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Epigenetic induction of lipocalin 2 expression drives acquired resistance to 5-fluorouracil in colorectal cancer through integrin β3/SRC pathway

Oncogene volume 40, pages 6369–6380 (2021)Cite this article

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Abstract

The therapeutic efficacy of 5-fluorouracil (5-FU) is often reduced by the development of drug resistance. We observed significant upregulation of lipocalin 2 (LCN2) expression in a newly established 5-FU-resistant colorectal cancer (CRC) cell line. In this study, we demonstrated that 5-FU-treated CRC cells developed resistance through LCN2 upregulation caused by LCN2 promoter demethylation and that feedback between LCN2 and NF-κB further amplified LCN2 expression. High LCN2 expression was associated with poor prognosis in CRC patients. LCN2 attenuated the cytotoxicity of 5-FU by activating the SRC/AKT/ERK-mediated antiapoptotic program. Mechanistically, the LCN2-integrin β3 interaction enhanced integrin β3 stability, thus recruiting SRC to the cytomembrane for autoactivation, leading to downstream AKT/ERK cascade activation. Targeting LCN2 or SRC compromised the growth of CRC cells with LCN2-induced 5-FU resistance. Our findings demonstrate a novel mechanism of acquired resistance to 5-FU, suggesting that LCN2 can be used as a biomarker and/or therapeutic target for advanced CRC.

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Fig. 1: LCN2 is upregulated in 5-FU-resistant CRC cells.
Fig. 2: LCN2 expression is associated with liver metastasis, recurrence, and prognosis in patients with CRC.
Fig. 3: LCN2 confers 5-FU resistance on CRC cells.
Fig. 4: LCN2 drives 5-FU resistance in CRC cells through SRC-mediated AKT/ERK cascades.
Fig. 5: The LCN2-integrin β3 interaction recruits SRC to the cytomembrane for phosphorylation.
Fig. 6: LCN2 expression is elevated through promoter CpG demethylation and LCN2/NF-κB feedback.
Fig. 7: Proposed molecular mechanism.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (Grant Nos. 81972765 and 81772966) and Zhejiang Provincial Natural Science Foundation (No. LZ21H160007). The Superbiotek Inc. (Shanghai, China) provided CRC tissue microarray analysis. The authors also thank the Laboratory Animal Research Center in Wenzhou Medical University for technical assistance.

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Authors and Affiliations

  1. School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, China

    Wenyi Zhang, Rulu Pan, Mei Lu, Qian Zhang, Ziqi Lin, Yuan Qin, Zhanyu Wang, Siqing Gong, Huan Lin, Shuyi Chong, Liting Lu & Xincheng Lu

  2. Department of Radiotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

    Wenyi Zhang

  3. Department of Basic Medicine and Biomedical Engineering, Foshan University, Foshan, 528200, China

    Wanqin Liao

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WZ designed, performed experiments, analyzed the data, and was a major contributor in writing the manuscript. RP and ML analyzed and interpreted the patient data. QZ, ZW, SG and HL partially contributed to the experiments presented in this manuscript. ZL and YQ contributed to the animal care and experiments. SC and LL provided technical assistance. WL provided assistance in manuscript writing. XL conceived the study, designed the experiments, and wrote and finalized the manuscript. All authors read and approved the final manuscript.

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Correspondence to Xincheng Lu.

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Zhang, W., Pan, R., Lu, M. et al. Epigenetic induction of lipocalin 2 expression drives acquired resistance to 5-fluorouracil in colorectal cancer through integrin β3/SRC pathway. Oncogene 40, 6369–6380 (2021). https://doi.org/10.1038/s41388-021-02029-4

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