Yin Yang 1 contributes to gastric carcinogenesis and its nuclear expression correlates with shorter survival in patients with early stage gastric adenocarcinoma

Journal of Translational Medicine

Ka Fai To¹  Alfred SL Cheng⁴  Jun Yu⁵  Simon SM Ng⁶  Frankie MC Sin³  Weiqin Yang⁵  Shiyan Wang²  Yujuan Dong²  Junhong Zhao²  Anthony WH Chan⁷  Joanna HM Tong³  Wei Kang¹ 

[1] Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China;Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China;Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, PR China;School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, PR China;Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, PR China;Department of Surgery, The Chinese University of Hong Kong, Hong Kong, PR China;Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, PR China

关键词: Oncogenic function;    Prognostic marker;    Gastric adenocarcinoma;    Yin Yang 1;   

Others  :  817398
DOI  :  10.1186/1479-5876-12-80

 received in 2014-01-25, accepted in 2014-03-24,  发布年份 2014

【 摘 要 】

Background

Yin Yang 1 (YY1) is a transcription factor that regulates diverse biological processes and increasing recognized to have important roles in carcinogenesis. The function and clinical significance of YY1 in gastric adenocarcinoma (GAC) have not been elucidated.

Methods

In this study, the functional role of YY1 in gastric cancer was investigated by MTT proliferation assays, monolayer colony formation, cell cycle analysis, signaling pathway analysis, Western blot analysis and in vivo study through YY1 knockdown or overexpression. Immunohistochemical study with YY1 antibody was performed on tissue microarray consisting of 247 clinical GAC samples. The clinical correlation and prognosis significance were evaluated.

Results

YY1 expression was up-regulated in gastric cancer cell lines and primary gastric cancers. Knocking down YY1 by siYY1 inhibited cell growth, inducing G1 phase accumulation and apoptosis. Ectopic YY1 expression enhanced cell proliferation in vitro and in vivo. Knocking down YY1 in gastric cancer cells suppressed proliferation by inhibiting Wnt/β-catenin pathway, whereas its overexpression exerted oncogenic property by activating Wnt/β-catenin pathway. In primary GAC samples, YY1 nuclear expression correlated with shorter survival and predicted poor prognosis in early stage GACs.

Conclusion

Our data demonstrated that YY1 contributes to gastric carcinogenesis in gastric cancer. In early stage GACs YY1 might serve as a poor prognostic marker and possibly as a potential therapeutic target.

【 授权许可】

   
2014 Kang et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ: Cancer statistics, 2007. CA Cancer J Clin 2007, 57:43-66.
• [2]Vrdoljak E, Wojtukiewicz MZ, Pienkowski T, Bodoky G, Berzinec P, Finek J, Todorovic V, Borojevic N, Croitoru A: Cancer epidemiology in Central, South and Eastern European countries. Croat Med J 2011, 52:478-487.
• [3]Milne AN, Carneiro F, O’Morain C, Offerhaus GJ: Nature meets nurture: molecular genetics of gastric cancer. Hum Genet 2009, 126:615-628.
• [4]Shi Y, Seto E, Chang LS, Shenk T: Transcriptional repression by YY1, a human GLI-Kruppel-related protein, and relief of repression by adenovirus E1A protein. Cell 1991, 67:377-388.
• [5]Zaravinos A, Spandidos DA: Yin yang 1 expression in human tumors. Cell Cycle 2010, 9:512-522.
• [6]Lee HY, Chaudhary J, Walsh GL, Hong WK, Kurie JM: Suppression of c-Fos gene transcription with malignant transformation of human bronchial epithelial cells. Oncogene 1998, 16:3039-3046.
• [7]Liao WR, Hsieh RH, Hsu KW, Wu MZ, Tseng MJ, Mai RT, Wu Lee YH, Yeh TS: The CBF1-independent Notch1 signal pathway activates human c-myc expression partially via transcription factor YY1. Carcinogenesis 2007, 28:1867-1876.
• [8]Allouche A, Nolens G, Tancredi A, Delacroix L, Mardaga J, Fridman V, Winkler R, Boniver J, Delvenne P, Begon DY: The combined immunodetection of AP-2alpha and YY1 transcription factors is associated with ERBB2 gene overexpression in primary breast tumors. Breast Cancer Res 2008, 10:R9. BioMed Central Full Text
• [9]Begon DY, Delacroix L, Vernimmen D, Jackers P, Winkler R: Yin Yang 1 cooperates with activator protein 2 to stimulate ERBB2 gene expression in mammary cancer cells. J Biol Chem 2005, 280:24428-24434.
• [10]Wan M, Huang W, Kute TE, Miller LD, Zhang Q, Hatcher H, Wang J, Stovall DB, Russell GB, Cao PD, Deng Z, Wang W, Zhang Q, Lei M, Torti SV, Akman SA, Sui G: Yin Yang 1 plays an essential role in breast cancer and negatively regulates p27. Am J Pathol 2012, 180:2120-2133.
• [11]Rayess H, Wang MB, Srivatsan ES: Cellular senescence and tumor suppressor gene p16. Int J Cancer 2012, 130:1715-1725.
• [12]Wu S, Murai S, Kataoka K, Miyagishi M: Cooperative regulation of p73 promoter by Yin Yang 1 and E2F1. Nucleic Acids Symp Ser (Oxf) 2007, 51:347-348.
• [13]Gronroos E, Terentiev AA, Punga T, Ericsson J: YY1 inhibits the activation of the p53 tumor suppressor in response to genotoxic stress. Proc Natl Acad Sci U S A 2004, 101:12165-12170.
• [14]Castellano G, Torrisi E, Ligresti G, Malaponte G, Militello L, Russo AE, McCubrey JA, Canevari S, Libra M: The involvement of the transcription factor Yin Yang 1 in cancer development and progression. Cell Cycle 2009, 8:1367-1372.
• [15]Palmer MB, Majumder P, Cooper JC, Yoon H, Wade PA, Boss JM: Yin yang 1 regulates the expression of snail through a distal enhancer. Mol Cancer Res 2009, 7:221-229.
• [16]de Nigris F, Rossiello R, Schiano C, Arra C, Williams-Ignarro S, Barbieri A, Lanza A, Balestrieri A, Giuliano MT, Ignarro LJ, Napoli C: Deletion of Yin Yang 1 protein in osteosarcoma cells on cell invasion and CXCR4/angiogenesis and metastasis. Cancer Res 2008, 68:1797-1808.
• [17]de Nigris F, Botti C, de Chiara A, Rossiello R, Apice G, Fazioli F, Fiorito C, Sica V, Napoli C: Expression of transcription factor Yin Yang 1 in human osteosarcomas. Eur J Cancer 2006, 42:2420-2424.
• [18]de Nigris F, Zanella L, Cacciatore F, De Chiara A, Fazioli F, Chiappetta G, Apice G, Infante T, Monaco M, Rossiello R, De Rosa G, Alberghini M, Napoli C: YY1 overexpression is associated with poor prognosis and metastasis-free survival in patients suffering osteosarcoma. BMC Cancer 2011, 11:472. BioMed Central Full Text
• [19]Castellano G, Torrisi E, Ligresti G, Nicoletti F, Malaponte G, Traval S, McCubrey JA, Canevari S, Libra M: Yin Yang 1 overexpression in diffuse large B-cell lymphoma is associated with B-cell transformation and tumor progression. Cell Cycle 2010, 9:557-563.
• [20]Deng Z, Wan M, Cao P, Rao A, Cramer SD, Sui G: Yin Yang 1 regulates the transcriptional activity of androgen receptor. Oncogene 2009, 28:3746-3757.
• [21]Zheng H, Chu J, Zeng Y, Loh HH, Law PY: Yin Yang 1 phosphorylation contributes to the differential effects of mu-opioid receptor agonists on microRNA-190 expression. J Biol Chem 2010, 285:21994-22002.
• [22]Beezhold K, Liu J, Kan H, Meighan T, Castranova V, Shi X, Chen F: miR-190-mediated downregulation of PHLPP contributes to arsenic-induced Akt activation and carcinogenesis. Toxicol Sci 2011, 123:411-420.
• [23]Lee MH, Lahusen T, Wang RH, Xiao C, Xu X, Hwang YS, He WW, Shi Y, Deng CX: Yin Yang 1 positively regulates BRCA1 and inhibits mammary cancer formation. Oncogene 2012, 31:116-127.
• [24]Lieberthal JG, Kaminsky M, Parkhurst CN, Tanese N: The role of YY1 in reduced HP1alpha gene expression in invasive human breast cancer cells. Breast Cancer Res 2009, 11:R42. BioMed Central Full Text
• [25]Wang CC, Tsai MF, Dai TH, Hong TM, Chan WK, Chen JJ, Yang PC: Synergistic activation of the tumor suppressor, HLJ1, by the transcription factors YY1 and activator protein 1. Cancer Res 2007, 67:4816-4826.
• [26]Wang CC, Tsai MF, Hong TM, Chang GC, Chen CY, Yang WM, Chen JJ, Yang PC: The transcriptional factor YY1 upregulates the novel invasion suppressor HLJ1 expression and inhibits cancer cell invasion. Oncogene 2005, 24:4081-4093.
• [27]Naidoo K, Clay V, Hoyland JA, Swindell R, Linton K, Illidge T, Radford JA, Byers RJ: YY1 expression predicts favourable outcome in follicular lymphoma. J Clin Pathol 2011, 64:125-129.
• [28]Kang W, Tong JH, Chan AW, Lee TL, Lung RW, Leung PP, So KK, Wu K, Fan D, Yu J, Sung JJ, To KF: Yes-associated protein 1 exhibits oncogenic property in gastric cancer and its nuclear accumulation associates with poor prognosis. Clin Cancer Res 2011, 17:2130-2139.
• [29]Zhang S, Jiang T, Feng L, Sun J, Lu H, Wang Q, Pan M, Huang D, Wang X, Wang L, Jin H: Yin Yang-1 suppresses differentiation of hepatocellular carcinoma cells through the downregulation of CCAAT/enhancer-binding protein alpha. J Mol Med (Berl) 2012, 90:1069-1077.
• [30]Tang S, Mishra M, Frazier DP, Moore ML, Inoue K, Deora R, Sui G, Dubey P: Positive and negative regulation of prostate stem cell antigen expression by Yin Yang 1 in prostate epithelial cell lines. PLoS One 2012, 7:e35570.
• [31]Moseley SC, Rizkallah R, Tremblay DC, Anderson BR, Hurt MM, Chadwick BP: YY1 associates with the macrosatellite DXZ4 on the inactive X chromosome and binds with CTCF to a hypomethylated form in some male carcinomas. Nucleic Acids Res 2012, 40:1596-1608.
• [32]Ishii H, Hulett MD, Li JM, Santiago FS, Parish CR, Khachigian LM: Yin Yang-1 inhibits tumor cell growth and inhibits p21WAF1/Cip1 complex formation with cdk4 and cyclin D1. Int J Oncol 2012, 40:1575-1580.
• [33]Nicholson S, Whitehouse H, Naidoo K, Byers RJ: Yin Yang 1 in human cancer. Crit Rev Oncog 2011, 16:245-260.
• [34]Zhang Q, Stovall DB, Inoue K, Sui G: The oncogenic role of Yin Yang 1. Crit Rev Oncog 2011, 16:163-197.
• [35]Joo M, Wright JG, Hu NN, Sadikot RT, Park GY, Blackwell TS, Christman JW: Yin Yang 1 enhances cyclooxygenase-2 gene expression in macrophages. Am J Physiol Lung Cell Mol Physiol 2007, 292:L1219-L1226.
• [36]Hu HM, Kanda K, Zhang L, Boxer LM: Activation of the c-myc p1 promoter in Burkitt’s lymphoma by the hs3 immunoglobulin heavy-chain gene enhancer. Leukemia 2007, 21:747-753.
• [37]de Nigris F, Crudele V, Giovane A, Casamassimi A, Giordano A, Garban HJ, Cacciatore F, Pentimalli F, Marquez-Garban DC, Petrillo A, Cito L, Sommese L, Fiore A, Petrillo M, Siani A, Barbieri A, Arra C, Rengo F, Hayashi T, Al-Omran M, Ignarro LJ, Napoli C: CXCR4/YY1 inhibition impairs VEGF network and angiogenesis during malignancy. Proc Natl Acad Sci U S A 2010, 107:14484-14489.
• [38]Wu S, Kasim V, Kano MR, Tanaka S, Ohba S, Miura Y, Miyata K, Liu X, Matsuhashi A, Chung UI, Yang L, Kataoka K, Nishiyama N, Miyagishi M: Transcription factor YY1 contributes to tumor growth by stabilizing hypoxia factor HIF-1alpha in a p53-independent manner. Cancer Res 2013, 73:1787-1799.
• [39]Zhang N, Li X, Wu CW, Dong Y, Cai M, Mok MT, Wang H, Chen J, Ng SS, Chen M, Sung JJ, Yu J: microRNA-7 is a novel inhibitor of YY1 contributing to colorectal tumorigenesis. Oncogene 2012, 32:5078-5088.
• [40]Monzon FA, Lyons-Weiler M, Buturovic LJ, Rigl CT, Henner WD, Sciulli C, Dumur CI, Medeiros F, Anderson GG: Multicenter validation of a 1,550-gene expression profile for identification of tumor tissue of origin. J Clin Oncol 2009, 27:2503-2508.