FNDC5 induces M2 macrophage polarization and promotes hepatocellular carcinoma cell growth by affecting the PPARγ/NF-κB/NLRP3 pathway

Liu, Huayuan; Wang, Mengya; Jin, Zhipeng; Sun, Dongxu; Zhu, Tian; Tan, Xueying; Shi, Guangjun

doi:10.1016/j.bbrc.2021.10.041

Cited by 29 publications

(23 citation statements)

References 21 publications

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“…As the role of FNDC5 has also been gradually revealed in tumors ( 23 , 24 ) and in the progression of HCC, FNDC5 has been suggested to play a role in promoting the proliferation of cancer cells. In our previous study, we found that the expression of FNDC5 was higher in cancer than in normal tissues ( 18 , 19 ). In the present study, we found that the expression of FNDC5 was elevated in sorafenib-resistant cells and that drug-resistant cells with high expression of FNDC5 were not sensitive to treatment with sorafenib, whereas FNDC5 -knockdown HCC cells were readily killed by sorafenib as observed using the EdU and CCK8 assays.…”

Section: Discussionmentioning

confidence: 89%

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FNDC5 Causes Resistance to Sorafenib by Activating the PI3K/Akt/Nrf2 Pathway in Hepatocellular Carcinoma Cells

et al. 2022

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In this study, we aimed to reveal the resistance mechanism of hepatocellular carcinoma (HCC) cells to sorafenib by exploring the effect of FNDC5 on sorafenib-induced ferroptosis in HCC cells. We compared the expression level of FNDC5 between sorafenib-resistant and sorafenib-sensitive HCC cell lines and the level of ferroptosis between the groups after treatment with sorafenib. We knocked down FNDC5 in drug-resistant cell lines and overexpressed it in sorafenib-sensitive HCC cell lines to further demonstrate the role of FNDC5 in sorafenib-induced ferroptosis. Using PI3K inhibitors, we revealed the specific mechanism by which FNDC5 functions. In addition, we verified our findings obtained in in vitro experiments using a subcutaneous tumorigenic nude mouse model. The findings revealed that FNDC5 inhibits sorafenib-induced ferroptosis in HCC cells. In addition, FNDC5 activated the PI3K/Akt pathway, which in turn promoted the nuclear translocation of Nrf2 and increased the intracellular antioxidant response, thereby conferring resistance to ferroptosis. Our study provides novel insights for improving the efficacy of sorafenib.

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Section: Discussionmentioning

confidence: 89%

“…Immunohistochemistry was performed as previously described ( 19 ). Tumor and adjacent noncancerous (normal) liver tissues (60 pairs in total) were obtained from patients with liver cancer, fixed with 4.0% paraformaldehyde, paraffin-embedded, and cut into 4-μm-thick sections.…”

Section: Methodsmentioning

confidence: 99%

FNDC5 Causes Resistance to Sorafenib by Activating the PI3K/Akt/Nrf2 Pathway in Hepatocellular Carcinoma Cells

et al. 2022

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“…Another is stimulated by multiple stimuli, such as ATP or viral RNA, and activate NLRP3 inflammasome through massive K + efflux (29). Mitochondrial dysfunction and Ca 2+ signaling are associated with activation of NLRP3 inflammasome (16). While previous study has demonstrated that NLRP3 inflammasome is associated with the pathogenesis of several human cancers (32), its role in HCC progression remains controversial.…”

Section: Discussionmentioning

confidence: 99%

“…The aberrant expression of NLRP3 has been shown to participate in the pathogenesis of inflammationrelated human diseases via facilitating a chronic inflammatory response (14). Considering that inflammation has been shown to be involved in the progression of multiple human cancers including HCC, the regulatory effects of NLRP3 on cancer growth and metastasis has been become a hotspot in molecular biology research (15,16). Chen et al (17) reported that IRAK1 silencing could suppress the malignant transformation of HCC cells via inhibiting the MAPKs/NLRP3/IL-1β pathway.…”

Section: Introductionmentioning

confidence: 99%

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

Chen¹,

Hu²,

Wei³

et al. 2022

J Gastrointest Oncol

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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.

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“…By using co-culture system embracing both HCC cells and TAMs, the same research group denoted HepG2/SMCC7721-derived FNDC5 overproduction results in increased M2 phenotype and decreased M1 phenotype in THP-1 induced macrophages (Ref. 116). Further mechanistic investigation implied that high FNDC5-expressed HCC cells may influence the PPAR γ /NF- κ B/NLRP3 pathway in TAMs, in consequence, promoting M2 polarisation.…”

Section: Hepatocellular Carcinomamentioning

confidence: 99%

The potential role of FNDC5/irisin in various liver diseases: awakening the sleeping beauties

Wang

Mao²,

Li³

et al. 2022

Expert Rev. Mol. Med.

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Fibronectin type III domain-containing protein 5 (FNDC5) is a transmembrane protein and the precursor of irisin, which serves as a systemic exerkine/myokine with multiple origins. Since its discovery in 2012, this hormone-like polypeptide has rapidly evolved to a component significantly involved in a gamut of metabolic dysregulations and various liver diseases. After a decade of extensive investigation on FNDC5/irisin, we are still surrounded by lots of open questions regarding its diagnostic and therapeutic values. In this review, we first concentrated on the structure–function relationship of FNDC5/irisin. Next, we comprehensively summarised the current knowledge and research findings regarding pathogenic roles/therapeutic applications of FNDC5/irisin in the context of non-alcoholic fatty liver disease, fibrosis, liver injury due to multiple detrimental insults, hepatic malignancy and intrahepatic cholestasis of pregnancy. Moreover, the prominent molecules involved in the underlying mechanisms and signalling pathways were highlighted. As a result, emerging evidence reveals FNDC5/irisin may act as a proxy for diagnosing liver disease pathology, a sensitive biomarker for assessing damage severity, a predisposing factor for surveilling illness progression and a treatment option with protective/preventive impact, all of which are highly dependent on disease grading and contextually pathological features.

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FNDC5 induces M2 macrophage polarization and promotes hepatocellular carcinoma cell growth by affecting the PPARγ/NF-κB/NLRP3 pathway

Cited by 29 publications

References 21 publications

FNDC5 Causes Resistance to Sorafenib by Activating the PI3K/Akt/Nrf2 Pathway in Hepatocellular Carcinoma Cells

FNDC5 Causes Resistance to Sorafenib by Activating the PI3K/Akt/Nrf2 Pathway in Hepatocellular Carcinoma Cells

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

The potential role of FNDC5/irisin in various liver diseases: awakening the sleeping beauties

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