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

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.