Lin Wen-Wen, Ou Guan-Yong, Dai Hui-Fang, Zhao Wei-Jiang
Department of Pathology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China.
School of Medicine, Southern University of Science and Technology, Shenzhen, China.
J Cell Biochem. 2024 May;125(5):e30551. doi: 10.1002/jcb.30551. Epub 2024 Mar 11.
Neuregulin-4 (Nrg4) and melatonin play vital roles in endocrine diseases. However, there is little discussion about the function and potential mechanism of Nrg4 and melatonin in prolactin (PRL) regulation. The human normal pituitary data from Gene Expression Profiling Interactive Analysis (GEPIA) database was used to explore the correlation between NRG4 and PRL. The expression and correlation of NRG4 and PRL were determined by Immunofluorescence staining (IF) and human normal pituitary tissue microarray. Western Blot (WB) was used to detect the expression of PRL, p-ErbB2/3/4, ErbB2/3/4, p-Erk1/2, Erk1/2, p-Akt and Akt in PRL-secreting pituitary GH3 and RC-4B/C cells treated by Nrg4, Nrg4-small interfering RNA, Erk1/2 inhibitor FR180204 and melatonin. The expression of NRG4 was significantly positively correlated with that of PRL in the GEPIA database and normal human pituitary tissues. Nrg4 significantly increased the expression and secretion of PRL and p-Erk1/2 expression in GH3 cells and RC-4B/C cells. Inhibition of Nrg4 significantly inhibited PRL expression. The increased levels of p-Erk1/2 and PRL induced by Nrg4 were abolished significantly in response to FR180204 in GH3 and RC-4B/C cells. Additionally, Melatonin promotes the expression of Nrg4, p-ErbB4, p-Erk1/2, and PRL and can further promote the expression of p-Erk1/2 and PRL in combination with Nrg4. Further investigation into the function of Nrg4 and melatonin on PRL expression and secretion may provide new clues to advance the clinical control of prolactinomas and hyperprolactinemia.
神经调节蛋白4（Nrg4）和褪黑素在内分泌疾病中发挥着重要作用。然而，关于Nrg4和褪黑素在催乳素（PRL）调节中的功能及潜在机制的讨论较少。利用基因表达谱交互式分析（GEPIA）数据库中的人类正常垂体数据来探究NRG4与PRL之间的相关性。通过免疫荧光染色（IF）和人类正常垂体组织芯片确定NRG4和PRL的表达及相关性。采用蛋白质免疫印迹法（WB）检测经Nrg4、Nrg4小干扰RNA、细胞外信号调节激酶1/2（Erk1/2）抑制剂FR180204和褪黑素处理的分泌PRL的垂体GH3和RC-4B/C细胞中PRL、磷酸化ErbB2/3/4、ErbB2/3/4、磷酸化Erk1/2、Erk1/2、磷酸化蛋白激酶B（Akt）和Akt的表达。在GEPIA数据库和正常人垂体组织中，NRG4的表达与PRL的表达显著正相关。Nrg4显著增加了GH3细胞和RC-4B/C细胞中PRL的表达和分泌以及磷酸化Erk1/2的表达。抑制Nrg4可显著抑制PRL的表达。在GH3和RC-4B/C细胞中，FR180204可显著消除Nrg4诱导的磷酸化Erk1/2和PRL水平的升高。此外，褪黑素可促进Nrg4、磷酸化ErbB4、磷酸化Erk1/2和PRL的表达，并且与Nrg4联合使用时可进一步促进磷酸化Erk1/2和PRL的表达。对Nrg4和褪黑素在PRL表达和分泌方面功能的进一步研究可能为推进催乳素瘤和高催乳素血症的临床控制提供新线索。
