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

  • Authors:
    • Lulu Tang
    • Li Zhang
    • Shun Yao
    • Xin Li
    • Yongfeng Wang
    • Qian Liu
    • Jiajia Li
    • Guorong Wen
    • Jiaxing An
    • Hai Jin
    • Jiaxing Zhu
    • Biguang Tuo
  • View Affiliations / Copyright

    Affiliations: Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
    Copyright: © Tang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 138
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    Published online on: July 7, 2025
       https://doi.org/10.3892/ijmm.2025.5579
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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.
View Figures

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.
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Copy and paste a formatted citation
Spandidos Publications style
Tang L, Zhang L, Yao S, Li X, Wang Y, Liu Q, Li J, Wen G, An J, Jin H, Jin H, et al: Role of MEX3A in tumorigenesis: Mechanisms, tumor‑specific effects and therapeutic implications (Review). Int J Mol Med 56: 138, 2025.
APA
Tang, L., Zhang, L., Yao, S., Li, X., Wang, Y., Liu, Q. ... Tuo, B. (2025). Role of MEX3A in tumorigenesis: Mechanisms, tumor‑specific effects and therapeutic implications (Review). International Journal of Molecular Medicine, 56, 138. https://doi.org/10.3892/ijmm.2025.5579
MLA
Tang, L., Zhang, L., Yao, S., Li, X., Wang, Y., Liu, Q., Li, J., Wen, G., An, J., Jin, H., Zhu, J., Tuo, B."Role of MEX3A in tumorigenesis: Mechanisms, tumor‑specific effects and therapeutic implications (Review)". International Journal of Molecular Medicine 56.3 (2025): 138.
Chicago
Tang, L., Zhang, L., Yao, S., Li, X., Wang, Y., Liu, Q., Li, J., Wen, G., An, J., Jin, H., Zhu, J., Tuo, B."Role of MEX3A in tumorigenesis: Mechanisms, tumor‑specific effects and therapeutic implications (Review)". International Journal of Molecular Medicine 56, no. 3 (2025): 138. https://doi.org/10.3892/ijmm.2025.5579
Copy and paste a formatted citation
x
Spandidos Publications style
Tang L, Zhang L, Yao S, Li X, Wang Y, Liu Q, Li J, Wen G, An J, Jin H, Jin H, et al: Role of MEX3A in tumorigenesis: Mechanisms, tumor‑specific effects and therapeutic implications (Review). Int J Mol Med 56: 138, 2025.
APA
Tang, L., Zhang, L., Yao, S., Li, X., Wang, Y., Liu, Q. ... Tuo, B. (2025). Role of MEX3A in tumorigenesis: Mechanisms, tumor‑specific effects and therapeutic implications (Review). International Journal of Molecular Medicine, 56, 138. https://doi.org/10.3892/ijmm.2025.5579
MLA
Tang, L., Zhang, L., Yao, S., Li, X., Wang, Y., Liu, Q., Li, J., Wen, G., An, J., Jin, H., Zhu, J., Tuo, B."Role of MEX3A in tumorigenesis: Mechanisms, tumor‑specific effects and therapeutic implications (Review)". International Journal of Molecular Medicine 56.3 (2025): 138.
Chicago
Tang, L., Zhang, L., Yao, S., Li, X., Wang, Y., Liu, Q., Li, J., Wen, G., An, J., Jin, H., Zhu, J., Tuo, B."Role of MEX3A in tumorigenesis: Mechanisms, tumor‑specific effects and therapeutic implications (Review)". International Journal of Molecular Medicine 56, no. 3 (2025): 138. https://doi.org/10.3892/ijmm.2025.5579
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