Role of MEX3A in tumorigenesis: Mechanisms, tumor‑specific effects and therapeutic implications (Review)

Abstract

Muscle excess 3A (MEX3A), a dual‑function RNA‑binding protein with E3 ubiquitin ligase activity, is a pivotal regulator of tumorigenesis. By modulating mRNA stability, translation and targeted protein degradation, MEX3A orchestrates key oncogenic processes, including tumor stemness maintenance, proliferation, migration and immune evasion. MEX3A is aberrantly expressed in various malignancies, such as colorectal and breast cancer, hepatocellular carcinoma and glioblastoma, where it engages key signaling pathways, including the Wnt/β‑catenin, PI3K/AKT and NF‑κB pathways. Mechanistically, MEX3A directly regulates oncogenic and tumor suppressor transcripts, influencing the cell dynamics within the tumor microenvironment. Furthermore, MEX3A upregulation is associated with a poor prognosis and therapy resistance, highlighting its potential as a prognostic biomarker and therapeutic target. The present review aimed to summarize the molecular functions, tumor‑specific roles and translational relevance of MEX3A, bridging the gap between mechanistic insight and clinical applications. Future studies exploring MEX3A‑targeted interventions may reveal novel strategies for precision oncology.

Keywords: E3 ubiquitin ligase; RNA‑binding protein; muscle excess 3A; oncogenic signaling pathway; post‑transcriptional regulation; precision oncology; tumorigenesis.

Figure 1

Structure and function of MEX3A. (A) Domain structure of the human MEX3A protein and its RNA-binding domain. The KH domain enables MEX3A to bind to target mRNAs and regulate their stability, translation or localization. Data were obtained from the UniProt database (uniprot. org/uniprotkb/A1L020/entry; accessed on 7 March 2025). (B) Predicted three-dimensional structures from AlphaFold for the MEX3A protein. The protein comprises two conserved K homology domains and a RING domain. Each KH domain adopts a topology consisting of three α-helices and three β-strands arranged in an open palm-like configuration. The C-terminal RING domain forms a compact cross-β structure stabilized by eight conserved cysteine residues that coordinate two zinc ions in a tetrahedral geometry. When binding RNA, the KH domain may form RNA-binding grooves through spatial alignment, similar to the complex structure of MEX3A and RNA, which bind specific sequences of single-stranded RNA. Data obtained from the GeneCards database (genards.org/cgi-bin/carddisp.pl?gene=MEX3A). (C) MEX3A protein inhibits autophagy in colon cancer cells by affecting the post-transcriptional decay of the PDE5A mRNA via the circMPP6 complex. (D) MEX3A can bind to RIG-I and induce its ubiquitination and proteasome-dependent degradation. RIG-I is a key pattern recognition receptor of the innate immune system that activates antitumor immune responses and inhibits tumor cell proliferation. In tissue with high MEX3A expression, RIG-I is inhibited, and tumor growth is rapid, however, in the case of low expression of MEX3A or depletion, RIG-I protein levels increase, thereby inhibiting the proliferation of tumor cells. MEX3A, Mex-3 RNA Binding Family Member A; KH, K-homology domain; RING, Really Interesting New Gene domain; PDE5A, Phosphodiesterase 5A; circMPP6, circular RNA derived from the MPP6 gene; RIG-I, retinoic acid-inducible gene I; P, phosphorylation.

Figure 2

Role of MEX3A in tumor cell signaling pathways. MEX3A regulates multiple oncogenic signaling pathways and promotes tumor cell proliferation, invasion, migration and immune evasion. MEX3A activates the RAP1GAP/MEK/ERK pathway, leading to increased E2F3 expression and upregulation of HIF-1α, a key transcription factor involved in tumor progression. Additionally, MEX3A activates the β-catenin-KLF4 axis, further promoting EMT, invasion and migration. MEX3A modulates WWC1/LATS1/YAP1/NF-κB signaling to promote cytoskeletal rearrangements, thereby increasing cell motility. Furthermore, through the PI3K/AKT pathway, MEX3A regulates the RhoA/ROCK/LIMK pathway, further increasing cell migration and invasion. MEX3A downregulates CDKN2B, leading to the disruption of the RB/E2F complex, which accelerates cell cycle progression and proliferation. MEX3A promotes immune evasion by inducing NMD of tumor suppressor genes, such as P53, thereby inhibiting ferroptosis and promoting cancer cell survival. Additionally, MEX3A facilitates the ubiquitin-mediated degradation of RIG-1, a key pattern recognition receptor, thereby impairing innate immune responses against tumors. MEX3A, Mex-3 RNA Binding Family Member A; RAP1GAP, RAP1 GTPase Activating Protein; KLF, Kruppel-Like Factor; EMT, Epithelial-Mesenchymal Transition; WWC, WW and C2 Domain Containing; LATS, Large Tumor Suppressor Kinase; LIMK, LIM Domain Kinase; CDKN2B, Cyclin-Dependent Kinase Inhibitor 2B; RB/E2F, Retinoblastoma protein/E2F Transcription Factor; NMD, Nonsense-Mediated mRNA Decay; RIG-I, Retinoic acid-inducible gene I; miR, microRNA; ETS, E twenty-six transcription factor family; DVL, Dishevelled; IGFBP, Like Growth Factor Binding Protein; LAMA, Laminin Subunit Alpha; Ub, Ubiquitin; TIMELESS, Timeless Regulator of DNA Damage Response.

Figure 3

MEX3A modulates the tumor immune microenvironment through cellular and molecular regulation. MEX3A is associated with immune cell infiltration in tumors, negatively associated with dendritic cell infiltration levels and positively associated with T cells and neutrophils. High MEX3A expression enhances tumor immune escape. MEX3A expression is associated with PD-1 expression. High MEX3A expression promotes the immunosuppressive microenvironment. Inhibiting proinflammatory cytokines and enhancing immunosuppressive factors to create an immunosuppressive microenvironment may enhance immune escape by regulating the Wnt/β-catenin pathway. MEX3A, Mex-3 RNA Binding Family Member A; DVL, Dishevelled; TCF, T Cell Factor.