LAMB3 drives gastric cancer progression through SAMD4A-mediated degradation of PHLPP2 mRNA leading to sustained PI3K-Akt activation
Menée à l'aide de lignées cellulaires, de xénogreffes sur des modèles murins ainsi que d'échantillons tumoraux et d'échantillons tissulaires adjacents provenant de patients atteints d'un cancer gastrique, cette étude met en évidence un mécanisme par lequel la surexpression de la sous-unité B3 de la laminine-332 favorise la progression tumorale en prolongeant l'activation de la voie de signalisation PI3K-Akt via la dégradation, induite par la protéine SAMD4A, de l'ARN messager de la phosphatase PHLPP2
Background : Laminin subunit beta 3 (LAMB3) overexpression has been implicated in cancer progression, but its molecular role in gastric cancer (GC) remains unclear. This study aimed to elucidate how LAMB3 promotes GC malignancy and identify the underlying signalling pathways.
Methods : The clinical significance of LAMB3 was analysed by bioinformatics and immunohistochemistry (IHC) on tissue microarrays. Correlations with clinicopathological parameters were evaluated using Chi-square or Fisher’s exact tests, and prognostic value was assessed by log-rank and multivariate Cox regression analyses. Functional assays, including CCK-8, colony formation, Transwell, and xenograft models, were performed to examine the roles of LAMB3 and its downstream effector. Mechanistic studies involved RNA sequencing (RNA-seq), gain- and loss-of-function experiments, RT-qPCR, RNA immunoprecipitation, and western blotting.
Results : LAMB3 was significantly upregulated in GC and correlated with aggressive features and poor prognosis. LAMB3 enhanced GC cell proliferation, migration, and invasion. RNA-seq identified sterile alpha motif domain-containing protein 4 A (SAMD4A) as a critical downstream effector. Silencing SAMD4A suppressed, while its restoration rescued, LAMB3-induced malignancy. Mechanistically, LAMB3 activated PI3K-Akt signalling through SAMD4A-mediated degradation of PHLPP2 mRNA.
Conclusions : This study uncovers a previously unrecognised LAMB3-SAMD4A-PHLPP2 regulatory axis that sustains PI3K-Akt activation and drives GC progression, offering potential prognostic and therapeutic value.
British Journal of Cancer , article en libre accès, 2026