Depression accelerates gastric cancer invasion and metastasis by inducing a neuroendocrine phenotype via the catecholamine/β_(2)-AR/MACC1 axis  

作　　者：Changqie Pan Jianhua Wu Siting Zheng Huiying Sun Yisheng Fang Zhenhua Huang Min Shi Li Liang Jianping Bin Yulin Liao Jinzhang Chen Wangjun Liao 

机构地区：[1]Department of Oncology,Nanfang Hospital,Southern Medical University,Guangzhou,Guangdong 510515,P.R.China [2]Department of Pathology,Nanfang Hospital,Southern Medical University,Guangzhou,Guangdong 510515,P.R.China [3]Department of Cardiology,Nanfang Hospital,Sout4hern Medical University,Guangzhou,Guangdong 510515,P.R.China

出　　处：《Cancer Communications》2021年第10期1049-1070,共22页癌症通讯（英文）

摘　　要：Background:Depression is a common,easily ignored,accompanied disease of gastric cancer(GC)patients and is often observed with elevated plasma catecholamine levels.Depression frequently promotes GC progression and leads to poor clinical outcomes;however,the molecular mechanisms underlying depression-induced GC progression remain poorly understood.We aimed to study the effects of depression on GC progression and explore possible mechanisms mediating the action of depression-associated catecholamines on GC.Methods:Depression states of GC patients were graded using the Patient Health Questionnaire-9,and plasma catecholamine levels were examined by high performance liquid chromatography coupled with tandem mass spectrometry.Migrative and invasive GC cells were examined using transwell assays,and metastatic GC niches were imaged using bioluminescence technology in a depression mouse model established with chronic unpredictable mild stress.Mouse depression-like behaviors were assessed through sucrose preference,forced swimming,and tail suspension tests.Characteristics of the neuroendocrine phenotype were observed via RT-PCR,Western blotting,flow cytometry,and transmission electron microscopy.Results:Fifty-one GC patients(age:53.61±1.79 years;cancer duration:3.71±0.33 months;depression duration:2.37±0.38 months;male-to-female ratio:1.55:1)were enrolled in the study.Depression grade was significantly higher in GC patients showing higher plasma levels of catecholamines(epinephrine:P=0.018;noradrenaline:P=0.009),higher oncogene metastasis-associated in colon cancer-1(MACC1)level(P=0.018),and metastasis(P<0.001).Further,depression-associated catecholamine specifically bound to the beta-2 adrenergic receptor(β_(2)-AR)and upregulated MACC1 expression,and thus promoting neuroendocrine phenotypic transformation through direct binding betweenMACC1 and synaptophysin.Eventually,the neuroendocrine phenotypic transformation accelerated GC invasion in vitro and metastasis in vivo.However,β_(2)-AR antagonist ICI-118,551 or MACC1 s

关 键 词：CATECHOLAMINES DEPRESSION gastric cancer MACC1 neuroendocrine phenotype psychological stress tumor metastasis 

分 类 号：R73[医药卫生—肿瘤]