Decreased expression of LATS1 is correlated with the progression and prognosis of glioma

Journal of Experimental & Clinical Cancer Research

Xiuwu Bian²  Haiqiao Wu¹  Wensheng Yang¹  Wei Shao¹  Dan Liu¹  Tianhai Ji¹ 

[1] Department of Pathology, Chenggong Hospital, Xiamen University, Xiamen, Fujian, 361003, China;Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China

关键词: CCNA1;    Prognosis;    Tumor suppressor;    LATS1;   

Others  :  826130
DOI  :  10.1186/1756-9966-31-67

 received in 2012-01-17, accepted in 2012-08-07,  发布年份 2012

【 摘 要 】

Background

LATS1 is a tumor suppressor genes implicated in the pathogenesis of certain types of tumors, but its role is not known in human glioma.

Methods

Using real-time PCR and immunohistochemistry, we detected the mRNA and protein expression of LATS1 in glioma. The effect of LATS1 on cell growth and invasion were investigated.

Results

We found that mRNA and protein of LATS1 expression is significantly downregulated in glioma compared with normal control brain tissues. Furthermore, reduced LATS1 expression was markedly negatively correlated with WHO grade and KPS (p<0.001 and p<0.001) in glioma patients. Patients with lower LATS1 expression had a significantly shorter overall survival time than did patients with higher LATS1 expression. Multivariate analysis suggested that the level of LATS1 expression was an independent prognostic indicator (p<0.001) for the survival of patients with glioma. Forced expression of LATS1 in glioma U251 cells not only significantly suppressed cell growth, migration and invasion, but retarded cell cycle progression from G2/M to G1 in vitro. Finally, we found that overexpressed LATS1 markedly inhibited the expression level of cell cycle factor CCNA1.

Conclusion

These results indicate that LATS1 is an important candidate tumor suppressor and its downregulated expression may contribute to glioma progression.

【 授权许可】

   
2012 Ji et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Kleihues P, Cavenee WK: World Health Organization Classification of Tumours-Pathology and Genetics -Tumors of the Nervous System. Lyon. France: IARC Press; 2000:9-52.
• [2]Wu M, Chen Q, Li D, Li X, Li X, Huang C, Tang Y, Zhou Y, Wang D, Tang K, Cao L, Shen S, Li G: LRRC4 inhibits human glioblastoma cells proliferation, invasion, and proMMP-2 activation by reducing SDF-1 alpha/CXCR4-mediated ERK1/2 and Akt signaling pathways. J Cell Biochem 2008, 103:245-255.
• [3]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.
• [4]Justice RW, Zilian O, Woods DF, Noll M, Bryant PJ: The Drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation. Genes Dev 1995, 9:534-546.
• [5]Xu T, Wang W, Zhang S, Stewart RA, Yu W: Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase. Development 1995, 121:1053-1063.
• [6]Tao W, Zhang S, Turenchalk GS, Stewart RA, St John MA, Chen W, Xu T: Human homologue of the Drosophila melanogaster lats tumour suppressor modulates CDC2 activity. Nat Genet 1999, 21:177-181.
• [7]St John MA, Tao W, Fei X, Fukumoto R, Carcangiu ML, Brownstein DG, Parlow AF, McGrath J, Xu T: Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction. Nat Genet 1999, 21:182-186.
• [8]Cooke IE, Shelling AN, Le Meuth VG, Charnock ML, Ganesan TS: Allele loss on chromosome arm 6q and fine mapping of the region at 6q27 in epithelial ovarian cancer. Genes Chromosomes Cancer 1996, 15:223-233.
• [9]Mazurenko N, Attaleb M, Gritsko T, Semjonova L, Pavlova L, Sakharova O, Kisseljov F: High resolution mapping of chromosome 6 deletions in cervical cancer. Oncol Rep 1999, 6:859-863.
• [10]Fujii H, Zhou W, Gabrielson E: Detection of frequent allelic loss of 6q23–q25.2 in microdissected human breast cancer tissues. Genes Chromosomes Cancer 1996, 16:35-39.
• [11]Yang X, Li D, Chen W, Xu T: Human homologue of the Drosophila lats, LATS1, negatively regulate growth by inducing G2/M arrest or apoptosis. Oncogene 2001, 20:6516-6523.
• [12]Xia H, Qi H, Li Y, Pei J, Barton J, Blackstad M, Xu T, Tao W: LATS1 tumor suppressor regulates G2/M transition and apoptosis. Oncogene 2002, 21:1233-1241.
• [13]Takahashi Y, Miyoshi Y, Takahata C, Irahara N, Taguchi T, Tamaki Y, Noguchi S: Down-regulation of LATS1 and LATS2 mRNA expression by promoter hypermethylation and its association with biologically aggressive phenotype in human breast cancers. Clin Cancer Res 2005, 11:1380-1385.
• [14]Jiang Z, Li X, Hu J, Zhou W, Jiang Y, Li G, Lu D: Promoter hypermethylation-mediated down-regulation of LATS1 and LATS2 in human astrocytoma. Neurosci Res 2006, 56:450-458.
• [15]Liu Z, Li X, He X, Jiang Q, Xie S, Yu X, Zhen Y, Xiao G, Yao K, Fang W: Decreased expression of updated NESG1 in nasopharyngeal carcinoma: its potential role and preliminarily functional mechanism. Int J Cancer. Int J Cancer 2011, 128:2562-2571.
• [16]Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 2001, 25:402-408.
• [17]Avgeropoulos NG, Batchelor TT: New treatment strategies for malignant gliomas. Oncologist 1999, 4:209-224.
• [18]Visser S, Yang X: LATS tumor suppressor: a new governor of cellular homeostasis. Cell Cycle 2010, 9:3892-3903.
• [19]Zhang J, Smolen GA, Haber DA: Negative regulation of YAP by LATS1 underscores evolutionary conservation of the Drosophila Hippo pathway. Cancer Res 2008, 68:2789-2794.
• [20]Iida S, Hirota T, Morisaki T, et al.: Tumor suppressor WARTS ensures genomic integrity by regulating both mitotic progression and G1 tetraploidy checkpoint function. Oncogene 2004, 23:5266-5274.
• [21]Visser S, Yang X: Identification of LATS transcriptional targets in HeLa cells using whole human genome oligonucleotide microarray. Gene 2010, 449:22-29.
• [22]Liu D, Liao C, Wolgemuth DJ: A role for cyclin A1 in the activation of MPF and G2-M transition during meiosis of male germ cells in mice. Dev Biol 2000, 224:388-400.
• [23]Diederichs S, Bäumer N, Ji P, Metzelder SK, Idos GE, Cauvet T, Wang W, Möller M, Pierschalski S, Gromoll J, Schrader MG, Koeffler HP, Berdel WE, Serve H, Müller-Tidow C: Identification of interaction partners and substrates of the cyclin A1-CDK2 complex. J Biol Chem 2004, 279:33727-33741.
• [24]Cho NH, Choi YP, Moon DS, Kim H, Kang S, Ding O, Rha SY, Yang YJ, Cho SH: Induction of cell apoptosis in non-small cell lung cancer cells by cyclin A1 small interfering RNA. Cancer Sci 2006, 97:1082-1092.
• [25]Bois C, Delalande C, Bouraïma-Lelong H, Durand P, Carreau S: 17β-Estradiol regulates cyclin A1 and cyclin B1 gene expression in adult rat seminiferous tubules. J Mol Endocrinol 2012, 48:89-97.