Low BRMS1 expression promotes nasopharyngeal carcinoma metastasis in vitro and in vivo and is associated with poor patient survival

BMC Cancer

Jun Ma³  Hui-Yun Wang¹  Ying Guo⁴  Jing Zeng⁵  Jing-Ping Yun⁵  Lei Chen²  Ning Jiang¹  Mo Chen²  Ling-Long Tang²  Ying Sun²  Bi-Jun Huang¹  Wen-Fei Li²  Qing-Mei He¹  Na Liu¹  Rui-Xue Cui¹ 

[1]Present address: State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, Peoples Republic of China

[2]Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China

[3]Department of Radiation Oncology State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Peoples Republic of China

[4]Department of National Clinical Study Center for Anticancer Drugs, Sun Yat-sen University Cancer Center, Guangzhou, Peoples Republic of China

[5]Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, Peoples Republic of China

关键词: Prognosis;    Metastasis;    Nasopharyngeal carcinoma;    BRMS1;   

Others  :  1080232
DOI  :  10.1186/1471-2407-12-376

 received in 2012-04-09, accepted in 2012-08-14,  发布年份 2012

【 摘 要 】

Background

Breast cancer metastasis suppressor 1 (BRMS1) is a metastasis suppressor gene. This study aimed to investigate the impact of BRMS1 on metastasis in nasopharyngeal carcinoma (NPC) and to evaluate the prognostic significance of BRMS1 in NPC patients.

Methods

BRMS1 expression was examined in NPC cell lines using quantitative reverse transcription-polymerase chain reaction and Western blotting. NPC cells stably expressing BRMS1 were used to perform wound healing and invasion assays in vitro and a murine xenograft assay in vivo. Immunohistochemical staining was performed in 274 paraffin-embedded NPC specimens divided into a training set (n = 120) and a testing set (n = 154).

Results

BRMS1 expression was down-regulated in NPC cell lines. Overexpression of BRMS1 significantly reversed the metastatic phenotype of NPC cells in vitro and in vivo. Importantly, low BRMS1 expression was associated with poor distant metastasis-free survival (DMFS, P < 0.001) and poor overall survival (OS, P < 0.001) in the training set; these results were validated in the testing set and overall patient population. Cox regression analysis demonstrated that low BRMS1 expression was an independent prognostic factor for DMFS and OS in NPC.

Conclusions

Low expression of the metastasis suppressor BRMS1 may be an independent prognostic factor for poor prognosis in NPC patients.

【 授权许可】

   
2012 Cui et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Aea J: Global cancer statistics. CA Cancer J Clin 2011, 61(2):69-90.
• [2]Yu MC, Yuan JM: Epidemiology of nasopharyngeal carcinoma. Semin Cancer Biol 2002, 12(6):421-429.
• [3]Kwong DL, Sham JS, Au GK, Chua DT, Kwong PW, Cheng AC, Wu PM, Law MW, Kwok CC, Yau CC, et al.: Concurrent and adjuvant chemotherapy for nasopharyngeal carcinoma: a factorial study. J Clin Oncol 2004, 22(13):2643-2653.
• [4]Wee J, Tan EH, Tai BC, Wong HB, Leong SS, Tan T, Chua ET, Yang E, Lee KM, Fong KW, et al.: Randomized trial of radiotherapy versus concurrent chemoradiotherapy followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/International Union against cancer stage III and IV nasopharyngeal cancer of the endemic variety. J Clin Oncol 2005, 23(27):6730-6738.
• [5]Lee N, Xia P, Quivey JM, Sultanem K, Poon I, Akazawa C, Akazawa P, Weinberg V, Fu KK: Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: an update of the UCSF experience. Int J Radiat Oncol Biol Phys 2002, 53(1):12-22.
• [6]Lai SZ, Li WF, Chen L, Luo W, Chen YY, Liu LZ, Sun Y, Lin AH, Liu MZ, Ma J: How does intensity-modulated radiotherapy versus conventional two-dimensional radiotherapy influence the treatment results in nasopharyngeal carcinoma patients? Int J Radiat Oncol Biol Phys 2011, 80(3):661-668.
• [7]Germanov E, Berman JN, Guernsey DL: Current and future approaches for the therapeutic targeting of metastasis (review). Int J Mol Med 2006, 18(6):1025-1036.
• [8]Seraj MJ, Samant RS, Verderame MF, Welch DR: Functional evidence for a novel human breast carcinoma metastasis suppressor, BRMS1, encoded at chromosome 11q13. Cancer Res 2000, 60(11):2764-2769.
• [9]Shevde LA, Samant RS, Goldberg SF, Sikaneta T, Alessandrini A, Donahue HJ, Mauger DT, Welch DR: Suppression of human melanoma metastasis by the metastasis suppressor gene, BRMS1. Exp Cell Res 2002, 273(2):229-239.
• [10]Li J, Cheng Y, Tai D, Martinka M, Welch DR, Li G: Prognostic significance of BRMS1 expression in human melanoma and its role in tumor angiogenesis. Oncogene 2011, 30(8):896-906.
• [11]Zhang S, Lin QD, Di W: Suppression of human ovarian carcinoma metastasis by the metastasis-suppressor gene, BRMS1. Int J Gynecol Cancer 2006, 16(2):522-531.
• [12]Seraj MJ, Harding MA, Gildea JJ, Welch DR, Theodorescu D: The relationship of BRMS1 and RhoGDI2 gene expression to metastatic potential in lineage related human bladder cancer cell lines. Clin Exp Metastasis 2000, 18(6):519-525.
• [13]Smith PW, Liu Y, Siefert SA, Moskaluk CA, Petroni GR, Jones DR: Breast cancer metastasis suppressor 1 (BRMS1) suppresses metastasis and correlates with improved patient survival in non-small cell lung cancer. Cancer Lett 2009, 276(2):196-203.
• [14]Liao WT, Song LB, Zhang HZ, Zhang X, Zhang L, Liu WL, Feng Y, Guo BH, Mai HQ, Cao SM, et al.: Centromere protein H is a novel prognostic marker for nasopharyngeal carcinoma progression and overall patient survival. Clin Cancer Res 2007, 13(2 Pt 1):508-514.
• [15]Edge SB, Compton CC: The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010, 17(6):1471-1474.
• [16]Soumaoro LT, Uetake H, Higuchi T, Takagi Y, Enomoto M, Sugihara K: Cyclooxygenase-2 expression: a significant prognostic indicator for patients with colorectal cancer. Clin Cancer Res 2004, 10(24):8465-8471.
• [17]Zlobec I, Steele R, Terracciano L, Jass JR, Lugli A: Selecting immunohistochemical cut-off scores for novel biomarkers of progression and survival in colorectal cancer. J Clin Pathol 2007, 60(10):1112-1116.
• [18]Stark AM, Tongers K, Maass N, Mehdorn HM, Held-Feindt J: Reduced metastasis-suppressor gene mRNA-expression in breast cancer brain metastases. J Cancer Res Clin Oncol 2005, 131(3):191-198.
• [19]Hicks DG, Yoder BJ, Short S, Tarr S, Prescott N, Crowe JP, Dawson AE, Budd GT, Sizemore S, Cicek M, et al.: Loss of breast cancer metastasis suppressor 1 protein expression predicts reduced disease-free survival in subsets of breast cancer patients. Clin Cancer Res 2006, 12(22):6702-6708.
• [20]Metge BJ, Liu S, Riker AI, Fodstad O, Samant RS, Shevde LA: Elevated osteopontin levels in metastatic melanoma correlate with epigenetic silencing of breast cancer metastasis suppressor 1. Oncology 2010, 78(1):75-86.
• [21]Nagji AS, Liu Y, Stelow EB, Stukenborg GJ, Jones DR: BRMS1 transcriptional repression correlates with CpG island methylation and advanced pathological stage in non-small cell lung cancer. J Pathol 2010, 221(2):229-237.
• [22]Liu Y, Mayo MW, Nagji AS, Smith PW, Ramsey CS, Li D, Jones DR: Phosphorylation of RelA/p65 promotes DNMT-1 recruitment to chromatin and represses transcription of the tumor metastasis suppressor gene BRMS1. Oncogene 2012, 31(9):1145-1154.
• [23]Kelly LM, Buggy Y, Hill A, O'Donovan N, Duggan C, McDermott EW, O'Higgins NJ, Young L, Duffy MJ: Expression of the breast cancer metastasis suppressor gene, BRMS1, in human breast carcinoma: lack of correlation with metastasis to axillary lymph nodes. Tumour Biol 2005, 26(4):213-216.
• [24]Li J, Li G: Cell cycle regulator ING4 is a suppressor of melanoma angiogenesis that is regulated by the metastasis suppressor BRMS1. Cancer Res 2010, 70(24):10445-10453.
• [25]Zhang Z, Yamashita H, Toyama T, Yamamoto Y, Kawasoe T, Iwase H: Reduced expression of the breast cancer metastasis suppressor 1 mRNA is correlated with poor progress in breast cancer. Clin Cancer Res 2006, 12(21):6410-6414.
• [26]Lombardi G, Di Cristofano C, Capodanno A, Iorio MC, Aretini P, Isola P, Tancredi M, Collecchi P, Naccarato AG, Porta RP, et al.: High level of messenger RNA for BRMS1 in primary breast carcinomas is associated with poor prognosis. Int J Cancer 2007, 120(6):1169-1178.
• [27]Metge BJ, Frost AR, King JA, Dyess DL, Welch DR, Samant RS, Shevde LA: Epigenetic silencing contributes to the loss of BRMS1 expression in breast cancer. Clin Exp Metastasis 2008, 25(7):753-763.
• [28]Meehan WJ, Samant RS, Hopper JE, Carrozza MJ, Shevde LA, Workman JL, Eckert KA, Verderame MF, Welch DR: Breast cancer metastasis suppressor 1 (BRMS1) forms complexes with retinoblastoma-binding protein 1 (RBP1) and the mSin3 histone deacetylase complex and represses transcription. J Biol Chem 2004, 279(2):1562-1569.
• [29]Cicek M, Fukuyama R, Welch DR, Sizemore N, Casey G: Breast cancer metastasis suppressor 1 inhibits gene expression by targeting nuclear factor-kappaB activity. Cancer Res 2005, 65(9):3586-3595.
• [30]Cicek M, Fukuyama R, Cicek MS, Sizemore S, Welch DR, Sizemore N, Casey G: BRMS1 contributes to the negative regulation of uPA gene expression through recruitment of HDAC1 to the NF-kappaB binding site of the uPA promoter. Clin Exp Metastasis 2009, 26(3):229-237.
• [31]Vaidya KS, Harihar S, Phadke PA, Stafford LJ, Hurst DR, Hicks DG, Casey G, DeWald DB, Welch DR: Breast cancer metastasis suppressor-1 differentially modulates growth factor signaling. J Biol Chem 2008, 283(42):28354-28360.
• [32]Samant RS, Clark DW, Fillmore RA, Cicek M, Metge BJ, Chandramouli KH, Chambers AF, Casey G, Welch DR, Shevde LA: Breast cancer metastasis suppressor 1 (BRMS1) inhibits osteopontin transcription by abrogating NF-kappaB activation. Mol Cancer 2007, 6:6. BioMed Central Full Text