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Clinicopathological analysis of UHRF1 expression in medulloblastoma tissues and its regulation on tumor cell proliferation

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Abstract

Studies have showed the involvement of ubiquitin-like with PHD and RING finger domains 1 (UHRF1) in tumorigenesis and progression. This study focused on the relationships between UHRF1 and medulloblastoma (MB). Immunostaining and western blotting demonstrated differential expression of UHRF1 in MB tissues and no UHRF1 expression in normal cerebellum tissues. Univariate survival analysis revealed MB patients with high UHRF1 expression had significantly shorter OS and PFS than patients with low UHRF1 (OS p = 0.009, PFS p = 0.003). Multivariate analysis illustrated that UHRF1 expression level is an independent prognostic factor influencing the OS and PFS (OS p = 0.038, PFS p = 0.014). UHRF1 expression levels were significantly different among molecular subgroups of MB (p = 0.003). Down-regulation of UHRF1 by RNAi inhibited proliferation and clonogenic ability of MB cell lines with cell cycle arrest in G1/G2-phase. Meanwhile, cells transfected with lenti-shUHRF1 showed increased p16 expression and location shift of CDK4 in MB cells. These findings indicate UHRF1 may promote cell proliferation and be a potential biomarker that can be used as a prognostic parameter and a therapeutic target for MB.

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References

  1. Packer RJ, Cogen P, Vezina G, Rorke LB. Medulloblastoma: clinical and biologic aspects. Neuro-oncology. 1999;1:232–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kool M, Korshunov A, Remke M, Jones DT, Schlanstein M, Northcott PA, et al. Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas. Acta Neuropathol. 2012;123:473–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Gottardo NG, Hansford JR, McGlade JP, Alvaro F, Ashley DM, Bailey S, et al. Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group. Acta Neuropathol. 2014;127:189–201.

    Article  PubMed  Google Scholar 

  4. del Charco JO, Bolek TW, McCollough WM, Maria BL, Kedar A, Braylan RC, et al. Medulloblastoma: time–dose relationship based on a 30-year review. Int J Radiat Oncol Biol Phys. 1998;42:147–54.

    PubMed  Google Scholar 

  5. Friedrich C, Warmuth-Metz M, von Bueren AO, Nowak J, Bison B, von Hoff K, et al. Improved survival with the use of adjuvant chemotherapy in the treatment of medulloblastoma. J Neurosurg. 1991;74:433–40.

    Article  Google Scholar 

  6. Northcott PA, Korshunov A, Witt H, Hielscher T, Eberhart CG, Mack S, et al. Medulloblastoma comprises four distinct molecular variants. J Clin Oncol. 2011;29:1408–14.

    Article  PubMed  Google Scholar 

  7. Robinson G, Parker M, Kranenburg TA, Lu C, Chen X, Ding L, et al. Novel mutations target distinct subgroups of medulloblastoma. Nature. 2012;488:43–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ellison DW, Dalton J, Kocak M, Nicholson SL, Fraga C, et al. Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol. 2011;121:381–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Northcott PA, Korshunov A, Witt H. Medulloblastoma comprises four distinct molecular variants. J Clin Oncol. 2011;29(11):1408–14.

    Article  PubMed  Google Scholar 

  10. Taylor MD, Northcott PA, Korshunov A. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012;123(4):465–72.

    Article  CAS  PubMed  Google Scholar 

  11. Li KK, Lau KM, Ng HK. Signaling pathway and molecular subgroups of medulloblastoma. Int J Clin Exp Pathol. 2013;6:1211–22.

    PubMed  PubMed Central  Google Scholar 

  12. Bronner C, Achour M, Arima Y, Chataigneau T, Saya H, Schini-Kerth VB. The UHRF family: oncogenes that are drugable targets for cancer therapy in the near future? Pharmacol Ther. 2007;115:419–34.

    Article  CAS  PubMed  Google Scholar 

  13. Muto M, Kanari Y, Kubo E, Takabe T, Kurihara T, Fujimori A, et al. Targeted disruption of NP95 gene renders murine embryonic stem cells hypersensitive to DNA damaging agents and DNA replication blocks. J Biol Chem. 2002;277:34549–55.

    Article  CAS  PubMed  Google Scholar 

  14. Mudbhary R, Hoshida Y, Chernyavskaya Y, Jacob V, Villanueva A, Fiel MI, et al. UHRF1 overexpression drives DNA hypomethylation and hepatocellular carcinoma. Cancer Cell. 2014;25:196–209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yan F, Tan XY, Geng Y, Ju HX, Gao YF, Zhu MC. Inhibition effect of siRNA-downregulated UHRF1 on breast cancer growth. Cancer Biother Radiopharm. 2011;26:183–9.

    Article  CAS  PubMed  Google Scholar 

  16. Liang D, Xue H, Yu Y, Lv F, You W, Zhang B. Elevated expression of UHRF1 predicts unfavorable prognosis for patients with hepatocellular carcinoma. Int J Clin Exp Pathol. 2015;8:9416–21.

    PubMed  PubMed Central  Google Scholar 

  17. Geng Y, Gao Y, Ju H, Yan F. Diagnostic and prognostic value of plasma and tissue ubiquitin-like, containing PHD and RING finger domains 1 in breast cancer patients. Cancer Sci. 2013;104:194–9.

    Article  CAS  PubMed  Google Scholar 

  18. Zhou L, Zhao X, Han Y, Lu Y, Shang Y, Liu C, et al. Regulation of UHRF1 by miR-146a/b modulates gastric cancer invasion and metastasis. FASEB J. 2013;27:4929–39.

    Article  CAS  PubMed  Google Scholar 

  19. Wang F, Yang YZ, Shi CZ, Zhang P, Moyer MP, Zhang HZ, et al. UHRF1 promotes cell growth and metastasis through repression of p16(ink4a) in colorectal cancer. Ann Surg Oncol. 2012;19:2753–62.

    Article  PubMed  Google Scholar 

  20. Qin Y, Wang J, Gong W, Zhang M, Tang Z, Zhang J, et al. UHRF1 depletion suppresses growth of gallbladder cancer cells through induction of apoptosis and cell cycle arrest. Oncol Rep. 2014;31:2635–43.

    CAS  PubMed  Google Scholar 

  21. Yang GL, Zhang LH, Bo JJ, Chen HG, Cao M, Liu DM, et al. UHRF1 is associated with tumor recurrence in non-muscle-invasive bladder cancer. Med Oncol. 2012;29:842–7.

    Article  CAS  PubMed  Google Scholar 

  22. Zhang Y, Huang Z, Zhu Z, Zheng X, Liu J, Han Z, et al. Upregulated UHRF1 promotes bladder cancer cell invasion by epigenetic silencing of KiSS1. PLoS ONE. 2014;9:e104252.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Jazirehi AR, Arle D, Wenn PB. UHRF1: a master regulator in prostate cancer. Epigenomics. 2012;4:251–2.

    Article  CAS  PubMed  Google Scholar 

  24. Babbio F, Pistore C, Curti L, Castiglioni I, Kunderfranco P, Brino L, Oudet P, et al. The SRA protein UHRF1 promotes epigenetic crosstalks and is involved in prostate cancer progression. Oncogene. 2012;31:4878–87.

    Article  CAS  PubMed  Google Scholar 

  25. Daskalos A, Oleksiewicz U, Filia A, Nikolaidis G, Xinarianos G, Gosney JR, et al. UHRF1-mediated tumor suppressor gene inactivation in nonsmall cell lung cancer. Cancer. 2011;117:1027–37.

    Article  CAS  PubMed  Google Scholar 

  26. Pi JT, Lin Y, Quan Q, Chen LL, Jiang LZ, Chi W, et al. Overexpression of UHRF1 is significantly associated with poor prognosis in laryngeal squamous cell carcinoma. Med Oncol. 2013;30:613.

    Article  PubMed  Google Scholar 

  27. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114:97–109.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Min HS, Lee JY, Kim SK, Park SH. Genetic grouping of medulloblastomas by representative markers in pathologic diagnosis. Transl Oncol. 2013;6:265–72.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Goschzik T, Zur Mühlen A, Kristiansen G, Haberler C, Stefanits H, Friedrich C, et al. Molecular stratification of medulloblastoma: comparison of histological and genetic methods to detect Wnt activated tumours. Neuropathol Appl Neurobiol. 2015;41:135–44.

    Article  CAS  PubMed  Google Scholar 

  30. Dai DL, Martinka M, Li G. Prognostic significance of activated Akt expression in melanoma: a clinicopathologic study of 292 cases. J Clin Oncol. 2005;23:1473–82.

    Article  CAS  PubMed  Google Scholar 

  31. Ke AW, Shi GM, Zhou J, Wu FZ, Ding ZB, Hu MY, et al. Role of overexpression of CD151 and/or c-Met in predicting prognosis of hepatocellular carcinoma. Hepatology. 2009;49:491–503.

    Article  CAS  PubMed  Google Scholar 

  32. Zhu XD, Zhang JB, Zhuang PY, Zhu HG, Zhang W, Xiong YQ, et al. High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J Clin Oncol. 2008;26:2707–16.

    Article  PubMed  Google Scholar 

  33. Zhu M, Xu Y, Ge M, Gui Z, Yan F. Regulation of UHRF1 by microRNA-9 modulates colorectal cancer cell proliferation and apoptosis. Cancer Sci. 2015;106:833–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lorenzato M, Caudroy S, Bronner C, Evrard G, Simon M, Durlach A, et al. Cell cycle and/or proliferation markers: what is the best method to discriminate cervical high-grade lesions? Hum Pathol. 2005;36:1101–7.

    Article  CAS  PubMed  Google Scholar 

  35. Arima Y, Hirota T, Bronner C, Mousli M, Fujiwara T, Niwa S, et al. Down-regulation of nuclear protein ICBP90 by p53/p21Cip1/WAF1-dependent DNA-damage checkpoint signals contributes to cell cycle arrest at G1/S transition. Genes Cells. 2004;9:131–42.

    Article  CAS  PubMed  Google Scholar 

  36. Jenkins Y, Markovtsov V, Lang W, Sharma P, Pearsall D, Warner J, et al. Critical role of the ubiquitin ligase activity of UHRF1, a nuclear RING finger protein, in tumor cell growth. Mo Biol Cell. 2005;16:5621–9.

    Article  CAS  Google Scholar 

  37. Karagianni P, Amazit L, Qin J, Wong J. ICBP90, a novel methyl K9 H3 binding protein linking protein ubiquitination with heterochromatin formation. Mol Cell Biol. 2008;28:705–17.

    Article  CAS  PubMed  Google Scholar 

  38. Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science. 1994;264:436–40.

    Article  CAS  PubMed  Google Scholar 

  39. Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993;366:704–7.

    Article  CAS  PubMed  Google Scholar 

  40. Zhao X, Song T, He Z, Tang L, Zhu Y. A novel role of cyclinD1 and p16 in clinical pathology and prognosis of childhood medulloblastoma. Med Oncol. 2010;27:985–91.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by the Research Special Fund for Public Welfare Industry of Health (201402008), Shanghai Municipal Commission of Health and Family Planning (20124354).

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    Authors and Affiliations

    1. Department of Neurosurgery, Huashan Hospital, Fudan University, Wulumuqi Zhong Road 12, Shanghai, 200040, China

      Zhen-Yu Zhang, Jia-Jun Cai, Zhou Ping, Yu Yao & Ying Mao

    2. Department of Neurosurgery, First Affiliated Hospital of Zhengzhou University, Jianshe Dong Road 1, Zhengzhou, 450001, Henan, China

      Zhen-Yu Zhang

    3. Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Jianshe Dong Road 1, Zhengzhou, 450001, Henan, China

      Jin Hong

    4. Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, N.T., Hong Kong, China

      Kay Ka-Wai Li & Ho-Keung Ng

    5. Department of Neuropathology, Huashan Hospital, Fudan University, Wulumuqi Zhong Road 12, Shanghai, 200040, China

      Yin Wang

    6. State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences and Institutes of Brain Science, Fudan University, Shanghai, 200032, China

      Ying Mao

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    Zhen-Yu Zhang, Jia-Jun Cai and Jin Hong have contributed equally to this work.

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    Supplementary Figure 1

    UHRF1 expression among molecular subgroups of MB The proportion of high UHRF1 expression in WNT subtype was lower than the other subgroups (p = 0.003) (TIFF 32 kb)

    Supplementary Figure 2

    Prognostic value of UHRF1 expression in molecular and histological subgroups of MB UHRF1 expression had prognostic significance in WNT subgroup (OS p = 0.008, PFS p = 0.004) and CMB (OS p = 0.022, PFS p = 0.004), but not in SHH subtype, non-SHH/WNT subtype, DMB and AMB (TIFF 1242 kb)

    Supplementary material 3 (DOC 73 kb)

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    Zhang, ZY., Cai, JJ., Hong, J. et al. Clinicopathological analysis of UHRF1 expression in medulloblastoma tissues and its regulation on tumor cell proliferation. Med Oncol 33, 99 (2016). https://doi.org/10.1007/s12032-016-0799-8

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