Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, And the Department of Physiology, Shanxi Medical University, Taiyuan, China; Department of Anesthesiology, Shanxi Provincial Peoples Hospital, Taiyuan, China
Lu-Zi Yang
Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, And the Department of Physiology, Shanxi Medical University, Taiyuan, China
Lan Zhou
Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, And the Department of Physiology, Shanxi Medical University, Taiyuan, China
Li-Juan Gao
Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, And the Department of Physiology, Shanxi Medical University, Taiyuan, China
Jia-Yi Hou
Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, And the Department of Physiology, Shanxi Medical University, Taiyuan, China
Zi Yan
Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, And the Department of Physiology, Shanxi Medical University, Taiyuan, China
Xiao-Gang Bi
Department of Anesthesiology, Shanxi Provincial Peoples Hospital, Taiyuan, China
Cai-Ping Yan
Center of Translational Medicine, Shanxi Medical University, Taiyuan, China
De-Ping Wang
Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, And the Department of Physiology, Shanxi Medical University, Taiyuan, China; Corresponding author.
Ji-Min Cao
Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, And the Department of Physiology, Shanxi Medical University, Taiyuan, China; Corresponding author.
Objective: This study aimed to address the status, role, and mechanism of sympathetic nerve infiltration in the progression of stomach adenocarcinoma (STAD). Methods: Sympathetic nerve and its neurotransmitter NE, β-ARs, and associated signaling molecules in the STAD tissues and the adjacent tissues from 46 STAD patients were examined using immunostaining, HPLC, and western blotting. The effects and mechanisms of β2-AR activation on the proliferation, migration and invasion of AGS and SGC-7901 gastric cancer (GC) cell lines were examined using CCK-8, transwell, and western blotting assays. Correlations between genes and STAD survival were analyzed using bioinformatics. Results: Striking sympathetic nerve infiltration, elevations of NGF, TrkA, GAP43, TH, S100, NE, β2-AR, YKL-40, syndecan-1, MMP9, CD206, and CD31 were observed in the STAD tissues compared to the adjacent tissues. Activation of β2-AR in the two GC cell lines significantly amplified the expressions of NGF, YKL-40, MMP9, syndecan-1, p-STAT3 and p-ERK, and increased GC cell proliferation, migration and invasion. Bioinformatic analyses revealed positive correlations of NGF, β2-AR, syndecan-1, and macrophage infiltration, respectively, with low survival of STAD, of β2-AR respectively with STAT3, ERK1/2 (MAPK1/3), YKL-40, MMP9, and syndecan-1, and of YKL-40 with MMP9. Conclusion: Sympathetic nerves significantly infiltrated into human STAD tissues as a result of high NGF and TrkA expressions; elevated NE led to overactivation of β2-AR-STAT3/ERK-YKL-40 signaling pathway, and finally caused cancer cell growth and invasion, M2 macrophage infiltration, angiogenesis, matrix degradation and STAD metastasis and progression.
