Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
Department of Surgery, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, Korea.
Int J Mol Sci. 2021 Mar 11;22(6):2859. doi: 10.3390/ijms22062859.
It is challenging to overcome the low response rate of everolimus in the treatment of patients with hepatocellular carcinoma (HCC). To overcome this challenge, we combined everolimus with Ku0063794, the inhibitor of mTORC1 and mTORC2, to achieve higher anticancer effects. However, the precise mechanism for the synergistic effects is not clearly understood yet. To achieve this aim, the miRNAs were selected that showed the most significant variation in expression according to the mono- and combination therapy of everolimus and Ku0063794. Subsequently, the roles of specific miRNAs were determined in the processes of the treatment modalities. Compared to individual monotherapies, the combination therapy significantly reduced viability, increased apoptosis, and reduced autophagy in HepG2 cells. The combination therapy led to significantly lower expression of miR-4790-3p and higher expression of zinc finger protein225 (ZNF225)-the predicted target of miR-4790-3p. The functional study of miR-4790-3p and ZNF225 revealed that regarding autophagy, miR-4790-3p promoted it, while ZNF225 inhibited it. In addition, regarding apoptosis, miR-4790-3p inhibited it, while ZNF225 promoted it. It was also found that HCC tissues were characterized by higher expression of miR-4790-3p and lower expression of ZNF225; HCC tissues were also characterized by higher autophagic flux. We, thus, conclude that the potentiated anticancer effect of the everolimus and Ku0063794 combination therapy is strongly associated with reduced autophagy resulting from diminished expression of miR-4790-3p, as well as higher expression of ZNF225.
克服索拉非尼治疗肝细胞癌（HCC）患者低反应率具有挑战性。为了克服这一挑战，我们将索拉非尼与 mTORC1 和 mTORC2 的抑制剂 Ku0063794 联合使用，以达到更高的抗癌效果。然而，协同作用的确切机制尚不清楚。为了实现这一目标，根据索拉非尼和 Ku0063794 的单一和联合治疗，选择表达变化最显著的 miRNAs。随后，确定了特定 miRNAs 在治疗方式过程中的作用。与单独的单药治疗相比，联合治疗可显著降低 HepG2 细胞的活力，增加细胞凋亡，减少自噬。联合治疗导致 miR-4790-3p 的表达显著降低，锌指蛋白 225（ZNF225）的表达升高，ZNF225 是 miR-4790-3p 的预测靶标。miR-4790-3p 和 ZNF225 的功能研究表明，就自噬而言，miR-4790-3p 促进自噬，而 ZNF225 抑制自噬。此外，就凋亡而言，miR-4790-3p 抑制凋亡，而 ZNF225 促进凋亡。还发现 HCC 组织中 miR-4790-3p 表达较高，ZNF225 表达较低；HCC 组织还表现出较高的自噬通量。因此，我们得出结论，索拉非尼和 Ku0063794 联合治疗增强的抗癌作用与 miR-4790-3p 表达降低导致的自噬减少以及 ZNF225 表达升高密切相关。
