Positive feedback between slug and Akt promotes hepatocellular carcinoma growth via CDK6 expression

Abstract Background Hepatocellular carcinoma (HCC) is a rapidly growing tumor associated with a propensity for vascular invasion and metastasis, but the mechanism of HCC growth is not fully understood. The objective of this study is to investigate the role of the transcriptional repressor slug in HCC growth and its detailed mechanism. Methods Lentivirus-mediated slug overexpression as well as CRISPR/Cas9-mediated slug knockout were conducted in hepatic or HCC cells. Then cell growth was evaluated in culture dishes as well as nude mice xenografts. Transcriptome analysis was used to explore the detailed mechanism of slug-induced HCC growth. Results Slug significantly facilitated HCC growth in vitro and in vivo. Mechanism dissection via transcriptome analysis revealed that slug transcriptionally upregulated PIK3CD and PIK3R3 expression and then activated the Akt/CDK6 signaling pathway. Administration of either the PI3K/Akt signaling inhibitor MK2206 or the CDK4/6 inhibitor PD-0332991 abrogated slug-induced HCC growth. In addition, administration of MK2206 also suppressed slug expression in HCC cells. Immunohistochemistry staining indicated that Akt activity and CDK6 expression were significantly associated with slug expression in human HCC tissues. Conclusions Our study determined the promoting role of slug in HCC growth and revealed that the positive feedback between slug and Akt conferred HCC growth via CDK6 expression. The CDK4/6 inhibitor PD-0332991 might be a promising drug for slug/Akt-induced HCC growth.