmulappa RK, Kensler TW, Yamamoto M, Biswal S, Dore S (2007) Role of Nrf2 in protection against intracerebral hemorrhage injury in mice. Free Radic Biol Med 43(3):408–414

    Article  PubMed Central  PubMed  Google Scholar 

  • Wang S, Liu H, Ren L, Pan Y, Zhang Y (2008) Inhibiting colorectal carcinoma growth and metastasis by blocking the expression of VEGF using RNA interference 10(4):399–407

    CAS  Google Scholar 

  • Xie D, Sham JS, Zeng WF, Lin HL, Che LH, Wu HX, Wen JM, Fang Y, Hu L, Guan XY (2003) Heterogeneous expression and association of beta-catenin, p16 and c-myc in multistage colorectal tumorigenesis and progression detected by tissue microarray. Int J Cancer 107(6):896–902

    Article  CAS  PubMed  Google Scholar 

  • Yan W, Wang HD, Feng XM, Ding YS, Jin W, Tang K (2009) The expression of NF-E2-related factor 2 in the rat brain after traumatic brain injury. J Trauma 66(5):1431–1435

    Article  CAS  PubMed  Google Scholar 

  • Zhang DD (2006) Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev 38(4):769–789

    Article  CAS  PubMed  Google Scholar 

  • Zhang DD, Lo SC, Cross JV, Templeton DJ, Hannink M (2004) Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol Cell Biol 24(24):10941–10953

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Correspondence to Jingwang Bi.

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Kainan Li and Chen Zhong have contributed equally to this work.

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Li, K., Zhong, C., Wang, B. et al. Nrf2 expression participates in growth and differentiation of endometrial carcinoma cells in vitro and in vivo. J Mol Hist 45, 161–167 (2014). https://doi.org/10.1007/s10735-013-9538-z

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  • DOI: https://doi.org/10.1007/s10735-013-9538-z

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