PCSK9 Suppresses M2-Like Tumor-Associated Macrophage Polarization by Regulating the Secretion of OX40L from Hepatocellular Carcinoma Cells

Hu, Jing; Zhang, Meixia; Gui, Ling; Wan, Qin-Si; Zhong, Jiawei; Bai, Liangliang; He, Min

doi:10.1080/08820139.2022.2027439

Cited by 8 publications

(2 citation statements)

References 46 publications

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“… 344 However, in a liver cancer study, it was proposed that PCSK9 could suppress the M2-polarization of TAMs through the regulation of OX40L secretion from HCC cells. 378 Further, in PCSK9KO mice on HCD, a multitude of macrophages were seen amassing around hepatocytes containing cholesterol crystals and lipid droplets, forming crown-like configurations. These structures were accompanied by elevated levels of apoptosis and hepatic inflammation and fibrosis, phenomena not observed in WT mice.…”

Section: The Role Of Pcsk9 In Various Disordersmentioning

confidence: 94%

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

Bao,

Liang,

Chang

et al. 2024

Sig Transduct Target Ther

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases (CVD). This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9, extending beyond CVD to emphasize its significance in diverse physiological and pathological states, including liver diseases, infectious diseases, autoimmune disorders, and notably, cancer. Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors (LDLRs), elucidating its substantial impact on cholesterol homeostasis and cardiovascular health. It also details the evolution of PCSK9-targeted therapies, translating foundational bench discoveries into bedside applications for optimized patient care. The advent and clinical approval of innovative PCSK9 inhibitory therapies (PCSK9-iTs), including three monoclonal antibodies (Evolocumab, Alirocumab, and Tafolecimab) and one small interfering RNA (siRNA, Inclisiran), have marked a significant breakthrough in cardiovascular medicine. These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia, reducing cardiovascular risks, and have showcased profound value in clinical applications, offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders. Furthermore, emerging research, inclusive of our findings, unveils PCSK9’s potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment. This review also highlights PCSK9’s aberrant expression in various cancer forms, its association with cancer prognosis, and its crucial roles in carcinogenesis and cancer immunity. In conclusion, this synthesized review integrates existing knowledge and novel insights on PCSK9, providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders. It emphasizes the clinical value and effect of PCSK9-iT, underscoring its potential in advancing the landscape of biomedical research and its capabilities in heralding new eras in personalized medicine.

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Section: The Role Of Pcsk9 In Various Disordersmentioning

confidence: 94%

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

Bao,

Liang,

Chang

et al. 2024

Sig Transduct Target Ther

View full text Add to dashboard Cite

show abstract

“…PCSK9 regulates the degradation of low-density lipoprotein receptors (LDLR) on the surface of liver cells via the endosome/lysosome pathway, revealing a new concern in low-density cholesterol homeostasis. In addition to this classical pathway, recent research has also found that PCSK9 plays other roles in the development of atherosclerosis via non-classical mechanisms, such as inflammation, apoptosis and immune pathways [ 11 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Association between serum PCSK9 and coronary heart disease in patients with type 2 diabetes mellitus

Huang,

Gu,

Wang

et al. 2023

Diabetol Metab Syndr

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Background and aims Proprotein convertase subtilisin/kexin type 9 (PCSK9) is considered a new biomarker for atherosclerosis, but its ability to predict cardiovascular outcomes has been controversial. This study aimed to address the lack of data on PCSK9, coronary heart disease (CHD) severity, and major cardiovascular events (MACEs) in patients with type 2 diabetes mellitus (T2DM). Methods A total of 2984 T2DM patients underwent selective coronary angiography, and their serum PCSK9 levels were measured using enzyme-linked immunosorbent assay. Correlation and logistic regression analyses were performed to investigate the association between PCSK9 expression and CHD severity. This study used Cox regression analysis to assess the association between circulating PCSK9 levels and the risk of MACEs. Results Circulating PCSK9 levels were significantly higher in the CHD group than in the non-CHD group [554.62 (265.11) ng/mL vs. 496.86 (129.05) ng/mL, p < 0.001]. Circulating PCSK9 levels positively correlated with CHD severity (diseased vessels: r = 0.35, p < 0.001; Gensini score: r = 0.46, p < 0.001). Elevated PCSK9 levels are an independent risk factor for CHD risk and severity (CHD group vs. non–CHD group: OR = 2.829, 95% CI: 1.771–4.520, p < 0.001; three vessel disease group vs. one vessel disease group: OR = 4.800, 95% CI: 2.387–9.652, p < 0.001; high GS group vs. low GS group: OR = 5.534, 95% CI: 2.733–11.208, p < 0.001). Through a six-year follow-up and multivariate Cox regression analysis, elevated circulating PCSK9 levels were found to be independently associated with MACEs in all participants (HR: 3.416, 5% CI: 2.485–4.697, p < 0.001; adjusted HR: 2.780, 95% CI: 1.930–4.004, p < 0.001). Conclusions Serum PCSK9 levels were positively correlated with multi-vessel CHD and Gensini score. Elevated circulating PCSK9 levels are an independent risk factor for CHD and increased incidence of MACEs in T2DM.

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The role of tumor‐associated macrophages in hepatocellular carcinoma progression: A narrative review

Zhang,

Yu,

Zhao

et al. 2023

Cancer Medicine

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Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world, with complex etiology and mechanism, and a high mortality rate. Tumor‐associated macrophages (TAMs) are an important part of the HCC tumor microenvironment. Studies in recent years have shown that TAMs are involved in multiple stages of HCC and are related to treatment and prognosis in HCC. The specific mechanisms between TAMs and HCC are gradually being revealed. This paper reviews recent advances in the mechanisms associated with TAMs in HCC, concentrating on an overview of effects of TAMs on drug resistance in HCC and the signaling pathways linked with HCC, providing clues for the treatment and prognosis determination of HCC.

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PCSK9 Suppresses M2-Like Tumor-Associated Macrophage Polarization by Regulating the Secretion of OX40L from Hepatocellular Carcinoma Cells

Cited by 8 publications

References 46 publications

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

Association between serum PCSK9 and coronary heart disease in patients with type 2 diabetes mellitus

The role of tumor‐associated macrophages in hepatocellular carcinoma progression: A narrative review

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