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

ABSTRACT

Background

Proprotein convertase subtilisin/kexin type 9 (PCSK9) participates in the development of various cancers, including hepatocellular carcinoma (HCC). Here, we attempted to reveal the underlying mechanism of PCSK9 in HCC.

Methods

Tumor tissues and adjacent tissues were separated from HCC patients to detect PCSK9 expression. Then, PCSK9 was overexpressed or silenced in HCC cells (MHCC97H or Huh7), and then the cell supernatant was incubated with THP-1 macrophages. OX40L neutralizing antibody (nAb) was used to inhibit OX40L activity. The expression of macrophage markers was examined by immunohistochemical staining and flow cytometry. Finally, tumor-bearing mouse model was constructed by inoculation of LV-PCSK9 infected MHCC97H cells to verify the role of PCSK in HCC.

Results

PCSK9 expression was decreased in tumor tissues of HCC patient specimens. HCC patients displayed M2 macrophage infiltration in tumor tissues. Moreover, PCSK9-silenced Huh7 cell supernatant promoted cell migration, and enhanced the proportion of CD206-positive cells and the expression of M2 macrophage markers IL-10 and ARG-1 in THP-1 macrophages. PCSK9-overexpressing MHCC97H cell supernatant inhibited THP-1 macrophage migration and M2-like tumor-associated macrophage (TAM) polarization, which was abolished by OX40L nAb treatment. PCSK9 overexpression enhanced the expression of OX40L in MHCC97H cells. In tumor-bearing mouse models, PCSK9 overexpression inhibited tumor growth and M2 polarization of TAMs in HCC by promoting OX40L expression. Conclusion: This work demonstrated that PCSK9 suppressed M2-like TAM polarization by regulating the secretion of OX40L from hepatocellular carcinoma cells. This study suggests that PCSK9 may be a potential target for HCC treatment.

KEYWORDS:

• Hepatocellular carcinoma
• migration
• PCSK9
• polarization
• tumor-associated macrophage

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (Grant No. 81802461), Jiangxi Provincial Department of Science and Technology (Grant No. 20202ACBL216012) and Education Department of Jiangxi Province (Grant No. GJJ170010).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the Education Department of Jiangxi Province [GJJ170010]; Jiangxi Provincial Department of Science and Technology [20202ACBL216012]; National Natural Science Foundation of China [81802461].