title: LGR5 regulates survival through mitochondria-mediated apoptosis and by targeting the Wnt/β-catenin signaling pathway in colorectal cancer cells.
abstract: Colorectal cancer (CRC) is one of the most common causes of cancer-related death worldwide. The leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is a newly identified surface marker of colorectal cancer stem cells (CSCs). Expression level of LGR5 is commonly elevated in human CRCs. Our previous study demonstrated that the elevated expression of LGR5 is associated with CRC initiation and progression. However, the role of LGR5 in CRC pathogenesis has not been sufficiently established. In this study, we aimed to characterize the role of LGR5 in CRC pathogenesis using the loss-of-function approach. Depletion of LGR5 suppressed the growth of several cultured CRC cells and caused an increase in the fraction of apoptotic cells, which were analyzed using Annexin V/PI staining and DNA fragmentation assay. Furthermore, depleting LGR5 induced apoptosis through the loss of mitochondrial membrane potential. Additionally, depletion of LGR5 suppressed β-catenin nuclear translocation and blocked the activity of Wnt/β-catenin signaling as manifested in the reduced expression of c-myc and cyclin D, two Wnt/β-catenin targets in CRC cells. Treatment with Wnt3a considerably alleviated the growth inhibition and apoptotic cell death induced by LGR5 depletion in CRC cells. These data suggested that LGR5 regulates cell proliferation and survival by targeting the Wnt/β-catenin signaling pathway. Thus, the findings of this study suggest that LGR5 plays a vital role in CRC pathogenesis and has the potential to serve as a diagnostic marker and a therapeutic target for CRC patients.
authors.affiliation: Division of Hematology-Oncology, Chang Gung Memorial Hospital at Linkou, 5 Fu-Hsing Street, Kwei-Shan, Tao-Yuan 333, Taiwan, ROC; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan 333, Taiwan, ROC.
authors.forename: Hung-Chih
authors.initials: HC
authors.lastname: Hsu
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.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: Kai-Chi
authors.initials: KC
authors.lastname: Tseng
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; Molecular Medicine Research Center, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan 333, Taiwan, ROC; Department of Biomedical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan 333, Taiwan, ROC. Electronic address: btan@mail.cgu.edu.tw.
authors.forename: Bertrand Chin-Ming
authors.initials: BC
authors.lastname: Tan
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; Molecular Medicine Research Center, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan 333, Taiwan, ROC; Department of Biomedical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan 333, Taiwan, ROC. Electronic address: sjchen3730@gmail.com.
authors.forename: Shu-Jen
authors.initials: SJ
authors.lastname: Chen
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; Molecular Medicine Research Center, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan 333, Taiwan, ROC; Department of Biomedical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan 333, Taiwan, ROC. Electronic address: hcchen3729@gmail.com.
authors.forename: Hua-Chien
authors.initials: HC
authors.lastname: Chen
mesh_terms: D017304:Annexin A5 / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053938:DNA Fragmentation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D017304:Annexin A5; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C116884:LGR5 protein, human; D009363:Neoplasm Proteins; D043562:Receptors, G-Protein-Coupled; D051176:beta Catenin
keywords: Apoptosis; Colorectal cancer; LGR5; Wnt/β-catenin signaling