| Summary: | 博士 === 長庚大學 === 臨床醫學研究所 === 103 === Colorectal cancer (CRC) is the most prevalent form of cancer among Taiwanese and one of leading cause of cancer deaths with a worldwide cumulative incidence rate of 9.4%. The leucine-rich repeat-containing G protein coupled receptor 5 (LGR5) is not only an adult intestinal stem cell but also a CRC stem cell marker. CRC stem cell often account for therapy resistance. However, the value of LGR5 level in CRC prognosis and pathogenesis has not been well characterized. In addition, lysine-specific demethylase1 (LSD1) was highly expressed in several malignancies and had been implicated in pathological processes of cancer cells. LSD1 inhibitor was reported to selectively inhibit the growth of several cancer stem cells. Thus in this study, we proposed to evaluate the role of LGR5 in pathogenesis and prognosis of CRC. We also used an LSD1 inhibitor, CBB1003, as a probe, to assess the association between LSD1 and LGR5 in CRC carcinogenesis. Our study found that elevated LGR5 level was associated with poor survival and chemoresistance in CRC patients. We also demonstrated that LGR5 was a functional CRC stem cell marker and regulated CRC cell survival via modulating Wnt/β-catenin signaling and intrinsic mitochondrial apoptotic pathway. Furthermore, we found that LSD1 overexpression promotes CRC development and that the LSD1 inhibitor inhibits CRC cell growth by downregulating LGR5 levels and inactivates the Wnt/β-catenin pathway. These results suggested that LGR5 could be a marker to predict clinical outcome and therapy response in CRC patients. Due to a functional CRC stem cell marker, LGR5 may also serve as a potential therapeutic target for CRC therapy. In addition, LSD1 and its inhibitor might provide a new target or a useful strategy for therapy of CRC.
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