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

Funding Information:

Shandong Province Natural Science Foundation (Grant No.ZR2024MH328, ZR2021QH079, ZR2019MH008, ZR2020MH238)
Shandong Province Key R&D Program (Major Scientific Innovation Projects, 2021CXGC011105)
National Natural Science Foundation of China (Grant No. 81900728, 82072676, 82172791, 82203766)
Shandong Medical and Health Technology Development Project (Grant No. 2018WSB20002)
Clinical Research Foundation of Shandong University (Grant No. 2020SDUCRCA018)
Key Research and Development Program of Shandong Province (Grant No. 2019GSF108254)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

Scopus CiteScore: 7.3 | Impact Factor: 6.9

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