Decreased PCSK9 expression in human hepatocellular carcinoma

Abstract

BackgroundThe management of hepatocellular carcinoma (HCC) is limited by the lack of adequate screening biomarkers and chemotherapy. In response, there has been much interest in tumor metabolism as a therapeutic target. PCSK9 stimulates internalization of the LDL-receptor, decreases cholesterol uptake into hepatocytes and affects liver regeneration. Thus, we investigated whether PCSK9 expression is altered in HCC, influencing its ability to harness cholesterol metabolism.MethodsThirty-nine patients undergoing partial hepatectomy or liver transplantation for HCC were consented for use of HCC tissue to construct a tissue microarray (TMA). The TMA was immunostained for PCSK9. Imagescope software was used to objectively determine staining, and assess for pathological and clinical correlations. PCSK9 and LDL receptor mRNA levels in flash-frozen HCC and adjacent liver tissue were determined by quantitative RT-PCR. Serum PCSK9 levels were determined by ELISA.ResultsBy immunohistochemistry, there was significantly lower expression of PCSK9 in HCC as compared to adjacent cirrhosis (p-value < 0.0001, wilcoxon signed-rank test). Significantly greater staining of PCSK9 was present in cirrhosis compared to HCC (p value <0.0001), and positivity (percentage of positive cells) was significantly greater in cirrhosis compared to HCC (p-value < 0.0001). Conversely, significantly higher expression of LDL-R was present in HCC as compared to the adjacent cirrhosis (p-value < 0.0001). There was no significant correlation of PCSK9 staining with grade of tumor, but there were significant correlations between PCSK9 staining and stage of fibrosis, according to spearman correlation test.PCSK9 mRNA levels were relatively less abundant within HCC compared to adjacent liver tissue (p-value =0.08) and normal control tissue (p-value =0.02). In contrast, serum PCSK9 levels were significantly increased among patients with HCC compared to those with chronic liver disease without HCC (p-value =0.029). LDL receptor mRNA was consistantly greater in HCC when compared to normal control tissue (p-value = 0.06) and, in general, was significantly greater in HCC when compared to adjacent liver (p-value = 0.04).ConclusionsThe decreased expression of PCSK9 and conversely increased LDL-R expression in HCC suggests that HCC modulates its local microenvironment to enable a constant energy supply. Larger-scale studies should be conducted to determine whether PCSK9 could be a therapeutic target for HCC.

Pro-inflammation NF-κB signaling triggers a positive feedback via enhancing cholesterol accumulation in liver cancer cells

“…Decreased PCSK9 and increased LDLR expression have been demonstrated in HCC tissues, supporting a constant cholesterol supply in the HCC microenvironment [33]. HMGCR is the rate-limiting enzyme in de novo synthesis of cholesterol in vivo.…”

Ligand-based targeted therapy: a novel strategy for hepatocellular carcinoma

“…225 Increased expression of LDL-R was found in HCC compared with adjacent liver tissue. 226 N-succinyl chitosan NPs were coupled with LDL for target co-delivery of cholesterol-conjugated siRNA and DOX by Zhu et al 227 The LDL-decorated delivery system exhibited superior cytotoxicity against HepG2 cells over non-targeted system and also manifested enhanced liver tumor-targeting effects and relatively lower systemic toxicity in mice bearing hepatoma cell tumor, suggesting their potential for HCC therapy. LDL was also utilized to modify osthole-loading N-succinyl chitosan NPs, attaining high targeting efficacy indicated by investigations in vitro and in vivo.…”

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

“…However, only a few studies have reported the relationship between PCSK9 and cancer [6,8]. One study on HCC reported a decrease in PCSK9 expression in human HCC tissues but did not clarify the speci c signi cance of low PCSK9 expression levels in the carcinogenesis and development of HCC [4]. Our study has demonstrated, for the rst time, that PCSK9 can interact with GSTP1, affect JNK phosphorylation levels, and inhibit HCC proliferation, which is of great signi cance for further understanding the function of the PCSK9 protein and suggests that PCSK9 may serve as a therapeutic target for patients with HCC.…”

“…In addition, PCSK9 has been reported to play an important role in a variety of biological processes, including the in ammatory response, immune response, metabolism, cell cycle, and apoptosis [1][2][3]. A previous study reported that PCSK9 expression in HCC tissues is lower than that in paracancerous tissues [4], and our previous study found that Chinese kiwifruit root extract had the effect of inhibiting the development of hepatocarcinoma cells, and PCSK9 is the key molecule of the Chinese herbal extract to inhibit the proliferation of liver cancer cells [5]. In addition, PCSK9 has been found to be closely related to the occurrence and development of a variety of tumors, including melanoma, prostate cancer, and lung cancer.…”