LPAR2-mediated action promotes human renal cell carcinoma via MAPK/NF-κB signaling to regulate cytokine network
LPAR2-mediated action promotes human renal cell carcinoma via MAPK/NF-κB signaling to regulate cytokine network
复制标题
LPAR2 介导的作用通过 MAPK/NF-κB 信号传导调节细胞因子网络促进人肾细胞癌
DOI：
10.1007/s00432-022-04197-6
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发表时间：
2022-07-20
影响因子：
3.6
通讯作者：
Damirin，Alatangaole
中科院分区：
文献类型：
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作者：
Wang，Yuewu;Qi，Zhimin;Damirin，Alatangaole
目的溶血磷脂酸 (LPA) 通过激活其独特的 G 蛋白偶联 LPA 受体来发挥各种生理和病理作用。我们证明LPA可以增加肾癌细胞的迁移和增殖。同时，LPAR1和LPAR2优先在肾癌（RC）细胞系中表达。因此，本研究旨在确定参与LPA诱导作用的LPA受体亚型，以及它们是否可以作为肾癌的精准治疗靶点。方法采用生物学方法结合大数据分析来证明LPAR2在肾癌进展中的作用。结果我们发现，在LPAR2过表达的肾癌细胞中，响应LPA的增殖、克隆形成和迁移增强，而细胞中的LPAR2拮抗剂抑制了这些作用。基于生物信息学分析和临床组织微阵列分析，LPAR2 还显示出对肾癌的临床诊断和预后价值。体内研究表明，LPAR2（过表达细胞）衍生的实体瘤中的肿瘤生长和转移显着增加。 LPA 刺激 MAPK 和 NF-κB 激活，而 LPA 诱导的作用分别被 MAPK 和 NF-κB 抑制剂抑制。随后，转录组结果显示，LPAR2 强烈影响细胞因子的产生，并且使用 Kit 检测再次证实了 IL6、CXCL8 和 TNF 的增加。结论我们已经确定，LPAR2 对于 LPA 促进的肾癌进展至关重要，其作用主要依赖于 MAPK 和 NF-κB 激活机制。然后，NF-κB 激活的炎症因子的表达也被怀疑参与了 LPAR2 介导的癌发生。因此，LPAR2可能是肾癌有前途的治疗靶点。
PurposeLysophosphatidic acid (LPA) exerts various physiological and pathological effects by activating its distinct G-protein-coupled LPA receptors. We demonstrated that LPA can increase the migration and proliferation of renal carcinoma cells. Meanwhile, LPAR1 and LPAR2 were preferentially expressed in renal cancer (RC) cell lines. So, the study aimed to determine the LPA receptor subtypes involved in LPA-induced actions and whether they could be used as a precision therapeutic target for renal cancer.MethodsBiological approaches combined with big data analysis were used to demonstrate the role of LPAR2 in the progression of renal cancer.ResultsWe found that the proliferation, clone formation, and migration in response to LPA were enhanced in LPAR2-overexpressing renal cancer cells, whereas, the actions were suppressed by LPAR2 antagonist in the cells. LPAR2 has also shown clinical diagnostic and prognostic value in renal carcinoma based on bioinformatics analysis and clinical tissue microarray analysis. In vivo study shown that tumor growth and metastasis were significantly increased in the LPAR2—overexpressing cells—derived solid tumors. LPA stimulated MAPK and NF-κB activation, and LPA-induced actions were inhibited by MAPKs and NF-κB inhibitors, respectively. Subsequently, the transcriptomic results revealed that LPAR2 strongly affected the cytokines production, and the increased IL6, CXCL8, and TNF were confirmed again using Kit assay.ConclusionsWe have identified that LPAR2 is critical for LPA-promoted renal cancer progression, and the actions mainly dependent the MAPK and NF-κB activation mechanism. Then, the expression of inflammatory factors activated by NF-κB is also suspected to be involved in LPAR2-mediated carcinogenesis. Thus, LPAR2 may be a promising therapeutic target for renal cancer.