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LncRNA-NEF suppressed oxaliplatin resistance and epithelial-mesenchymal transition in colorectal cancer through epigenetically inactivating MEK/ERK signaling

Cancer Gene Therapy volume 30, pages 855–865 (2023)Cite this article

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Abstract

A major cause of oxaliplatin chemoresistance in colorectal cancer (CRC) is acquired epithelial-mesenchymal transition (EMT) in cancer cells, making the cancer cells easy to metastasis and recurrence. LncRNA Neighboring Enhancer of FOXA2 (lncRNA-NEF) has been characterized as a tumor suppressor to mediate cancer metastasis in multiple cancer types. However, whether it mediated the drug resistance remains unknown. In the present study, an oxaliplatin-resistant CRC cell line (SW620R) was established and lncRNA-NEF was obviously down-regulated in this resistant cell line. The further loss and gain-of-function studies demonstrated that this lncRNA suppressed oxaliplatin resistance as well as EMT programme in vitro and inhibited metastasis in vivo. Mechanistically, lncRNA-NEF epigenetically promoted the expression of DOK1 (Downstream of Tyrosine kinase 1), a negative regulator of MEK/ERK signaling, by disrupting DNA methyltransferases (DNMTs)-mediated DNA methylation. DOK1, in turn, induced the inactivation of MEK/ERK signaling, forming the lncRNA-NEF/DOK1/MEK/ERK regulatory axis to mediate oxaliplatin resistance in CRC. Collectively, our work reveals the critical function of lncRNA-NEF in mediating the oxaliplatin chemotherapy resistance in CRC, and provides a promising therapeutic strategy for CRC patients with oxaliplatin resistance.

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Fig. 1: Acquisition of oxaliplatin resistance induced EMT in CRC cells.
Fig. 2: LncRNA-NEF inhibited the oxaliplatin resistance and EMT in CRC cells.
Fig. 3: LncRNA-NEF knockdown promoted EMT transition as well as metastasis in CRC cells.
Fig. 4: LncRNA-NEF inhibited the metastasis of oxaliplatin-resistant CRC cells in vivo.
Fig. 5: LncRNA-NEF suppressed the activation of MEK/ERK signaling pathway through enhancing DOK1 expression.
Fig. 6: LncRNA-NEF suppressed the methylation of the DOK1 promoter in oxaliplatin-resistant SW620R cells.
Fig. 7: Overexpression of DOK1 rescued the promoted effects of sh-lncRNA-NEF on oxaliplatin resistance and metastasis in vitro and in vivo.
Fig. 8: The schematic overview of lncRNA-NEF inhibited the oxaliplatin resistance in CRC cells.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81773066, 81772404) and Natural Science Foundation of Guangdong Province (2020A1515010961; 2021A1515012111).

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Authors and Affiliations

  1. Cancer center, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, 518000, Guangdong, PR China

    Chuan-Jian Shi & Jin-Fang Zhang

  2. Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, PR China

    Chuan-Jian Shi, Zhi-He Xue, Wei-Qiang Zeng, Li-Qiang Deng & Wei-Ming Fu

  3. Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China

    Feng-Xiang Pang & Feng-Wei Zhang

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Contributions

JFZ and WMF conceptualized and designed all the experiments. CJS, ZHX, WQZ, LQD, FXP, and FWZ performed the experiments and analyzed the data. CJS, JFZ, and WMF prepared the manuscript.

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Correspondence to Wei-Ming Fu or Jin-Fang Zhang.

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Shi, CJ., Xue, ZH., Zeng, WQ. et al. LncRNA-NEF suppressed oxaliplatin resistance and epithelial-mesenchymal transition in colorectal cancer through epigenetically inactivating MEK/ERK signaling. Cancer Gene Ther 30, 855–865 (2023). https://doi.org/10.1038/s41417-023-00595-1

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