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: Genes & Diseases
Gallbladder cancer (GBC), the most common tumor of the biliary system, is prone to lymph node metastasis. Although extensive studies have been conducted on the etiology and progression of GBC, the underlying mechanism remains elusive, limiting the development of effective treatments. Therefore, identifying novel therapeutic targets is vital.
This research, published in the Genes & Diseases journal by a team from Shandong University, elucidates the molecular mechanism of lymph node (LN) metastasis in GBC.
The initial investigation involved transcriptome sequencing of six paired GBC tumors and metastatic LNs, revealing that eEF1A2 (eukaryotic translation elongation factor 1A2) is upregulated in GBC. Its high expression is strongly correlated with LN metastasis and poor prognosis in GBC patients. In vitro studies showed the migratory and invasive abilities of GBC cell lines were significantly reduced following eEF1A2 knockdown and enhanced upon eEF1A2 overexpression. Similarly, in vivo experiments showed that eEF1A2 knockdown inhibited tumor growth and LN metastasis, whereas its overexpression promoted these processes.
Further investigation showed that eEF1A2 is highly methylated in GBC cells, with two hypermethylated sites, K36 and K55. Moreover, the methylase of K36, EEF1AKMT4, was also highly expressed in GBC tissues. Interestingly, knockdown of EEF1AKMT4 inhibited the malignant phenotype of GBC, while its overexpression did not contribute to tumor formation. This suggests that the methylation status of eEF1A2 K36 plays an important role in GBC cell function.
Mechanistically, trimethylation at the K36 site of eEF1A2 enhanced its GTPase activity and activated tumor promoting signals including ERK1/2 and AKT by boosting the ribosome total protein synthesis. Notably, EEF1AKMT4 wild-type (WT) supplementation in EEF1AKMT4 knockdown cells restored the proliferation, migration, and invasion abilities of GBC cells. These findings indicate a significant role for K36me3 in eEF1A2-induced GBC progression and LN metastasis.
In conclusion, this study highlights the evolutionarily conserved EEF1AKMT4-eEF1A2K36me3-ribosome protein synthesis-tumor promoting signals axis as a key mechanism in GBC progression and identifies it as a potential therapeutic target for GBC LN metastasis.
Reference
Title of Original Paper: EEF1AKMT4-eEF1A2 synergistically facilitates the progression of GBC by promoting ribosomal protein output
Journal Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101619
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