An increasing number of studies indicate that adrenergic signalling plays a fundamental role in chronic stress-inducedtumour progression and metastasis. However, its function in gastric cancer (GC) and its potential mechanisms remainunknown. The expression levels of β-adrenergic receptor (ADRB) in GC cell lines were examined by using real-timepolymerase chain reaction (RT-PCR) and western blotting. The effects of β2 adrenergic receptor (ADRB2) activation andblockade were investigated in vitro in GC cells by using proliferation, migration, invasion, cell cycle and apoptosis assays.Chronic restraint stress (CRS) increased the plasma levels of catecholamines and cortisol and also induced progressionand metastasis of GC in vivo. Furthermore, immunohistochemical staining and a TUNEL assay were employed to observethe regulation of cell viability in vivo. The expression levels of ADRB2 in 100 human GC samples were measured by RTPCR and immunohistochemistry. The stress hormones epinephrine and norepinephrine significantly accelerated GC cellproliferation, invasion and viability in culture, as well as tumour growth in vivo. These effects were reversed by the ADRBantagonists propranolol and ICI118,551 (an ADRB2-specific antagonist). Moreover, the selective ADRB1 antagonistatenolol had almost no effect on tumour cell proliferation and invasion in vitro and in vivo. ADRB2 antagonistssuppressed proliferation, invasion and metastasis by inhibiting the ERK1/2-JNK-MAPK pathway and transcription factors,such as NF-κB, AP-1, CREB and STAT3. Analysis of xenograft models using GC cells revealed that ADRB2 antagonistssignificantly inhibited tumour growth and metastasis, and chronic stress antagonized these inhibitory effects. In addition,chronic stress increased the expression of VEGF, MMP-2, MMP-7 and MMP-9 in transplanted tumour tissue, andcatecholamine hormones enhanced the expression of metastasis-related proteins. The expression of ADRB2 wasupregulated in tumour tissues and positively correlated with tumour size, histological grade, lymph node metastasis andclinical stage in human GC samples. Stress hormone-induced activation of the ADRB2 signalling pathway plays a crucialrole in GC progression and metastasis. These findings indicate that ADRB2 signalling regulates GC progression andsuggest β2 blockade as a novel strategy to complement existing therapies for GC.
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