RBMX promotes colorectal liver metastasis by stabilizing MTHFD2 mRNA to regulate redox homeostasis

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metastasis Research

Background:

• Colorectal cancer (CRC) liver metastasis (CRLM) is a major cause of cancer mortality.
• The molecular drivers of CRLM progression are not fully understood.
• Investigating novel molecular mechanisms in CRLM is crucial for therapeutic development.

Purpose of the Study:

• To elucidate the role of RNA-binding motif protein X (RBMX) in colorectal liver metastasis.
• To identify the molecular mechanisms by which RBMX influences CRLM progression.
• To explore the potential of the RBMX pathway as a therapeutic target for CRLM.

Main Methods:

• Analysis of RBMX expression in public and in-house datasets.
• In vitro and in vivo models to assess metastatic potential.
• RNA sequencing, RIP, and pull-down assays to identify RBMX targets.
• Metabolic profiling, ROS quantification, and signaling pathway analysis.

Main Results:

• RBMX is upregulated in CRLM and associated with poor prognosis.
• RBMX promotes CRC cell migration, invasion, and liver metastasis.
• RBMX directly stabilizes MTHFD2 mRNA, increasing MTHFD2 protein levels.
• This leads to enhanced one-carbon metabolism, increased NADPH production, and ROS buffering.
• RBMX suppresses ROS-dependent p38/JNK signaling, promoting metastatic cell survival.

Conclusions:

• RBMX drives CRLM by stabilizing MTHFD2 mRNA, thereby maintaining redox homeostasis.
• The RBMX-MTHFD2-Redox axis links RNA stability with metabolic plasticity in CRLM.
• This pathway represents a novel vulnerability and potential therapeutic target for CRLM.