IGFBP2/Her-2/GPX1通路在胆汁酸上调食管腺癌活性氧过程中的作用机制

胆汁酸反流在胃食管反流病-Barrett’s食管-食管腺癌发生发展过程起关键作用，其诱导的活性氧是影响食管腺癌发展的重要因素，但调控机制仍不明确。我们研究发现：胆汁酸可诱导食管腺癌活性氧上调、引起DNA损伤及细胞凋亡；IGFBP2在食管腺癌高表达且被胆汁酸上调，抑制了胆汁酸诱导的活性氧、DNA损伤及细胞凋亡，机制不明；沉默IGFBP2抑制了胆汁酸诱导的Her-2核转运；IGFBP2与GPX1表达呈正相关，沉默GPX1增加了胆汁酸诱导的活性氧。我们推测：胆汁酸促进IGFBP2的转录翻译，后者与Her-2形成转录复合物介导GPX1上调，降低了细胞内活性氧。我们拟通过食管腺癌细胞、IGFBP2-/-小鼠的胃食管反流-腺癌模型，利用CRISPR/Cas9等技术对猜想进行验证，阐明IGFBP2调控胆汁酸诱导活性氧的具体机制及其在食管腺癌发生发展中的作用，从氧化应激的角度，为食管腺癌治疗提供理论基础。

Bile acid reflux plays a key role in the development of gastroesophageal reflux disease, Barrett's esophagus, and esophageal adenocarcinoma sequence. Reactive oxygen species (ROS) induced by bile acid are noted in the development of esophageal adenocarcinoma, but the regulatory mechanism is still unclear. Our study revealed that bile acid could induce ROS, DNA damage and apoptosis in esophageal adenocarcinoma; IGFBP2 was highly expressed in esophageal adenocarcinoma and up-regulated by bile acid, and inhibited bile acid-induced ROS, DNA damage and apoptosis; silencing IGFBP2 inhibited bile acid-induced Her-2 nuclear transport; IGFBP2 was positively correlated with GPX1 expression, and silencing GPX1 increased bile acid-induced ROS. We hypothesize that bile acid promotes the transcription and translation of IGFBP2, which forms a transcription complex with Her-2, and mediates the upregulation of GPX1, thus reducing the intracellular ROS. We plan mimic gastroesophageal reflux condition on cells, IGFBP2-/- mice model to verify the above hypothesis by utilizing CRISPR/Cas9 and other technologies. We aim to clarify the specific mechanism of IGFBP2 in regulating bile acid-induced ROS and its role in the occurrence and development of esophageal adenocarcinoma, which may provide a theoretical basis for the treatment of esophageal adenocarcinoma from the perspective of oxidative stress.