title: Overexpression of the circadian clock gene Bmal1 increases sensitivity to oxaliplatin in colorectal cancer.
abstract: OBJECTIVE
  The circadian clock gene Bmal1 is involved in cancer cell proliferation and DNA damage sensitivity. The aim of this study was to explore the effect of Bmal1 on oxaliplatin sensitivity and to determine its clinical significance in colorectal cancer.
  
  
  METHODS
  Three colorectal cancer cell lines, HCT116, THC8307 and HT29, were used. The Bmal1-mediated control of colorectal cancer cell proliferation was tested in vitro and in vivo. MTT and colony formation assays were performed to determine the sensitivity of colorectal cancer cells to oxaliplatin. Flow cytometry was used to examine changes in the cell-cycle distribution and apoptosis rate. Proteins expressed downstream of Bmal1 upon its overexpression were determined by Western blotting. Immunohistochemistry was used to analyze Bmal1 expression in 82 archived colorectal cancer tumors from patients treated with oxaliplatin-based regimens.
  
  
  RESULTS
  Bmal1 overexpression inhibited colorectal cancer cell proliferation and increased colorectal cancer sensitivity to oxaliplatin in three colorectal cancer cell lines and HCT116 cells model in vivo. Furthermore, the overall survival of patients with colorectal cancer with high Bmal1 levels in their primary tumors was significantly longer than that of patients with low Bmal1 levels (27 vs. 19 months; P = 0.043). The progression-free survival of patients with high Bmal1 expression was also significantly longer than that of patients with low Bmal1 expression (11 vs. 5 months; P = 0.015). Mechanistically, the effect of Bmal1 was associated with its ability to regulate G2-M arrest by activating the ATM pathway.
  
  
  CONCLUSIONS
  Bmal1 shows the potential as a novel prognostic biomarker and may represent a new therapeutic target in colorectal cancer.
authors.affiliation: Authors' Affiliations: State Key Laboratory of Oncology in Southern China and Departments of Experimental Research and Medical Oncology, Cancer Center, Sun Yat-Sen University, Guangzhou, Guangdong, China; and School of Engineering, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Zhao-lei
authors.initials: ZL
authors.lastname: Zeng
authors.forename: Hui-yan
authors.initials: HY
authors.lastname: Luo
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Wen-jing
authors.initials: WJ
authors.lastname: Wu
authors.forename: Dong-liang
authors.initials: DL
authors.lastname: Chen
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
authors.forename: Rui-hua
authors.initials: RH
authors.lastname: Xu
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D057906:Circadian Clocks; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D059565:G2 Phase Cell Cycle Checkpoints; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D023041:Xenograft Model Antitumor Assays
chemical_list: D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin