Gankyrin activates IL-8 to promote hepatic metastasis of colorectal cancer
Menée in vitro et in vivo, cette étude met en évidence le rôle joué par la gankyrine dans la formation de métastases hépatiques d'un cancer colorectal
Hepatic metastasis is responsible for the majority of colorectal cancer (CRC)-related mortalities. Although Gankyrin (PSMD10) has been implicated in cancer metastasis, its exact role and underlying mechanisms of CRC hepatic metastasis remain largely unknown. Herein, we demonstrated that the expression of Gankyrin was higher in primary CRC with hepatic metastasis compared to CRC without metastasis. RNAi-mediated silencing of Gankyrin expression in highly metastatic human CRC cells impaired their migratory and metastatic capacity in vivo. Genome-wide transcriptome profiling revealed activation of the IL-8 signaling pathway by Gankyrin. Protein levels of IL-8 and cyclin D1 (CCND1), the two important molecules in the IL-8 pathway, were positively correlated with Gankyrin expression in human CRC specimens. Furthermore, genetic deletion of cyclin D1 demonstrated its requirement in Gankyrin-mediated cell migration. Lastly, administration of recombinant IL-8 rescued the migratory defect of CRC cells where Gankyrin expression was silenced. Together, our findings highlight the importance of Gankyrin in hepatic metastasis of CRC and point out its candidacy as a potential prognostic marker and therapeutic target to improve the clinical management of metastatic CRC.