DJ-1 is activated in medulloblastoma and is associated with cell proliferation and differentiation

World Journal of Surgical Oncology

Zhi Li⁴  Xiao-ying Tian²  Yang Li⁴  Bin Li⁴  Bin-cai Pan¹  Jia-ping Lin³ 

[1] Department of Pathology, Tongjiang Hospital of Guangdong, Nanguo Road East, Shunde District, Foshan 528300, China;School of Chinese Medicine, Hong Kong Baptist University, 7, Baptist University Road, Kowloon Tong, Hong Kong, China;Department of Neurosurgery, the First Affiliated Hospital, Sun Yat-sen University, 58, Zhongshan Road II, Guangzhou 510080, China;Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, 58, Zhongshan Road II, Guangzhou 510080, China

关键词: Prognosis;    PTEN;    PI3K/Akt pathway;    DJ-1;    Medulloblastoma;   

Others  :  1147033
DOI  :  10.1186/1477-7819-12-373

 received in 2014-06-04, accepted in 2014-11-18,  发布年份 2014

【 摘 要 】

Background

DJ-1 is a key regulator in human tumorigenesis, including brain malignancies. The mechanisms by which DJ-1 contributes to the pathogenesis of medulloblastoma (MB) remain unclear, and its impact on the prognosis for patients with MB has not been identified. The aim of this study was to determine whether the DJ-1 protein is associated with tumorigenesis of MBs, and whether DJ-1 is a valuable factor for predicting the prognosis of patients with MB.

Methods

We collected 66 pairs of MB and adjacent normal cerebellum samples. Expression of DJ-1, Ser ⁴⁷³-phosphorylated-Akt (p-Akt), PTEN, and Ki-67 (MIB-1) was detected by immunohistochemical staining, and the correlation of these immunostaining results with the clinicopathological features of patients with MB was determined.

Results

High DJ-1 expression (48.5%, 32/66) in tumor cells of MBs was significantly associated with the classic MB variant (P = 0.003), high proliferative activity (P = 0.002) and undifferentiated tumor (P = 0.001), whereas high p-Akt expression (56.1%, 37/66) was associated with tumor metastasis stage (P = 0.007), undifferentiated tumor (P = 0.007), and high-risk tumor (P = 0.002). High DJ-1 expression also correlated with high p-Akt expression and high MIB-1 index. However, only high levels of DJ-1(P = 0.009) and high MIB-1 index (P = 0.001) were strong independent prognostic factors associated with worse overall survival.

Conclusions

Although the validity of the preliminary data in this study needs to be confirmed by a larger number of cases, our study indicates that DJ-1, PTEN, and p-Akt might play important roles in cell proliferation and differentiation of MBs. The evaluation of expression of DJ-1 and related proteins might be useful for predicting the prognosis of patients with MB.

【 授权许可】

   
2014 Lin et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Stevens MC, Cameron AH, Muir KR, Parkes SE, Reid H, Whitwell H: Descriptive epidemiology of primary central nervous system tumours in children: a population-based study. Clin Oncol (R Coll Radiol) 1991, 3:323-329.
• [2]Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007, 114:97-109.
• [3]Gajjar A, Chintagumpala M, Ashley D, Kellie S, Kun LE, Merchant TE, Woo S, Wheeler G, Ahern V, Krasin MJ, Fouladi M, Broniscer A, Krance R, Hale GA, Stewart CF, Dauser R, Sanford RA, Fuller C, Lau C, Boyett JM, Wallace D, Gilbertson RJ: Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. Lancet Oncol 2006, 7:813-820.
• [4]Packer RJ, Gajjar A, Vezina G, Rorke-Adams L, Burger PC, Robertson PL, Bayer L, LaFond D, Donahue BR, Marymont MH, Muraszko K, Langston J, Sposto R: Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol 2006, 24:4202-4208.
• [5]Kool M, Korshunov A, Remke M, Jones DT, Schlanstein M, Northcott PA, Cho YJ, Koster J, Schouten-van Meeteren A, van Vuurden D, Clifford SC, Pietsch T, von Bueren AO, Rutkowski S, McCabe M, Collins VP, Bäcklund ML, Haberler C, Bourdeaut F, Delattre O, Doz F, Ellison DW, Gilbertson RJ, Pomeroy SL, Taylor MD, Lichter P, Pfister SM: 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, 123:473-484.
• [6]Nagakubo D, Taira T, Kitaura H, Ikeda M, Tamai K, Iguchi-Ariga SM, Ariga H: DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras. Biochem Biophys Res Commun 1997, 231:509-513.
• [7]Hod Y: Differential control of apoptosis by DJ-1 in prostate benign and cancer cells. J Cell Biochem 2004, 92:1221-1233.
• [8]Bai J, Guo C, Sun W, Li M, Meng X, Yu Y, Jin Y, Tong D, Geng J, Huang Q, Qi J, Fu S: DJ-1 may contribute to metastasis of non-small cell lung cancer. Mol Biol Rep 2012, 39:2697-2703.
• [9]Zhu XL, Wang ZF, Lei WB, Zhuang HW, Jiang HY, Wen WP: DJ-1: a novel independent prognostic marker for survival in glottic squamous cell carcinoma. Cancer Sci 2010, 101:1320-1325.
• [10]Davidson B, Hadar R, Schlossberg A, Sternlicht T, Slipicevic A, Skrede M, Risberg B, Flørenes VA, Kopolovic J, Reich R: Expression and clinical role of DJ-1, a negative regulator of PTEN, in ovarian carcinoma. Hum Pathol 2008, 39:87-95.
• [11]Kim RH, Peters M, Jang Y, Shi W, Pintilie M, Fletcher GC, DeLuca C, Liepa J, Zhou L, Snow B, Binari RC, Manoukian AS, Bray MR, Liu FF, Tsao MS, Mak TW: DJ-1, a novel regulator of the tumor suppressor PTEN. Cancer Cell 2005, 7:263-273.
• [12]Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P: Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 1997, 7:261-269.
• [13]Song G, Ouyang G, Bao S: The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 2005, 9:59-71.
• [14]Bigner SH, Mark J, Friedman HS, Biegel JA, Bigner DD: Structural chromosomal abnormalities in human medulloblastoma. Cancer Genet Cytogenet 1988, 30:91-101.
• [15]Griffin CA, Hawkins AL, Packer RJ, Rorke LB, Emanuel BS: Chromosome abnormalities in pediatric brain tumors. Cancer Res 1988, 48:175-180.
• [16]Chow LM, Baker SJ: PTEN function in normal and neoplastic growth. Cancer Lett 2006, 241:184-196.
• [17]Hartmann W, Digon-Söntgerath B, Koch A, Waha A, Endl E, Dani I, Denkhaus D, Goodyer CG, Sörensen N, Wiestler OD, Pietsch T: Phosphatidylinositol 3′-kinase/AKT signaling is activated in medulloblastoma cell proliferation and is associated with reduced expression of PTEN. Clin Cancer Res 2006, 12:3019-3027.
• [18]Louis DN, Ohgaki H, Wiestler OD: WHO Classification of Tumours of the Central Nervous System. Lyon: IARC press; 2007.
• [19]Wang C, Fang M, Zhang M, Li W, Guan H, Sun Y, Xie S, Zhong X: The positive correlation between DJ-1 and β-catenin expression shows prognostic value for patients with glioma. Neuropathology 2013, 33:628-636.
• [20]Varan A: Risk-adapted chemotherapy in childhood medulloblastoma. Expert Rev Anticancer Ther 2001, 11:771-780.
• [21]Ellison DW, Clifford SC, Gajjar A, Gilbertson RJ: What’s new in neuro-oncology? Recent advances in medulloblastoma. Eur J Paediatr Neurol 2003, 7:53-66.
• [22]Gilbertson RJ: Medulloblastoma: signaling a change in treatment. Lancet Oncol 2004, 5:209-218.
• [23]Hinkle DA, Mullett SJ, Gabris BE, Hamilton RL: DJ-1 expression in glioblastomas shows positive correlation with p53 expression and negative correlation with epidermal growth factor receptor amplification. Neuropathology 2011, 31:29-37.
• [24]Pei XJ, Wu TT, Li B, Tian X, Li Z, Yang QX: Increased expression of macrophage migration inhibitory factor and DJ-1 contribute to cell invasion and metastasis of nasopharyngeal carcinoma. Int J Med Sci 2013, 11:106-115.
• [25]Li Y, Cui J, Zhang CH, Yang DJ, Chen JH, Zan WH, Li B, Li Z, He YL: High-expression of DJ-1 and loss of PTEN associated with tumor metastasis and correlated with poor prognosis of gastric carcinoma. Int J Med Sci 2013, 10:1689-1697.
• [26]Rizzu P, Hinkle DA, Zhukareva V, Bonifati V, Severijnen LA, Martinez D, Ravid R, Kamphorst W, Eberwine JH, Lee VM, Trojanowski JQ, Heutink P: DJ-1 colocalizes with tau inclusions: a link between parkinsonism and dementia. Ann Neurol 2004, 55:113-118.
• [27]Bandopadhyay R, Kingsbury AE, Cookson MR, Reid AR, Evans IM, Hope AD, Pittman AM, Lashley T, Canet-Aviles R, Miller DW, McLendon C, Strand C, Leonard AJ, Abou-Sleiman PM, Healy DG, Ariga H, Wood NW, de Silva R, Revesz T, Hardy JA, Lees AJ: The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson’s disease. Brain 2004, 127:420-430.
• [28]Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P: Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 2003, 299:256-259.
• [29]Gilbertson RJ, Jaros E, Perry RH, Kelly PJ, Lunec J, Pearson AD: Mitotic percentage index: a new prognostic factor for childhood medulloblastoma. Eur J Cancer 1997, 33:609-615.
• [30]McManamy CS, Lamont JM, Taylor RE, Cole M, Pearson AD, Clifford SC, Ellison DW: United Kingdom Children’s Cancer Study Group: Morphophenotypic variation predicts clinical behavior in childhood non-desmoplastic medulloblastomas. J Neuropathol Exp Neurol 2003, 62:627-632.
• [31]Ohta T, Watanabe T, Katayama Y, Kurihara J, Yoshino A, Nishimoto H, Kishimoto H: TrkA expression is associated with an elevated level of apoptosis in classic medulloblastomas. Neuropathology 2006, 26:170-177.
• [32]Ito S, Hoshino T, Prados MD, Edwards MS: Cell kinetics of medulloblastomas. Cancer 1992, 70:671-678.
• [33]Wang JY, Del Valle L, Gordon J, Rubini M, Romano G, Croul S, Peruzzi F, Khalili K, Reiss K: Activation of the IGF-IR system contributes to malignant growth of human and mouse medulloblastomas. Oncogene 2001, 20:3857-3868.
• [34]MacDonald TJ, Brown KM, LaFleur B, Peterson K, Lawlor C, Chen Y, Packer RJ, Cogen P, Stephan DA: Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease. Nat Genet 2001, 29:143-152.
• [35]Chilton-Macneill S, Ho M, Hawkins C, Gassas A, Zielenska M, Baruchel S: C-kit expression and mutational analysis in medulloblastoma. Pediatr Dev Pathol 2004, 7:493-498.
• [36]Klein RS, Rubin JB, Gibson HD, DeHaan EN, Alvarez-Hernandez X, Segal RA, Luster AD: SDF-1 alpha induces chemotaxis and enhances Sonic hedgehog-induced proliferation of cerebellar granule cells. Development 2001, 128:1971-1981.
• [37]Rubin JB, Kung AL, Klein RS, Chan JA, Sun Y, Schmidt K, Kieran MW, Luster AD, Segal RA: A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proc Natl Acad Sci U S A 2003, 100:13513-13518.
• [38]Martelli AM, Cocco L, Capitani S, Miscia S, Papa S, Manzoli FA: Nuclear phosphatidylinositol 3, 4, 5-trisphosphate, phosphatidylinositol 3-kinase, Akt, and PTen: emerging key regulators of anti-apoptotic signaling and carcinogenesis. Eur J Histochem 2007, 51:125-131.
• [39]Reardon DA, Michalkiewicz E, Boyett JM, Sublett JE, Entrekin RE, Ragsdale ST, Valentine MB, Behm FG, Li H, Heideman RL, Kun LE, Shapiro DN, Look AT: Extensive genomic abnormalities in childhood medulloblastoma by comparative genomic hybridization. Cancer Res 1997, 57:4042-4027.
• [40]Rasheed BK, Stenzel TT, McLendon RE, Parsons R, Friedman AH, Friedman HS, Bigner DD, Bigner SH: PTEN gene mutations are seen in high-grade but not in low-grade gliomas. Cancer Res 1997, 57:4187-4190.
• [41]Baeza N, Weller M, Yonekawa Y, Kleihues P, Ohgaki H: PTEN methylation and expression in glioblastomas. Acta Neuropathol 2003, 106:479-485.
• [42]Berman DM, Karhadkar SS, Hallahan AR, Pritchard JI, Eberhart CG, Watkins DN, Chen JK, Cooper MK, Taipale J, Olson JM, Beachy PA: Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 2002, 297:1559-1561.
• [43]Thompson MC, Fuller C, Hogg TL, Dalton J, Finkelstein D, Lau CC, Chintagumpala M, Adesina A, Ashley DM, Kellie SJ, Taylor MD, Curran T, Gajjar A, Gilbertson RJ: Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol 2006, 24:1924-1931.
• [44]Romer J, Curran T: Targeting medulloblastoma: small-molecule inhibitors of the Sonic Hedgehog pathway as potential cancer therapeutics. Cancer Res 2005, 65:4975-4878.
• [45]Sasai K, Romer JT, Lee Y, Finkelstein D, Fuller C, McKinnon PJ, Curran T: Shh pathway activity is down-regulated in cultured medulloblastoma cells: implications for preclinical studies. Cancer Res 2006, 66:4215-4222.