title: Bmi-1 is a novel molecular marker of nasopharyngeal carcinoma progression and immortalizes primary human nasopharyngeal epithelial cells.
abstract: The Bmi-1 oncoprotein regulates proliferation and oncogenesis in human cells. Its overexpression leads to senescence bypass in human fibroblasts and immortalization of human mammary epithelial cells. In this study, we report that compared with normal nasopharyngeal epithelial cells (NPEC), Bmi-1 is overexpressed in nasopharyngeal carcinoma cell lines. Importantly, Bmi-1 was also found to be overexpressed in 29 of 75 nasopharyngeal carcinoma tumors (38.7%) by immunohistochemical analysis. In contrast to nasopharyngeal carcinoma, there was no detectable expression of Bmi-1 in noncancerous nasopharyngeal epithelium. Moreover, high Bmi-1 expression positively correlated with poor prognosis of nasopharyngeal carcinoma patients. We also report that the overexpression of Bmi-1 leads to bypass of senescence and immortalization of NPECs, which normally express p16(INK4a) and exhibit finite replicative life span. Overexpression of Bmi-1 in NPECs led to the induction of human telomerase reverse transcriptase activity and reduction of p16(INK4a) expression. Mutational analysis of Bmi-1 showed that both RING finger and helix-turn-helix domains of it are required for immortalization of NPECs. Our findings suggest that Bmi-1 plays an important role in the development and progression of nasopharyngeal carcinoma, and that Bmi-1 is a valuable marker for assessing the prognosis of nasopharyngeal carcinoma patients. Furthermore, this study provides the first cellular proto-oncogene immortalized nasopharyngeal epithelial cell line, which may serve as a cell model system for studying the mechanisms involved in the tumorigenesis of nasopharyngeal carcinoma.
authors.affiliation: State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Li-Bing
authors.initials: LB
authors.lastname: Song
authors.forename: Mu-Sheng
authors.initials: MS
authors.lastname: Zeng
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Liao
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Hao-Yuan
authors.initials: HY
authors.lastname: Mo
authors.forename: Wan-Li
authors.initials: WL
authors.lastname: Liu
authors.forename: Jian-Yong
authors.initials: JY
authors.lastname: Shao
authors.forename: Qiu-Liang
authors.initials: QL
authors.lastname: Wu
authors.forename: Man-Zhi
authors.initials: MZ
authors.lastname: Li
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Xia
authors.forename: Li-Wu
authors.initials: LW
authors.lastname: Fu
authors.forename: Wen-Lin
authors.initials: WL
authors.lastname: Huang
authors.forename: Goberdhan P
authors.initials: GP
authors.lastname: Dimri
authors.forename: Vimla
authors.initials: V
authors.lastname: Band
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000235:genetics; D004249:DNA Damage; D018450:Disease Progression; D015536:Down-Regulation; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009303:Nasopharyngeal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D063150:Polycomb Repressive Complex 1; D011379:Prognosis; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D019098:Telomerase / Q000378:metabolism
chemical_list: C069077:BMI1 protein, human; D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; C000715470:MAS1 protein, human; D009687:Nuclear Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1; D019098:Telomerase