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

  • Cancer Gene Ther. 2023 Feb 13. doi: 10.1038/s41417-023-00595-1.
Chuan-Jian Shi  1  2 ,  Zhi-He Xue  2 ,  Wei-Qiang Zeng  2 ,  Li-Qiang Deng  2 ,  Feng-Xiang Pang  3 ,  Feng-Wei Zhang  3 ,  Wei-Ming Fu  4 ,  Jin-Fang Zhang  5
Affiliations
  • 1. Cancer center, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, 518000, Guangdong, PR China.
  • 2. Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, PR China.
  • 3. Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China.
  • 4. Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, PR China. [email protected].
  • 5. Cancer center, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, 518000, Guangdong, PR China. [email protected].
PMID: 36782047 DOI: 10.1038/s41417-023-00595-1
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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