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

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International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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.

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Acknowledgments

This work was supported by grants from the Chang Gung Memorial Hospital, Taiwan (CMRPG380891) to H.C. Hsu. We thank the Cell Bank at the Bioresource Collection and Research Center (BCRC) for providing the STR profiling data. We also thank the Pathology Core at the Molecular Medicine Research Center in Chang Gung University for the help in immunohistochemical staining and quantification.

Conflict of interest

No potential conflicts of interest were disclosed.

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Correspondence to Shu-Jen Chen or Hua-Chien Chen.

Additional information

Hung-Chih Hsu and Yi-Shiuan Liu contributed equally to this work.

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Hsu, HC., Liu, YS., Tseng, KC. et al. Overexpression of Lgr5 correlates with resistance to 5-FU-based chemotherapy in colorectal cancer. Int J Colorectal Dis 28, 1535–1546 (2013). https://doi.org/10.1007/s00384-013-1721-x

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