title: Unconjugated Bilirubin Is a Novel Prognostic Biomarker for Nasopharyngeal Carcinoma and Inhibits Its Metastasis via Antioxidation Activity.
abstract: Distant metastasis is the most common cause of treatment failure and mortality in nasopharyngeal carcinoma (NPC) patients. Thus, it is important to understand the mechanism of NPC metastasis and identify reliable prognostic factors. In this study, we investigated the prognostic value of unconjugated bilirubin (UCB), which was previously considered a byproduct of heme catabolism, in NPC patients and examined the effects of UCB on NPC metastasis. The receiver operating characteristic analysis-generated UCB cutoff point for DMFS was 9.7 μmol/L. We found that higher UCB levels were significantly associated with favorable distant metastasis-free survival (DMFS, 93.3% vs. 84.2%, P < 0.001) in NPC patients and was an independent predictor for DMFS (HR, 0.416; 95% confidence interval, 0.280-0.618; P < 0.001). We next found that UCB treatment impaired the invasion capability of NPC cells and potently inhibited lung metastasis of NPC cells in nude mice. Further investigation showed that UCB inhibited reactive oxygen species production, which is involved in the repression of ERK1/2 activation and matrix metalloproteinase-2 (MMP-2) expression. Moreover, lower levels of ERK1/2 phosphorylation and MMP-2 expression were observed in the NPC lung metastases of nude mice administered UCB. Taken together, our results indicate that UCB is a significantly favorable factor for DMFS in NPC patients and may play an important role in NPC chemoprevention.
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Cheng-Cheng
authors.initials: CC
authors.lastname: Deng
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Department of Gynecologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Xiao-Lin
authors.initials: XL
authors.lastname: Luo
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Yu-Jia
authors.initials: YJ
authors.lastname: Zhu
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Rou
authors.initials: R
authors.lastname: Jiang
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Meng-Xia
authors.initials: MX
authors.lastname: Zhang
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Jin-Ju
authors.initials: JJ
authors.lastname: Lei
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Lian
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Zou
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Rui
authors.initials: R
authors.lastname: You
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Li-Zhen
authors.initials: LZ
authors.lastname: Chen
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Qi-Sheng
authors.initials: QS
authors.lastname: Feng
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Jin-Xin
authors.initials: JX
authors.lastname: Bei
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, China. zengyix@mail.sysu.edu.cn chmingy@mail.sysu.edu.cn.
authors.forename: Ming-Yuan
authors.initials: MY
authors.lastname: Chen
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China. zengyix@mail.sysu.edu.cn chmingy@mail.sysu.edu.cn.
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis; D001663:Bilirubin / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D002277:Carcinoma; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D001663:Bilirubin