Gallbladder cancer (GBC), the most common tumour of the biliary system, is prone to lymph node metastasis.

Although extensive studies have been conducted on the aetiology 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 tumours 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 tumour 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 tumour 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 tumour 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-tumour promoting signals axis as a key mechanism in GBC progression and identifies it as a potential therapeutic target for GBC LN metastasis.

Source: Compuscript Ltd