Protein convertase subtilisin/Kexin type 9 inhibits hepatocellular carcinoma growth by interacting with GSTP1 and suppressing the JNK signaling pathway
Mingyan He, Jing Hu, Tingting Fang, Wenqing Tang, Bei Lv, Biwei Yang, Jinglin Xia
Abstract
Objective: Protein convertase subtilisin/Kexin type 9 (PCSK9) has been found to be closely associated with the occurrence anddevelopment of numerous tumors. However, the precise role of PCSK9 and its relationship to the development of hepatocellularcarcinoma (HCC) remain largely unknown. This study aimed to clarify these issues. Methods: The expression levels of PCSK9 in HCC tissues and HCC cell lines were determined by the quantitative reverse transcriptionpolymerase chain reaction, Western blot, and immunohistochemical analyses, and the effects of PCSK9 expression on HCC cellbiological traits were investigated by overexpressing and downregulating PCSK9 expression in vivo and in vitro. Additionally, themechanism by which PCSK9 mediated dissociation of glutathione S-transferase Pi 1 (GSTP1) dimers and phosphorylation of theJun N-terminal kinase (JNK) pathway components were investigated. Results: PCSK9 expression levels were significantly lower in HCC tissues than in adjacent non-tumor samples. In vivo andin vitro experiments suggested that PCSK9 inhibited HCC cell proliferation and metastasis. Further analysis showed that PCSK9interacted with GSTP1 and promoted GSTP1 dimer dissociation and JNK signaling pathway inactivation in HCC cells. Moreover,the relationships between PCSK9 protein expressions and clinical outcomes were investigated. The PCSK9-lo group displayed asignificantly shorter overall survival (OS; median OS: 64.2 months vs. 83.2 months; log-rank statistic: 4.237; P = 0.04) and recurrencefreesurvival (RFS; median RFS: 26.5 months vs. 46.6 months; log-rank statistic: 10.498; P = 0.001) time than the PCSK9-hi group. Conclusions: PCSK9 inhibited HCC cell proliferation, cell cycle progression, and apoptosis by interacting with GSTP1 andsuppressing JNK signaling, suggesting that PCSK9 might act as a tumor suppressor and be a therapeutic target in HCC patients.