image: (A) Volcano plot showing DEGs of six pairs of tumors (T) and the corresponding metastasized lymph node tissues (LN). ∣log2FC∣ > 1, adjusted p value (padj) < 0.05. (B) Relative mRNA expression of 8 differentially expressed genes was further quantified by qRT-PCR in 10 paired gallbladder cancer tissues and adjacent normal tissues. (C–D) Expression of eEF1A2 in GBC tumor tissues and paired normal tissues was examined by Western blotting (C) and analyzed with ImageJ (D). (E–F) IHC staining was performed in a GBC microarray (cohort 1) to examine the expression of eEF1A2 in GBC tissues and its prognostic value. (E)Representative images of low and high eEF1A2 expression in Cohort 1. Scale bar: 100 μm. (F) Overall survival curves based on tumor eEF1A2 expression using the Kaplan–Meier method and analyzed by log-rank test. (G) Representative images of IHC staining for high and low eEF1A2 expression in GBC cohort 2. Scale bar: 100 μm. (H) IHC scores of eEF1A2 in GBC tumors and adjacent normal tissues in cohort 2 were analyzed. (I) Representative images of IHC staining for eEF1A2 expression in lymph nodes with no metastasis and those with GBC metastasis. Scale bar: 100 μm. (J) IHC scores of eEF1A2 expression in GBC lymph nodes with and without metastasis in cohort 2 were analyzed. (K) The overall survival curves based on tumor eEF1A2 expression in Cohort 2 were drawn using the Kaplan–Meier method and analyzed using the log-rank test. (L–M) Correlation analysis of tumor eEF1A2 expression and lymph node metastasis in gallbladder cancer cohort 1 (L) and cohort 2 (M). Statistical significance between groups was assessed using the chi-square test. Statistical significance between groups was assessed using Student's t-test. ns, not significant; ∗, p < 0.05; ∗∗ represents p < 0.01; ∗∗∗ represents p < 0.001.
Credit: Yun-cheng Li, Qiang Gao, Yong-chang Tang, Zhen-yu Shao, Jia-ming Hu, Zeng-li Liu, An-da Shi, Shao-hui Huang, Yun-fei Xu, Zong-li Zhang, Kang-shuai Li
This new research, published in the Genes & Diseases journal by a scientific team from Qilu Hospital of Shandong University, investigated the precise role of eEF1A2 and its specific methyltransferase, EEF1AKMT4, in GBC tumor progression and lymphatic spread.
Transcriptome sequencing of paired GBC tumors and metastatic lymph nodes, alongside clinical cohort analyses, revealed that eEF1A2 is significantly overexpressed in GBC and tightly correlates with advanced lymph node metastasis and poor patient survival. Through rigorous in vitro and in vivo experiments, including a specialized mouse popliteal lymph node metastasis model, researchers demonstrated that eEF1A2 significantly promotes GBC cell proliferation, migration, and invasion.
Mass spectrometry and functional analyses identified that EEF1AKMT4 specifically trimethylates eEF1A2 at the K36 site, a location critically positioned near the protein's GDP-binding pocket. This specific K36 trimethylation increases the GTPase catalytic activity of eEF1A2, thereby accelerating overall ribosomal protein synthesis. This elevated translational output consequently upregulates key tumor-promoting signals, most notably the ERK1/2 and AKT pathways.
Further functional experiments validated this mechanism, showing that introducing a K36R mutation to block methylation, or knocking down EEF1AKMT4 entirely, successfully abolished eEF1A2’s oncogenic effects.
Remarkably, in vivo models confirmed that inhibiting the EEF1AKMT4-eEF1A2 signaling axis significantly impaired tumor growth and sharply reduced the volume of metastatic lymph nodes. While these collective data robustly highlight the critical influence of localized protein translation efficiency on GBC aggressiveness, additional studies are necessary to fully realize these targeted interventions in a clinical setting.
In conclusion, targeting the evolutionarily conserved EEF1AKMT4-eEF1A2K36me3 signaling axis offers a powerful strategy to suppress translation-driven tumor growth and halt lymphatic spread. This profound finding positions specific inhibitors of eEF1A2 and its K36 trimethylation as compelling therapeutic candidates for the next generation of gallbladder cancer treatments.
Reference
Title of Original Paper: EEF1AKMT4-eEF1A2 synergistically facilitates the progression of GBC by promoting ribosomal protein output
Journal: Genes & Diseases
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DOI: https://doi.org/10.1016/j.gendis.2025.101619
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