慢性应激促进胃癌进展和转移：ADRB2 的重要作用。,Cell Death & Disease

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慢性应激促进胃癌进展和转移：ADRB2 的重要作用。
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-10-17 , DOI: 10.1038/s41419-019-2030-2
Xuan Zhang _{1,

2} , Yi Zhang _{2,

3} , Zhongyuan He ₂ , Kai Yin ₄ , Bowen Li ₂ , Lu Zhang ₂ , Zekuan Xu ₂

Affiliation

越来越多的研究表明，肾上腺素信号在慢性应激诱导的肿瘤进展和转移中发挥着重要作用。然而，其在胃癌（GC）中的功能及其潜在机制仍不清楚。使用实时聚合酶链反应（RT-PCR）和蛋白质印迹法检测GC细胞系中β-肾上腺素能受体（ADRB）的表达水平。通过增殖、迁移、侵袭、细胞周期和凋亡测定，体外研究了 GC 细胞中 β2 肾上腺素受体 (ADRB2) 激活和阻断的影响。慢性束缚应激（CRS）会增加儿茶酚胺和皮质醇的血浆水平，并诱导体内GC的进展和转移。此外，采用免疫组织化学染色和TUNEL测定来观察体内细胞活力的调节。通过RT-PCR和免疫组织化学检测100份人类GC样本中ADRB2的表达水平。应激激素肾上腺素和去甲肾上腺素显着加速培养物中GC细胞的增殖、侵袭和活力，以及体内肿瘤的生长。ADRB 拮抗剂普萘洛尔和 ICI118,551（ADRB2 特异性拮抗剂）可逆转这些作用。而且，选择性ADRB1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。ADRB2 拮抗剂通过抑制 ERK1/2-JNK-MAPK 通路和转录因子（如 NF-κB、AP-1、CREB 和 STAT3）来抑制增殖、侵袭和转移。使用GC细胞对异种移植模型的分析表明，ADRB2拮抗剂显着抑制肿瘤生长和转移，而慢性应激会拮抗这些抑制作用。此外，慢性应激使移植肿瘤组织中VEGF、MMP-2、MMP-7和MMP-9的表达增加，儿茶酚胺激素增强转移相关蛋白的表达。在人GC样本中，ADRB2在肿瘤组织中表达上调，并与肿瘤大小、组织学分级、淋巴结转移和临床分期呈正相关。应激激素诱导的 ADRB2 信号通路激活在 GC 进展和转移中发挥着至关重要的作用。这些发现表明 ADRB2 信号传导调节 GC 进展，并表明 β2 阻断可作为补充现有 GC 疗法的新策略。

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Chronic stress promotes gastric cancer progression and metastasis: an essential role for ADRB2.

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.

更新日期：2019-10-17

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