Chronic stress promotes gastric cancer progression and metastasis: an essential role for ADRB2
Chronic stress promotes gastric cancer progression and metastasis: an essential role for ADRB2
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慢性应激促进胃癌进展和转移：ADRB2的重要作用
DOI：
10.1038/s41419-019-2030-2
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发表时间：
2019-10-17
影响因子：
9
通讯作者：
Xu, Zekuan
中科院分区：
文献类型：
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作者：
Zhang, Xuan;Zhang, Yi;Xu, Zekuan
越来越多的研究表明，肾上腺素能信号在慢性应激诱导的肿瘤进展和转移中起着重要作用。然而，其在胃癌（GC）中的功能及其潜在机制仍不清楚。采用实时荧光定量PCR（RT-PCR）和Western blotting方法检测胃癌细胞β肾上腺素能受体（ADRB）的表达水平。采用体外细胞增殖、迁移、侵袭、细胞周期和凋亡等方法，研究了β2肾上腺素能受体（ADRB 2）激活和阻断对胃癌细胞增殖、迁移、侵袭、细胞周期和凋亡的影响。慢性束缚应激（CRS）可增加血浆中的儿茶酚胺和皮质醇水平，并可诱导体内GC的进展和转移。此外，免疫组化染色和TUNEL法检测细胞活力的调节。采用RT-PCR和免疫组化方法检测100例胃癌组织中ADRB 2的表达水平。应激激素肾上腺素和去甲肾上腺素显着加速GC细胞的增殖，侵袭和活力的文化，以及在体内肿瘤的生长。这些作用被ADRB拮抗剂普萘洛尔和ICI 118，551（ADRB 2特异性拮抗剂）逆转。此外，选择性ADRB 1拮抗剂阿替洛尔在体外和体内对肿瘤细胞增殖和侵袭几乎没有影响。ADRB 2拮抗剂通过抑制ERK 1/2-JNK-MAPK通路和转录因子NF-κB、AP-1、CREB和STAT 3等抑制细胞增殖、侵袭和转移。使用GC细胞的异种移植模型的分析显示，ADRB 2拮抗剂显着抑制肿瘤生长和转移，和慢性应激拮抗这些抑制作用。此外，慢性应激增加了移植瘤组织中VEGF、MMP-2、MMP-7和MMP-9的表达，并且儿茶酚胺类激素增强了转移相关蛋白的表达。ADRB 2在胃癌组织中表达上调，且与胃癌大小、组织学分级、淋巴结转移和临床分期呈正相关。应激诱导的ADRB 2信号通路的激活在GC进展和转移中起着至关重要的作用。这些发现表明ADRB 2信号传导调节GC进展，并表明β2阻断是一种补充现有GC治疗的新策略。
An increasing number of studies indicate that adrenergic signalling plays a fundamental role in chronic stress-induced tumour progression and metastasis. However, its function in gastric cancer (GC) and its potential mechanisms remain unknown. The expression levels of β-adrenergic receptor (ADRB) in GC cell lines were examined by using real-time polymerase chain reaction (RT-PCR) and western blotting. The effects of β2 adrenergic receptor (ADRB2) activation and blockade 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 progression and metastasis of GC in vivo. Furthermore, immunohistochemical staining and a TUNEL assay were employed to observe the regulation of cell viability in vivo. The expression levels of ADRB2 in 100 human GC samples were measured by RT-PCR and immunohistochemistry. The stress hormones epinephrine and norepinephrine significantly accelerated GC cell proliferation, invasion and viability in culture, as well as tumour growth in vivo. These effects were reversed by the ADRB antagonists propranolol and ICI118,551 (an ADRB2-specific antagonist). Moreover, the selective ADRB1 antagonist atenolol had almost no effect on tumour cell proliferation and invasion in vitro and in vivo. ADRB2 antagonists suppressed 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 antagonists significantly 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, and catecholamine hormones enhanced the expression of metastasis-related proteins. The expression of ADRB2 was upregulated in tumour tissues and positively correlated with tumour size, histological grade, lymph node metastasis and clinical stage in human GC samples. Stress hormone-induced activation of the ADRB2 signalling pathway plays a crucial role in GC progression and metastasis. These findings indicate that ADRB2 signalling regulates GC progression and suggest β2 blockade as a novel strategy to complement existing therapies for GC.