P65-Driven MIR4435-2HG Enhances Prognostic Value and Mediates Oxaliplatin Resistance via the miR-378G/ABCB9 Axis in Colorectal Cancer

  • Macromol Biosci. 2025 Jun 10:e00663. doi: 10.1002/mabi.202400663.
Xiaopeng Zhuang  1  2 ,  Jinji Jin  1 ,  Jun Cheng  1 ,  Zhejing Chen  1 ,  Weijian Zhu  3 ,  Xielin Huang  1 ,  Jiancheng Sun  1 ,  Chengyin Lin  1 ,  Qiantong Dong  1 ,  Dongwang Yan  2 ,  Xiaoliang Qi  4 ,  Wenyi Wu  1
Affiliations
  • 1. Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 2. Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3. Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 4. National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
PMID: 40493018 DOI: 10.1002/mabi.202400663
Abstract

Long non-coding RNA MIR4435-2HG has emerged as a pivotal oncogenic factor across various cancers. However, its role in chemoresistance, particularly in colorectal Cancer (CRC), remains unclear. This work demonstrates that MIR4435-2HG is significantly overexpressed in CRC tissues, correlating with poor prognosis and resistance to oxaliplatin (L-OHP) based chemotherapy. Mechanistically, MIR4435-2HG binds to miR-378g, leading to elevated ABCB9 levels, a crucial factor in drug resistance. Both in vitro and in vivo experiments indicate that the MIR4435-2HG/miR-378g/ABCB9 axis confers L-OHP resistance in CRC cells by reducing DNA damage and enhancing cell survival. Additionally, P65, a component of the NF-κB pathway, directly promotes MIR4435-2HG transcription, triggering subsequent chemoresistance. Based on these results, MIR4435-2HG is recognized as a reliable prognostic marker and serves as a target for therapeutic strategies, presenting new approaches to counteract L-OHP resistance and enhance CRC patient outcomes.

Keywords
ABCB9; L‐OHP; MIR4435‐2HG; colorectal cancer; miR‐378g; resistance.
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