The Atypical MAP Kinase MAPK15 Is Required for Lung Adenocarcinoma Metastasis via Its Interaction with NF-κB p50 Subunit and Transcriptional Regulation of Prostaglandin E2 Receptor EP3 Subtype.
The Atypical MAP Kinase MAPK15 Is Required for Lung Adenocarcinoma Metastasis via Its Interaction with NF-κB p50 Subunit and Transcriptional Regulation of Prostaglandin E2 Receptor EP3 Subtype.
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非典型 MAP 激酶 MAPK15 通过与 NF-κB p50 亚基的相互作用以及前列腺素 E2 受体 EP3 亚型的转录调节，是肺腺癌转移所必需的
作者：
由于肺癌缺乏有效的早期诊断标志物，肺部血液循环丰富，极易引起肺癌的淋巴结转移和远处转移，使肺癌成为世界上死亡率最高的十大癌症类型之一。本研究发现，MAPK15在肺腺癌淋巴结转移患者的组织中高表达，MAPK15与p50相互作用，在转录水平调控EP3的表达，从而促进癌细胞迁移。这说明MAPK15在肺癌细胞转移中起着关键作用，MAPK15可作为肺癌早期诊断或预后评估的分子标志物。其调控肺癌转移的分子机制可以在分子水平上为新的治疗方案提供有价值的信息和见解。研究相对未被充分开发的非典型MAP激酶MAPK15对癌症进展/患者预后的影响及其对下游基因的潜在转录调控，对于肺腺癌（LUAD）等恶性肿瘤的诊断、预后和潜在的肿瘤治疗具有重要价值。本研究采用免疫组织化学方法检测MAPK15在LUAD中的表达，并分析其与淋巴结转移、临床分期等临床参数的相关性。检测前列腺素E2受体EP3亚型（EP3）与LUAD组织中MAPK15表达的相关性，并采用荧光素酶报告基因法、免疫印迹法、qRT-PCR和transwell法研究MAPK15在LUAD细胞株中对EP3和细胞迁移的转录调控。我们发现MAPK15在伴有淋巴结转移的LUAD中高表达。此外，在LUAD组织中，EP3与MAPK15的表达呈正相关，我们证实了MAPK15通过转录调控EP3的表达。敲低MAPK15后，EP3的表达下调，细胞在体外的迁移能力下降；同样，在体内动物实验中，MAPK15敲低细胞的肠系膜转移能力也受到抑制。在机制上，我们首次证明MAPK15与NF-κB p50相互作用并进入细胞核，NF-κB p50结合EP3启动子并转录调节EP3的表达。综上所述，我们发现一种新的非典型MAPK和NF-κB亚基相互作用通过转录调节EP3促进LUAD细胞迁移，而较高的MAPK15水平与LUAD患者的淋巴结转移有关。
Simple Summary Due to the lack of effective early diagnostic markers for lung cancer and the rich blood circulation in the lungs, it is very easy to cause lymph node metastasis and distant metastasis of lung cancer, making lung cancer as one of the top ten cancer types with the highest mortality rate in the world. This study found that MAPK15 is highly expressed in the tissues of patients with lung adenocarcinoma lymph node metastasis, and MAPK15 interacts with p50 to regulate the expression of EP3 at the transcriptional level, thereby promoting cancer cell migration. This suggests that MAPK15 plays a key role in the metastasis of lung cancer cells, and MAPK15 can be used as a molecular marker for the early diagnosis or prognosis assessment of lung cancer. Its molecular mechanism for regulating lung cancer metastasis can provide valuable information and insights on novel therapeutic options at molecular levels. Abstract Studying the relatively underexplored atypical MAP Kinase MAPK15 on cancer progression/patient outcomes and its potential transcriptional regulation of downstream genes would be highly valuable for the diagnosis, prognosis, and potential oncotherapy of malignant tumors such as lung adenocarcinoma (LUAD). Here, the expression of MAPK15 in LUAD was detected by immunohistochemistry and its correlation with clinical parameters such as lymph node metastasis and clinical stage was analyzed. The correlation between the prostaglandin E2 receptor EP3 subtype (EP3) and MAPK15 expression in LUAD tissues was examined, and the transcriptional regulation of EP3 and cell migration by MAPK15 in LUAD cell lines were studied using the luciferase reporter assay, immunoblot analysis, qRT-PCR, and transwell assay. We found that MAPK15 is highly expressed in LUAD with lymph node metastasis. In addition, EP3 is positively correlated with the expression of MAPK15 in LUAD tissues, and we confirmed that MAPK15 transcriptionally regulates the expression of EP3. Upon the knockdown of MAPK15, the expression of EP3 was down-regulated and the cell migration ability was decreased in vitro; similarly, the mesenteric metastasis ability of the MAPK15 knockdown cells was inhibited in in vivo animal experiments. Mechanistically, we demonstrate for the first time that MAPK15 interacts with NF-κB p50 and enters the nucleus, and NF-κB p50 binds to the EP3 promoter and transcriptionally regulates the expression of EP3. Taken together, we show that a novel atypical MAPK and NF-κB subunit interaction promotes LUAD cell migration through transcriptional regulation of EP3, and higher MAPK15 level is associated with lymph node metastasis in patients with LUAD.
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