TLR2 promotes human intrahepatic cholangiocarcinoma cell migration and invasion by modulating NF-κB pathway-mediated inflammatory responses.
Intrahepatic cholangiocarcinoma (ICC) is a rare and aggressive malignancy that is often diagnosed at advanced stages, which limits treatment options. Despite its increasing incidence and mortality worldwide, the pathogenesis of ICC is not well understood. Here, we examined the effect of the dysregulation of innate immune responses on carcinogenesis by investigating the role of toll-like receptor (TLR)2 in the pathogenesis and invasiveness of ICC and explored the underlying mechanisms. Immunohistochemical analysis, real-time PCR, and western blotting showed higher TLR2 levels in ICC tissues and cell lines. Silencing and overexpression experiments indicated that TLR2 promotes ICC migration and invasion, induces the expression of epithelial-to-mesenchymal transition (EMT) markers, and upregulates the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β concomitant with the activation of NF-κB signaling. Inhibition of NF-κB activity abolished the effect of TLR2 on EMT, invasion and migration, and the TLR2-induced upregulation of proinflammatory cytokines, and suppressed the effect of exogenous TNF-α and IL-6 on restoring EMT, migration and invasion in the presence of TLR2. Taken together, our results indicate that TLR2 has protumorigenic and prometastatic effects in ICC through the upregulation of inflammatory cytokines induced by the activation of NF-κB signaling, suggesting potential novel therapeutic targets for the treatment of ICC.
Department of Interventional Radiology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, China.
Bingyan
B
Liu
Department of Interventional Radiology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, China.
Shuo
S
Yan
Department of Interventional Radiology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, China.
Yiping
Y
Jia
Department of Interventional Radiology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, China.
Jun
J
Ma
Department of Interventional Radiology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, China.
Shaoqiu
S
Wu
Department of Interventional Radiology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, China.
Yuyao
Y
Xu
Department of Interventional Radiology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, China. doctorshangmy@126.com.
Mingyi
M
Shang
Department of Interventional Radiology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, China. doctormaoaw@126.com.
Aiwu
A
Mao
D001650:Bile Duct Neoplasms / Q000276:immunology* / Q000473:pathology*; D001653:Bile Ducts, Intrahepatic / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D018281:Cholangiocarcinoma / Q000276:immunology* / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2
NF-κB signaling; epithelial-to-mesenchymal transition; intrahepatic cholangiocarcinoma; invasion and migration; toll-like receptor 2