ETV4 promotes pancreatic ductal adenocarcinoma metastasis through activation of the CXCL13/CXCR5 signaling axis
ETV4 promotes pancreatic ductal adenocarcinoma metastasis through activation of the CXCL13/CXCR5 signaling axis
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DOI：
10.1016/j.canlet.2021.09.026
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发表时间：
2021-10-19
期刊：
影响因子：
9.7
通讯作者：
Fan, Daiming
中科院分区：
文献类型：
--
作者：
Gao, Xiaoliang;Jiang, Mingzuo;Fan, Daiming
胰腺导管腺癌（PDAC）是所有实体瘤中死亡率最高的，在美国5年生存率仅为10%。PDAC的特征是早期转移。超过50%的患者在诊断时存在远处转移，并且大多数患者将在肿瘤切除后4年内发生转移。尽管广泛的研究，PDAC转移的分子机制仍然不清楚。多瘤增强子激活蛋白（PEA 3）亚家族在多种肿瘤的发生和发展中起重要作用。在此，我们发现ETS变体4（ETV 4）在PDAC组织中高度表达并且与较差的存活率相关。单因素和多因素分析显示ETV 4表达是患者生存的独立预后因素。进一步的实验表明，ETV 4过表达促进PDAC在体外和体内的侵袭和转移。这是我们第一次证明ETV 4通过直接结合CXCR 5启动子区域而增加CXCR 5表达的机制。敲低CXCR 5显著逆转ETV 4介导的PDAC迁移和侵袭，而CXCR 5过表达产生相反的作用。有趣的是，我们发现CXCL 13，CXCR 5的特异性配体，通过激活ERK 1/2途径增加ETV 4表达并促进PDAC侵袭和转移。ETV 4敲低显著消除了由CXCL 13/CXCR 5轴诱导的增强的迁移和侵袭能力。此外，CXCR 5中和抗体破坏了CXCL 13/ETV 4/CXCR 5正反馈循环并抑制细胞迁移和侵袭。总的来说，在这项研究中，我们证明了ETV 4在PDAC转移中起着至关重要的作用，并定义了一个新的CXCL 13/ETV 4/CXCR 5正反馈回路。靶向这一途径对PDAC治疗的潜在治疗策略具有意义。
Pancreatic ductal adenocarcinoma (PDAC) has the highest fatality rate of any solid tumor, with a five-year survival rate of only 10% in the USA. PDAC is characterized by early metastasis. More than 50% of patients present with distant metastases at the time of diagnosis, and the majority of patients will develop metastasis within 4 years after tumor resection. Despite extensive studies, the molecular mechanisms underlying PDAC metastasis remain unclear. The polyoma enhancer activator protein (PEA3) subfamily was reported to play a vital role in the initiation and progression of multiple tumors. Herein, we found that ETS variant 4 (ETV4) was highly expressed in PDAC tissues and associated with poor survival. Univariate and multivariate analyses revealed that ETV4 expression was an independent prognostic factor for patient survival. Further experiments showed that ETV4 overexpression promoted PDAC invasion and metastasis both in vitro and in vivo. For the first time, we demonstrated that, mechanistically, ETV4 increased CXCR5 expression by directly binding to the CXCR5 promoter region. Knockdown of CXCR5 significantly reversed ETV4-mediated PDAC migration and invasion, while CXCR5 overexpression exerted the opposite effects. Intriguingly, we found that CXCL13, a specific ligand of CXCR5, increased ETV4 expression and promoted PDAC invasion and metastasis by activating the ERK1/2 pathway. ETV4 knockdown significantly abrogated the enhanced migratory and invasive abilities induced by the CXCL13/CXCR5 axis. In addition, a CXCR5 neutralizing antibody disrupted the CXCL13/ETV4/ CXCR5 positive feedback loop and inhibited cell migration and invasion. Overall, in this study, we demonstrated that ETV4 plays a vital role in PDAC metastasis and defined a novel CXCL13/ETV4/CXCR5 positive feedback loop. Targeting this pathway has implications for potential therapeutic strategies for PDAC treatment.