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Updated: Mar 28, 2026
A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
Published on: August 28, 2018
Decreased PCSK9 expression in human hepatocellular carcinoma
Mamatha Bhat1, Nicolas Skill2, Victoria Marcus3
1Division of Gastroenterology, McGill University Health Centre, 687 Pine Avenue West, Montreal, H3A1A1, Canada. mamatha.bhat@mcgill.ca.
Background:
The 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.
Methods:
Thirty-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.
Results:
By 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).
Conclusions:
The 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.
Insights
Hepatocellular carcinoma (HCC) shows decreased PCSK9 expression and increased LDL-R, suggesting altered cholesterol metabolism for energy. Further research is needed to explore PCSK9 as a potential therapeutic target for HCC.
Area of Science:
- Hepatocellular carcinoma (HCC) research
- Tumor metabolism and cholesterol regulation
- Biomarker discovery in oncology
Background:
- Hepatocellular carcinoma (HCC) management is hindered by a lack of effective screening biomarkers and chemotherapy options.
- Tumor metabolism, particularly cholesterol metabolism, is a promising therapeutic target for HCC.
- PCSK9 influences low-density lipoprotein receptor (LDL-R) internalization and hepatic cholesterol uptake, impacting liver regeneration.
Purpose of the Study:
- To investigate alterations in PCSK9 expression within HCC.
- To determine the relationship between PCSK9 expression and cholesterol metabolism in HCC.
- To assess the potential of PCSK9 as a therapeutic target for HCC.
Main Methods:
- Tissue microarrays (TMAs) were constructed from HCC and adjacent liver tissues of 39 patients.
- Immunohistochemistry was used to assess PCSK9 expression, with objective staining analysis.
- Quantitative RT-PCR and ELISA were employed to measure PCSK9 and LDL receptor mRNA and serum levels, respectively.
Main Results:
- HCC tissues exhibited significantly lower PCSK9 expression compared to adjacent cirrhotic tissues (p < 0.0001).
- Conversely, LDL receptor (LDL-R) expression was significantly higher in HCC tissues than in adjacent cirrhosis (p < 0.0001).
- Serum PCSK9 levels were elevated in HCC patients compared to those with chronic liver disease without HCC (p = 0.029).
Conclusions:
- The observed downregulation of PCSK9 and upregulation of LDL-R in HCC suggests a metabolic adaptation for sustained energy supply.
- These findings highlight the potential role of altered cholesterol metabolism in HCC progression.
- Further large-scale studies are warranted to validate PCSK9 as a potential therapeutic target for hepatocellular carcinoma.
