IL-1 receptor-associated kinase 1 participates in the modulation of the NLRP3 inflammasome by tumor-associated macrophages in hepatocellular carcinoma

Abstract

Background: Hepatocellular carcinomas (HCCs) occur frequently in the digestive system and are associated with high mortality. This current study examined the regulatory relationship between interleukin (IL)-1 receptor-associated kinase 1 (IRAK1), NLR family pyrin domain-containing 3 (NLRP3) inflammasomes, and tumor-associated macrophages (TAMs) in the growth and metastasis of HCC. Methods:The expression of IRAK1 and NLRP3 was assessed in tissues and cells via quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. Immunohistology was performed to detect the macrophage markers CD68, CD163, and CD168 in tumor tissues. Small interfering (si)RNA targeting IRAK1 (si-IRAK1) was designed to silence IRAK1 expression. Following si-IRAK1 transfection and/or coculture with TAMs, HCC cell viability, proliferation, migration, and invasion, as well as the expression of NLRP3 and pro-inflammatory cytokines IL-1 β, IL-18, and monocyte chemotactic protein 1 (MCP-1) were assessed.Results: HCC tissues showed elevated expression of IRAK1 and NLRP3, as well as increased expression of the macrophage markers CD68, CD163, and CD168, compared to adjacent healthy tissues. Silencing of IRAK1 expression in HepG2 and Huh7 cells resulted in suppression of cell proliferation, migration, and invasion, and also reduced expression of NLRP3 and the pro-inflammatory cytokines IL-1β, IL-18, and MCP-1. Moreover, TAMs promoted HepG2 and Huh7 cell proliferation, migration, and invasion, and elevated the expression of NLRP3, IL-1β, IL-18, and MCP-1. Furthermore, IRAK1 silencing reversed the effects of TAMs on HepG2 and Huh7 cells. Conclusions:The expression of IRAK1 was associated with HCC growth and metastasis, as well as NLRP3 inflammasome activation. The ability of TAMs to promote HCC growth and metastasis may be activated by NLRP3 inflammasomes and regulated by IRAK1.

The roles of cancer stem cell-derived secretory factors in shaping the immunosuppressive tumor microenvironment in hepatocellular carcinoma

“…Several lncRNAs and miRNAs can exert immunosuppressive influence to facilitate HCC progression, such as lncMALAT1 ( 72 ), lncHULC ( 73 ), lncHOTAIR ( 74 ), lncLINC01132 ( 75 ), lncPVT1 ( 76 ), lncLINC00662 ( 77 ), lncβ-Catm ( 78 ), miR-23a-3p ( 79 ), and miR-146a-5p ( 80 ). Dysregulated expression of epigenetic regulators, including DNMT3α ( 81 ), KDM1A ( 82 , 83 ), YTHDF2 ( 84 ), and RALYL ( 85 ), as well as kinases and phosphatases such as IRAK1 ( 86 ) and SHP2 ( 87 ), may also contribute to the formation of an immunosuppressive TME in HCC. As an intricate malignancy, HCC is characterized by metabolic reprogramming, in which glycolytic and lipid metabolism aberrations can contribute to an immunosuppressive TME.…”

The role of NLRP3 inflammasome in digestive system malignancy

“…Many studies have shown that the NLRP3 inflammasome has a promoting effect on HCC. NLRP3 has been found highly expressed in HCC tissues, and inhibition of NLRP3 inflammasome activation could induce apoptosis and regulate the levels of inflammatory factors, which would suppress the growth of HCC cells (Chen et al, 2022) (Li et al, 2020a). Knockout of NLRP3 in HCC cells also inhibited tumor growth and metastasis in vivo, as well as increased the sensitivity to NK cell cytotoxicity (Lee et al, 2021).…”

Tumor-Associated Macrophages (TAMs) Polarization by Single-Cell Sequencing Combined with Bulk Data in Hepatocellular Carcinoma Cell

“…The surface antigen CD68 is a specific surface marker for monocyte macrophages, including Kupffer cells. Flow cytometry and immunohistochemistry are used to detect the number and distribution of macrophages, which can reveal Hao2 hepatocellular carcinoma and the distribution pattern of HCC [17][18][19][20].…”