AGTR1 promotes lymph node metastasis in breast cancer by upregulating CXCR4/SDF-1α and inducing cell migration and invasion
AGTR1 promotes lymph node metastasis in breast cancer by upregulating CXCR4/SDF-1α and inducing cell migration and invasion
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AGTR1通过上调CXCR4/SDF-1α诱导细胞迁移和侵袭促进乳腺癌淋巴结转移
DOI：
10.18632/aging.102032
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发表时间：
2019-06-30
期刊：
影响因子：
5.2
通讯作者：
Zhao, Yanxia
中科院分区：
文献类型：
--
作者：
Ma, Yuxi;Xia, Zihan;Zhao, Yanxia
血管紧张素II型受体（AGTR1）对肿瘤生长、血管生成、炎症和免疫有重要影响。然而，AGTR1在乳腺癌淋巴结转移（LNM）中的作用，与肿瘤进展和患者生存相关，尚未得到研究。Oncomine数据库证实，AGTR1在淋巴结阳性肿瘤组织中高表达。其次，通过生物发光成像（BLI），抑制AGTR1可以降低原位异种移植物的肿瘤生长和LNM。氯沙坦是一种agtr1特异性抑制剂，在体内可降低趋化因子对CXCR4/SDF-1 α的水平，并在体外抑制agtr1诱导的细胞迁移和侵袭。最后，通过下调正常细胞中的AGTR1或AGTR1（高）细胞中的CXCR4来评估AGTR1诱导细胞迁移和LNM的分子机制。经氯沙坦处理的agtr1沉默细胞显示较低的CXCR4表达。AGTR1过表达导致FAK/RhoA信号分子上调，而在AGTR1（高）细胞中敲低CXCR4则下调这些分子。总的来说，AGTR1通过增加趋化因子对CXCR4/SDF-1 α和肿瘤细胞的迁移和侵袭来促进LNM。agtr1介导的细胞运动的潜在机制依赖于激活FAK/RhoA通路。我们的研究表明，抑制AGTR1可能是早期乳腺癌LNM的潜在治疗靶点。
The angiotensin II type I receptor (AGTR1) has a strong influence on tumor growth, angiogenesis, inflammation and immunity. However, the role of AGTR1 on lymph node metastasis (LNM) in breast cancer, which correlates with tumor progression and patient survival, has not been examined. AGTR1 was highly expressed in lymph node-positive tumor tissues, which was confirmed by the Oncomine database. Next, inhibition of AGTR1 reduced tumor growth and LNM in orthotopic xenografts by bioluminescence imaging (BLI). Losartan, an AGTR1-specific inhibitor, decreased the chemokine pair CXCR4/SDF-1 alpha levels in vivo and inhibited AGTR1-induced cell migration and invasion in vitro. Finally, the molecular mechanism of AGTR1-induced cell migration and LNM was assessed by knocking down AGTR1 in normal cells or CXCR4 in AGTR1(high )cells. AGTR1-silenced cells treated with losartan showed lower CXCR4 expression. AGTR1 overexpression caused the upregulation of FAK/RhoA signaling molecules, while knocking down CXCR4 in AGTR1(high) cells downregulated these molecules. Collectively, AGTR1 promotes LNM by increasing the chemokine pair CXCR4/SDF-1 alpha and tumor cell migration and invasion. The potential mechanism of AGTR1-mediated cell movement relies on activating the FAK/RhoA pathway. Our study indicated that inhibiting AGTR1 may be a potential therapeutic target for LNM in early-stage breast cancer.