Ligustilide counteracts carcinogenesis and hepatocellular carcinoma cell-evoked macrophage M2 polarization by regulating yes-associated protein-mediated interleukin-6 secretion

Abstract

Cross-communication between cancer cells and macrophages within the tumor microenvironment fulfills the critical roles in the progression of cancers, including hepatocellular carcinoma (HCC). Ligustilide exerts anti-inflammation, anti-injury, and anti-tumor pleiotropic pharmacological functions. Nevertheless, its roles in HCC cells and tumor microenvironment remain elusive. In the current study, ligustilide dramatically restrained HCC cell viability and migration but had little cytotoxicity to normal hepatocytes. Importantly, ligustilide antagonized HCC cell co-culture-induced macrophage recruitment and M2 polarization by enhancing the percentage of CD14+CD206+ cells and macrophage M2 markers (CD163, Arg1, CD206, CCL22, IL-10, and TGF-β). Mechanistically, ligustilide repressed yes-associated protein (YAP) activation by reducing nuclear translocation, protein expression, transcriptional regulatory activity of YAP, and increasing p-YAP levels. Noticeably, blocking the YAP offset the suppressive effects of ligustilide on macrophage recruitment and M2 polarization evoked by HCC cells. Moreover, the release of interleukin-6 (IL-6) was mitigated by ligustilide in a YAP-dependent manner in HCC cells, concomitant with inhibition of IL-6R/STAT3 signaling activation. Of interest, interdicting the IL-6 aggravated ligustilide-mediated suppression in HCC-induced macrophage recruitment and M2 polarization; whereas exogenous IL-6 treatment reversed the above effects. Additionally, blockage of IL-6R signaling also overturned IL-6-induced macrophage recruitment and M2 phenotype. Consequently, these findings support a notion that ligustilide not only restrains HCC cell malignancy but also antagonizes HCC cell-evoked macrophage recruitment and M2 polarization by inhibiting YAP/IL-6 release-induced activation of the IL-6 receptor/signal transducer and activator of transcription 3 (IL-6R/STAT3) signaling. Thus, ligustilide may be a promising therapeutic agent to fight HCC by regulating cancer cells and cross-talk between tumor cells and macrophages in tumor microenvironment.

Chuanxiong Rhizoma extracts prevent liver fibrosis via targeting CTCF-c-MYC-H19 pathway

“…According to experimental analysis, we found that the differential protection of CX extracts may be attributed to different components and their regulation of different pathways. For example, representative components of CX AL and CX PHL , including TMP ( Li et al, 2022 , Wang, Xu, Yang, Chen, & Zhang, 2015 ), ligustilide ( Yang & Xing, 2021 ), ligustchuane A ( Wan et al, 2022 ) and ligustchuane B ( Qin et al, 2022 ) have been demonstrated to respectively affect c-myc or H19, which may explain the phenomenon about the superimposed regulation of these two CX extracts on CTCF-c-MYC-H19 pathway. While the components in CX PA may suppress hepatic fibrosis via other pathways but not CTCF-c-MYC-H19.…”

Gut-immunity-joint axis: a new therapeutic target for gouty arthritis

“…Additionally, activated macrophages also secrete hyperalgesic cytokines such as TNF-α, MCP-1, and IL-6, which promote polarization into pro-inflammatory M1 macrophages (Ren et al, 2021;Zhao J. et al, 2022;Nieradko-Iwanicka, 2022). M1 macrophages release reactive oxygen and nitrogen species, cyclooxygenase-2, and phospholipase A2, perpetuating inflammation and sensitizing TRPA1 pain channels (Yang and Xing, 2021) (Figure 1).…”

“…In order to treat pain of GA, scholars discovered that Qu-Zhuo-Tong-Bi decoction might alter macrophage polarization and block the synthesis of proinflammatory factors by altering the prevalence of butyrateproducing bacteria and SCFA production in C57/Bl6J mice (Wen et al, 2020). Other herbal formulations, including Si Miao San (Lin et al, 2020), Tongfu Ding (Yang and Xing, 2021) and Modified Baihu decoction , as well as individual botanical drugs extracts, including Cichorium intybus L. [Asteraceae; Cichorii radix], have all been demonstrated to be successful in preventing and treating GA pain (Bian et al, 2020;Han J. et al, 2021) (Table 1). Further exploration of the impact of botanical drug medications and formulations on the gut microbiota will contribute to a deeper understanding of how the gut microbiome and associated metabolites influence GA inflammation and pain.…”

Mechanisms of tumor-associated macrophages affecting the progression of hepatocellular carcinoma

“…Hepatic stellate cells activated within tumors exhibit high expression of fatty acid-binding protein 4 (FABP4), inducing NF-κB nuclear translocation and promoting the secretion of IL-6 and IL-1A ( Chiyonobu et al, 2018 ). By activating the IL-6-IL6R/STAT3 signaling pathway in Mφ, IL-6 induces the recruitment of Mφ and polarization toward the M2 phenotype ( Guo et al, 2017 ; Yang and Xing, 2021 ). Hypoxia leads to the expression of high-mobility group box 1 (HMGB1), which induces the infiltration of TAMs and an increase in IL-6 expression through HIF-1α ( Jiang et al, 2018 ).…”