Abstract
Aberrant substance P/neurokinin‐1 receptor (SP/NK‐1R) system activation plays a critical role in various disorders, however, little is known about the expression and the detailed molecular mechanism of the SP and NK‐1R in gallbladder cancer (GBC). In this study, we firstly analyzed the expression and clinical significance of them in patients with GBC. Then, cellular assays were performed to clarify their biological role in GBC cells. Moreover, we investigated the molecular mechanisms regulated by SP/NK‐1R. Meanwhile, mice xenografted with human GBC cells were analyzed regarding the effects of SP/NK1R complex in vivo. Finally, patient samples were utilized to investigate the effect of SP/NK‐1R. The results showed that SP and NK‐1R were highly expressed in GBC. We found that SP strongly induced GBC cell proliferation, clone formation, migration and invasion, whereas antagonizing NK‐1R resulted in the opposite effects. Moreover, SP significantly enhanced the expression of NF‐κB p65 and the tumor‐associated cytokines, while, Akt inhibitor could reverse these effects. Further studies indicated that decreasing activation of NF‐κB or Akt diminished GBC cell proliferation and migration. In consistent with results, immunohistochemical staining showed high levels of Akt, NF‐κB and cytokines in tumor tissues. Most importantly, the similar conclusion was obtained in xenograft mouse model. Our findings demonstrate that NK‐1R, after binding with the endogenous agonist SP, could induce GBC cell migration and spreading via modulation of Akt/NF‐κB pathway.
Highlights
Gallbladder cancer (GBC) is a rare and high lethal cancer that dif‐ fers from others involving the gastrointestinal tract, as being three times more common in women than men.[1]
Our results showed that SP and Neurokinin‐1 receptor (NK‐1R) were expressed at high protein levels in GBC tumor samples
We observed that NK‐1R could signifi‐ cantly increase the activity of NF‐κB throuth up‐regulating Akt
Summary
Gallbladder cancer (GBC) is a rare and high lethal cancer that dif‐ fers from others involving the gastrointestinal tract, as being three times more common in women than men.[1]. Hu et al find that the phosphorylation of Akt could be regulated to promote GBC cell growth, metastasis and epithelial‐mesenchymal transition (EMT).[19] In recent evidences indicate the occurrence of Akt hy‐ peractivation can significantly influence its downstream effectors, such as NF‐κB, which mediates cell survival and proliferation.[20,21] Researchers find that Akt transiently binds to the inhibitor of kappa B kinase (IKKα) and induces IKK activation, which in turn allows NF‐κB to translocate to the nucleus and trigger expression of tar‐ get genes.[22] it is found that inactivation of Akt could prevent the progression of breast cancer by block the NF‐κB path‐ way.[23] In another study, Akt/NF‐κB signaling is important for the oncogenic effect of cell cycle regulating genes in esophageal squa‐ mous cell carcinoma tissue.[24] the expression and func‐ tional role of SP/NK‐1R in GBC remain unknown. We examined the effects of SP/NK‐1R and explored the potential therapeutic function on human GBC
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