Overexpression of Lgr5 correlates with resistance to 5-FU-based chemotherapy in colorectal cancer

Abstract

The leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) is an adult intestinal stem cell marker frequently detected in human colorectal cancers (CRCs). However, the value of Lgr5 level in CRC prognosis and treatment prediction has not been well characterized. We examined Lgr5 expression in 384 formalin-fixed paraffin-embedded CRC specimens from 296 CRC patients, including 64 patients treated with 5-fluorouracil (5-FU)-based chemotherapy. The effects of Lgr5 on cell proliferation, survival, and drug resistance were examined in cultured CRC cells. Elevated expression of Lgr5 was observed in CRC tissues, and Lgr5 protein levels were significantly correlated with an advanced American Joint Committee on Cancer stage (P < 0.001), T stage (P < 0.001), N stage (P < 0.001), and distant metastasis (P < 0.001). High expression levels of Lgr5 were significantly associated with shorter disease-free survival (P < 0.001) and shorter cancer-specific survival (P = 0.007) in CRC patients. Among the chemotherapy-treated subgroups, patients with low Lgr5 level showed a better response rate (65 %) than patients with high Lgr5 level (37 %) towards 5-FU-based treatment (P = 0.025). In cultured CRC cell lines, knocking down Lgr5 suppressed cell proliferation and colony formation ability, while it enhanced apoptosis and rendered cells more sensitive to chemotherapeutic agents. In contrast, overexpression of Lgr5 increased cell proliferation and enhanced chemoresistance. These results suggest that elevated Lgr5 level is associated with CRC progression and treatment response and has the potential to serve as a therapeutic target in CRC patients.