Protein convertase subtilisin/Kexin type 9 inhibits hepatocellular carcinoma growth by interacting with GSTP1 and suppressing the JNK signaling pathway

Abstract

Objective: Protein convertase subtilisin/Kexin type 9 (PCSK9) has been found to be closely associated with the occurrence and development of numerous tumors. However, the precise role of PCSK9 and its relationship to the development of hepatocellular carcinoma (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 transcription polymerase chain reaction, Western blot, and immunohistochemical analyses, and the effects of PCSK9 expression on HCC cell biological traits were investigated by overexpressing and downregulating PCSK9 expression in vivo and in vitro. Additionally, the mechanism by which PCSK9 mediated dissociation of glutathione S-transferase Pi 1 (GSTP1) dimers and phosphorylation of the Jun 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 and in vitro experiments suggested that PCSK9 inhibited HCC cell proliferation and metastasis. Further analysis showed that PCSK9 interacted 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 a significantly shorter overall survival (OS; median OS: 64.2 months vs. 83.2 months; log-rank statistic: 4.237; P = 0.04) and recurrencefree survival (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 and suppressing JNK signaling, suggesting that PCSK9 might act as a tumor suppressor and be a therapeutic target in HCC patients.

Emerging Insights on the Diverse Roles of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Chronic Liver Diseases: Cholesterol Metabolism and Beyond

“…Nevertheless, tumor and nontumor tissues seem to differentially regulate PCSK9 expression. In patients, PCSK9 mRNA and protein were lower in HCC tissues compared to adjacent tissues [20,169]. These findings coincided with high LDL-R mRNA and protein levels in HCC tissues compared to adjacent nontumor tissues [20].…”

“…This decreased metastatic spread was lost upon feeding with a high-cholesterol diet, overriding genetic alterations that lower the risk for cancer cell spreading [168]. Another report showed PCSK9 to interact with glutathione S-transferase Pi 1 (GSTP1), thereby blocking activation of Jun N-terminal kinase (JNK) and consequently inhibiting HCC growth [169]. Furthermore, HCC patients exhibiting low PCSK9 levels had a shorter overall survival and recurrencefree survival time compared to HCC patients with high amounts of PCSK9 [20,169].…”

“…Another report showed PCSK9 to interact with glutathione S-transferase Pi 1 (GSTP1), thereby blocking activation of Jun N-terminal kinase (JNK) and consequently inhibiting HCC growth [169]. Furthermore, HCC patients exhibiting low PCSK9 levels had a shorter overall survival and recurrencefree survival time compared to HCC patients with high amounts of PCSK9 [20,169]. These opposite findings reflect data available from the Human Protein Atlas, which based on expression data from 365 patients, classified PCSK9 levels as not prognostic in liver cancer (www.proteinatlas.org, accessed on 16 January 2022) [170].…”

Angiogenesis in hepatocellular carcinoma: mechanisms and anti-angiogenic therapies

“…First, current anti-angiogenic clinical trials induce only a modest improvement in OS, measurable in just several months. Given that HCC has multiple pathways for recruiting vessels, blocking one target alone may have incomplete effects on tumor angiogenesis, because the tumor cells may switch from one mechanism to another 132 , 138 . However, the use of anti-angiogenic molecules may lead to a hypoxic TME, which alters the cell phenotype and enhances tumor invasiveness, whereas the tumor-infiltrating cells, including TAMs, TANs, and TAFs, may decrease the response to anti-angiogenic therapies 139 .…”

Animal Models of Hepatocellular Carcinoma: Current Applications in Clinical Research

“… 46 On the contrary, other studies reported decreased PCSK9 expression in HCC implying that liver tumors can modulate their local and adjacent microenvironment, thus enabling energy supply to fuel tumor growth. 47 A brilliant study demonstrated that deleting PCSK9 gene in rodent cancer cells substantially affects their growth in vivo and, notably, improves the efficacy of anti-programmed cell death protein 1 (PD1) therapy, opening the way towards combined immune checkpoint-based strategies. Mechanisms of action seem independent of the cholesterol regulation, rather relying on the recycling of MHC I molecules for degradation to lysosomes.…”