SP/NK‐1R promotes gallbladder cancer cell proliferation and migration

• Published in: Journal of cellular and molecular medicine Vol. 23; no. 12; pp. 7961 - 7973
• Main Authors: Deng, Xue‐Ting, Tang, Si‐Min, Wu, Pei‐Yao, Li, Quan‐Peng, Ge, Xian‐Xiu, Xu, Bo‐Ming, Wang, Hui‐Shan, Miao, Lin
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.12.2019; John Wiley and Sons Inc
• Subjects: Activation; Akt; AKT protein; Animals; Apoptosis; Cancer; Cell cycle; Cell growth; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Cell Movement - genetics; Cell proliferation; Cell Proliferation - drug effects; Cell Proliferation - genetics; Cytokines; Gallbladder; Gallbladder cancer; Gallbladder Neoplasms - genetics; Gallbladder Neoplasms - metabolism; Humans; Interleukin-1beta - metabolism; Interleukin-6 - metabolism; Kinases; Matrix Metalloproteinase 9 - metabolism; Medical prognosis; Medical research; Metastasis; Mice; Mice, Nude; Molecular modelling; Neurokinin; NF‐κB; NK‑1R; Original; Phosphorylation; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Receptors, Neurokinin-1 - genetics; Receptors, Neurokinin-1 - metabolism; RNA, Small Interfering; Signal Transduction - drug effects; Signal Transduction - genetics; Studies; Substance P; Substance P - pharmacology; Transcription Factor RelA - metabolism; Transplantation, Heterologous; Tumor Necrosis Factor-alpha - metabolism; Tumorigenesis; Xenografts; United States > US; China; NF-κB; gallbladder cancer; Akt; NK-1R; substance P
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.14230

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.