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

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.