KIF1Bbeta suppresses hepatocellular carcinoma by transporting and secreting FBLN5 to attenuate the integrin pathway
Menée in vitro et à l'aide de modèles murins ainsi que de données portant sur 1 934 patients atteints d'un carcinome hépatocellulaire et 1 446 témoins sains, cette étude met en évidence un mécanisme par lequel la protéine KIF1Bbêta, en interagissant avec le transport et la sécrétion de la fibuline-5, supprime la tumeur via la réduction de l'activation de la voie de signalisation de l'intégrine
Background : Our previous genome-wide association study (GWAS) identified that chromosome 1p36.22 locus contributes to the risk of hepatocellular carcinoma (HCC).
Objective : We aimed to identify the functional causative variant(s) and target gene(s) at this locus.
Design : Two independent HCC case–control populations, totally consisting of 1934 cases and 1446 controls, were used to validate the association between 1p36.22 locus and HCC risk. The expression quantitative trait locus (eQTL) and eQTL-GWAS co-localisation analyses were used to identify the target gene at 1p36.22. The effects of the target gene on tumourigenesis were assessed in HCC cells, nude mouse models and conditional knockout mouse models.
Results : We confirmed the association between 1p36.22 locus and HCC risk (p=4.99×10
−
24), and revealed that this locus is an eQTL of the kinesin family member 1B isoform
β (KIF1Bβ) gene. Further, we demonstrated that KIF1Bβ plays a tumour suppressive role in HCC in vitro and in vivo. Mechanistically, KIF1Bβ interacts with the cargo Fibulin-5 and mediates its intracellular anterograde transport and extracellular secretion, therefore, reducing the activation of the integrin pathway. We further identified the functional causative variant rs61784580 at 1p36.22, which is located in the promoter of KIF1Bβ and regulates its expression in an allele-specific manner. Finally, we observed that downregulation of KIF1Bβ sensitises HCC cells to integrin αv inhibitor cilengitide.
Conclusions
:
Our findings shed light on the genetic and molecular mechanisms of the HCC-associated susceptibility locus at 1p36.22 and provide potential new strategies for the treatment of HCC.
Gut , résumé, 2025