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.

中文翻译：

---

Neuregulin 4 (Nrg4) 与褪黑激素配合，通过 ErbB4/Erk 信号通路调节 PRL 表达，作为潜在的催乳素 (PRL) 调节剂

神经调节蛋白-4 (Nrg4) 和褪黑激素在内分泌疾病中发挥着重要作用。然而，关于Nrg4和褪黑激素在催乳素（PRL）调节中的功能和潜在机制的讨论却很少。使用基因表达谱交互分析（GEPIA）数据库中的人类正常垂体数据来探讨NRG4和PRL之间的相关性。通过免疫荧光染色（IF）和人正常垂体组织微阵列测定NRG4和PRL的表达和相关性。采用Western Blot（WB）检测PRL分泌垂体GH3和PRL、p-ErbB2/3/4、ErbB2/3/4、p-Erk1/2、Erk1/2、p-Akt和Akt的表达。用 Nrg4、Nrg4-小干扰 RNA、Erk1/2 抑制剂 FR180204 和褪黑激素处理的 RC-4B/C 细胞。GEPIA数据库和正常人垂体组织中NRG4的表达与PRL的表达呈显着正相关。Nrg4 显着增加 GH3 细胞和 RC-4B/C 细胞中 PRL 的表达和分泌以及 p-Erk1/2 的表达。抑制 Nrg4 可显着抑制 PRL 表达。在 GH3 和 RC-4B/C 细胞中，响应 FR180204，Nrg4 诱导的 p-Erk1/2 和 PRL 水平升高被显着消除。此外，褪黑素还能促进Nrg4、p-ErbB4、p-Erk1/2和PRL的表达，并且与Nrg4结合可以进一步促进p-Erk1/2和PRL的表达。进一步研究Nrg4和褪黑激素对PRL表达和分泌的作用可能为推进泌乳素瘤和高泌乳素血症的临床控制提供新的线索。