The camKK2/camKIV relay is an essential regulator of hepatic cancer

摘要: Hepatic cancer is one of the most lethal cancers worldwide. Here, we report that expression Ca2+/calmodulin-dependent protein kinase 2 (CaMKK2) significantly up-regulated in hepatocellular carcinoma (HCC) and negatively correlated with HCC patient survival. The CaMKK2 highly expressed all eight hepatic cell lines evaluated markedly relative to normal primary hepatocytes. Loss function sufficient inhibit liver growth, growth defect resulting from loss can be rescued by ectopic wild-type but not kinase-inactive mutants. Cellular ablation using RNA interference yields a gene signature correlates improvement survival, or pharmacological inhibition STO-609 impairs tumorigenicity cells vivo. Moreover, time-dependent manner carcinogen-induced mouse model, treatment regresses tumor burden this model. Mechanistically, signals through 4 (CaMKIV) control growth. Further analysis revealed serves as scaffold assemble CaMKIV key components mammalian target rapamycin/ribosomal S6 kinase, 70 kDa, pathway thereby stimulate synthesis phosphorylation. Conclusion: CaMKK2/CaMKIV relay an upstream regulator oncogenic pathway, importance axis confirmed potent inhibitory effects genetically pharmacologically decreasing activity; collectively, these findings suggest may represent potential targets for cancer. (Hepatology 2015;62:505–520