title: Lgr5 promotes cancer stemness and confers chemoresistance through ABCB1 in colorectal cancer.
abstract: BACKGROUND
  Chemotherapy failure is a major problem in patients with advanced colorectal carcinoma (CRC). Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is a well-established target gene of the Wnt pathway and is a bona fide marker of CRC cancer stem cells (CSCs). Our previous study showed that CRC patients with higher Lgr5 level are associated with poor response to 5-fluoracil-based treatment. In this study, we investigated the mechanisms underlying Lgr5-associated chemoresistance in cancer stem cells derived from cultured CRC cells.
  
  
  METHODS
  Cancer stem cells were isolated from CRC cell lines by spheroid culture. The effect of Lgr5 on CRC cancer stem cell was investigated using both gain- and loss-of-function approaches. Stemness property was evaluated using sphere formation assay, side population analysis, and stem cell marker expression. Lgr5 and ABCB1 expression in CRC tissues was determined using immunohistochemical staining.
  
  
  RESULTS
  Forced expression of Lgr5 increased the CRC sphere-forming efficiency and spheroid size while depletion of Lgr5 reduced the stem cell property in cultured CRC cells. Over-expression of Lgr5 also reduced the sensitivity of cultured CRC cells, including adherent and spheroids, towards 5-fluoracil and oxalipatin. In addition, Lgr5 positively regulates the expression of ABCB1 in both adherent and spheroid CRC cells. Finally, in human CRC tissues, higher expression levels of Lgr5 were associated with higher ABCB1 expression.
  
  
  CONCLUSIONS
  The present study demonstrated that Lgr5 plays an active role in promoting the cancer stem cell property and that Lgr5 confers chemoresistance to CRC cells via ABCB1 induction.
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, 259, Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan 333, Taiwan ROC.
authors.forename: Yi-Shiuan
authors.initials: YS
authors.lastname: Liu
authors.forename: Hung-Chih
authors.initials: HC
authors.lastname: Hsu
authors.forename: Kai-Chi
authors.initials: KC
authors.lastname: Tseng
authors.forename: Hua-Chien
authors.initials: HC
authors.lastname: Chen
authors.forename: Shu-Jen
authors.initials: SJ
authors.lastname: Chen
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000970:Antineoplastic Agents / Q000494:pharmacology; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis*; D018874:Spheroids, Cellular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; C116884:LGR5 protein, human; D009944:Organoplatinum Compounds; D043562:Receptors, G-Protein-Coupled; D000077150:Oxaliplatin; D005472:Fluorouracil
keywords: ABCB1; Chemoresistance; Lgr5