α7 nicotinic acetylcholine receptor in tumor-associated macrophages inhibits colorectal cancer metastasis through the JAK2/STAT3 signaling pathway

Abstract

Considerable evidence has implied that α7 nicotinic receptor subtypes play an important role in chronic inflammatory and neuropathic pain signaling. The aim of the present study was to determine the role of endogenous α7nAChR signaling in tumor-associated macrophages (TAMs) in human colorectal cancer (CRC) metastasis and prognosis. α7nAChR expression in primary tumor cells and adjacent stroma cells especially in TAMs in 51 CRC patients was observed. Using a human monocyte THP-derived macrophages (TMs) with α7nAChR-siRNA knockdown (TMα7−/−) and a CRC cell Transwell co-culture model, the migration and invasion of two CRC cells, LoVo and SW620, were determined. Western blotting was carried out to investigate the expression of multiple molecules involved in the NF-κB, STAT3, PI3K signaling pathways in mimic TAMs, i.e., TMs exposed to in-direct LoVo cell stimulation. A nicotinic α7 receptor antagonist [α-bungarotoxin (α-Btx)] and three pharmaceutical inhibitors: AG490 (JAK2/STAT3 inhibitor), LY294002 (PI3K inhibitor) and Bay 11–7082 (NF-κB inhibitor) were applied to evaluate whether these signaling pathways were associated with the enhanced migration of CRC cells when co-cultured with α7nAChR knockdown TMs. The results revealed that the expression of α7nAChR in TAMs differed in patients. However, CRC patients who had a high incidence of hepatic metastasis showed no or low expression of α7nAChR in TAMs. TMs with α7nAChR-siRNA knockdown (TMα7−/−) significantly enhanced the migration and invasion of the two CRC cell lines LoVo and SW620. α7nAChR knockdown in TMs significantly downregulated phosphorylation of STAT3, PI3K p85 and NF-κB p65 after co-culturing with LoVo cells. Inhibition of JAK2/STAT3 prevented the TMα7−/−-enhanced migration of LoVo cells. α7nAChR expressed in TAMs in human CRC patients plays an important role in preventing metastasis and could be a prognostic marker in CRCs, which may be regulated by the JAK2/STAT3 signaling pathway.

Emerging Role of Lymphocyte Antigen-6 Family of Genes in Cancer and Immune Cells

“…In the brain, activation of α7nAChR in macrophages inhibits production of inflammatory cytokines (63). In colorectal cancer, the activation of α7nAChR in tumor macrophages inhibits colorectal cancer metastasis through the JAK2/STAT3 signaling pathway (64). α7nAChR has been considered an important drug target for the inhibition of lung cancer (65).…”

Cryptotanshinone suppresses cell proliferation and glucose metabolism via STAT3/SIRT3 signaling pathway in ovarian cancer cells

“…STAT3 (signal transducer and activator of transcription 3) promotes multiple signaling pathways involving the mediation of cell proliferation, invasion, epithelial‐mesenchymal transition (EMT) and angiogenesis and has been considered as a key target for cancer therapy . Increasing evidence has shown the existence of genetic variation and amplification of STAT3 in major malignancies . STAT3 signaling pathway plays a vital role in cancer progression and tumor microenvironment, indicating that it may be used as a therapeutic target.…”

“…[17][18][19] Increasing evidence has shown the existence of genetic variation and amplification of STAT3 in major malignancies. [19][20][21][22] STAT3 signaling pathway plays a vital role in cancer progression and tumor microenvironment, 23,24 indicating that it may be used as a therapeutic target.…”

The Construction and Analysis of ceRNA Network and Patterns of Immune Infiltration in Colon Adenocarcinoma Metastasis

“…Infiltration of macrophages in the tumor stroma are negative prognostic factors in COAD (Waniczek et al, 2017). It has been confirmed that the α7 nicotinic acetylcholine receptor of tumor-associated macrophages could inhibit the metastasis of COAD through the JAK2/STAT3 signaling pathway (Fei et al, 2017). What's more, macrophages are critical factors in the process of liver metastasis of COAD (Zhou et al, 2010;Imano et al, 2011;Cui et al, 2013;Kee et al, 2014).…”