NDRG1 facilitates self-renewal of liver cancer stem cells by preventing EpCAM ubiquitination
Menée à l'aide de lignées cellulaires ainsi que d'échantillons tumoraux, d'échantillons tissulaires adjacents et d'échantillons de thrombus tumoraux de la veine porte issus de patients atteints d'un carcinome hépatocellulaire, cette étude met en évidence un mécanisme par lequel la protéine NDRG1 facilite l'auto-renouvellement des cellules souches cancéreuses en inhibant l'ubiquitinylation de la protéine EpCAM
Background : Portal vein tumour thrombus (PVTT) is the main pathway of HCC intrahepatic metastasis and is responsible for the poor prognosis of patients with HCC. However, the molecular mechanisms underlying PVTT vascular metastases have not been fully elucidated. Methods : NDRG1 expression was assessed by immunohistochemistry and immunoblotting in clinical specimens obtained from curative surgery. The functional relevance of NDRG1 was evaluated using sphere formation and animal models of tumorigenicity and metastasis. The relationship between NDRG1 and EpCAM was explored using molecular biological techniques. Results : NDRG1 protein was upregulated in HCC samples compared to non-tumorous tissues. Furthermore, NDRG1 expression was enhanced in the PVTT samples. Our functional study showed that NDRG1 was required for the self-renewal of tumour-initiating/cancer stem cells (CSCs). In addition, NDRG1 knockdown inhibited the proliferation and migration of PVTT-1 cells in vitro and in vivo. NDRG1 was found to stabilise the functional tumour-initiating cell marker EpCAM through protein–protein interactions and inhibition of EpCAM ubiquitination. Conclusion : Our findings suggest that NDRG1 enhances CSCs expansion, PVTT formation and growth capability through the regulation of EpCAM stability. NDRG1 may be a promising target for the treatment of patients with HCC and PVTT.