| Summary: | 碩士 === 長庚大學 === 生物醫學研究所 === 101 === Colorectal cancer 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 for intestinal stem cells and its expression level was commonly elevated in human colorectal cancers (CRCs). Our previous study demonstrated that the expression of LGR5 was significantly increased in the hyperplastic section and adenoma located adjacent to normal colon mucous. Expression of LGR5 continued to increase from adenoma to carcinoma of CRC and its levels were positively associated with tumor stages. These data suggest that LGR5 may be involved in CRC initiation and progression. However, the role of LGR5 in CRC pathogenesis has not been well established. In this study, we aim to characterize the role of LGR5 in CRC pathogenesis using the lose-of-function approach. Depletion of LGR5 suppressed the proliferation and reduced the colony forming ability of several cultured CRC cells. In addition, depletion of LGR5 in CRC cells caused an increase in the fraction of apoptotic cells as analyzed by Annexin V/PI staining and DNA fragmentation assay. Furthermore, depleting LGR5 induced a loss of mitochondrial membrane potential. Additionally, depletion of LGR5 suppressed β-catenin nuclear translocation and blocked the activity of Wnt/β-catenin signaling, resulted in reduced expression of c-myc and cyclin D, two Wnt/β-catenin targets in CRC cells. Treatment of Wnt3a significantly rescued the growth inhibition and apoptotic cell death induced by LGR5 depletion in CRC cells. Taken together, these data suggested that LGR5 may be involved in CRC tumorigenesis by targeting Wnt signaling and regulates cell proliferation and survival. Our findings suggest that LGR5 plays an important role in CRC pathogenesis and has the potential to serve as a diagnostic marker as well as a therapeutic target for CRC patients.
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