垂体泌乳素腺瘤首选药物如卡麦角林（CAB）治疗。我们最近对CAB的作用机制研究表明，CAB诱导细胞发生自噬和自噬依赖的细胞死亡，敲低ATG7能增加CAB治疗的耐药性。我们前期还针对敏感和耐药泌乳素腺瘤进行芯片检测，发现长链非编码RNA-H19在敏感中高表达；敲低H19使肿瘤细胞对CAB的耐药性增加，而过表达H19则敏感性增加。进一步发现，H19能调控ATG7的蛋白降解，而对mRNA水平没有影响。由此提出设想：H19绑定ATG7，阻止其蛋白的泛素化降解，从而增加药物治疗的敏感性。本课题后续将采用RNA pull down等技术，证明两者直接结合；同时寻找ATG7特定的E3泛素化连接酶，进而验证其功能；构建条件性H19敲除的转基因鼠模型，在体水平验证药物治疗效果；最后检测患者血液中H19水平作为判断药物治疗敏感性的生物标志物。本课题将从lncRNA的角度全新阐释泌乳素腺瘤药物治疗敏感性的机制。

Cabergoline is the first-line therapy of prolactinomas. Our recent study indicates that cabergoline induces autophagy of pituitary tumor cells, and finally results in autophagy-dependent cell death. Knockdown of ATG7 rescues cabergoline-mediated cell death and then increases the resistance of pituitary tumor to cabergoline treatment. In addition, according to the microarray results of sensitive- and resistant- prolactinomas, we find that expression of long non-coding RNA (lncRNA)-H19 in sensitive prolactinomas is higher than that in resistant prolactinomas. Knockdown of H19 obviously increases the resistance of pituitary tumor cells to cabergoline treatment, conversely, overexpression of H19 increases the sensitivity to cabergoline. Furthermore, H19 regulates the protein level of ATG7 without the change of ATG7 mRNA level. Therefore, we put forward our hypothesis that H19 possibly binds ATG7, blocks the ubiquitin degradation of ATG7 protein, and increases the sensitivity of tumor cell to cabergoline treatment. In order to further confirm our hypothesis, we need to investigate: ① the direct combination of H19 and ATG7 using the technique of RNA pull down; ② the possible ATG7-specific E3 ubiquitin ligase and the function of E3 ubiquitin ligase; ③ the in vivo effect of cabergoline treatment using transgenic mice with H19 knockout; ④ the serum H19 level of patients with prolactinoma, whether H19 is a sensitivity biomarker of prolactinomas to cabergoline treatment. This study from the angle of lncRNA blocking ATG protein ubiquitin will give us insight into the novel mechanism of CAB treatment to prolactinomas. If successful, the findings from this study provide us a new avenue for treatment of clinical dopamine-resistant prolactinomas, which has far-reaching clinical significance and academic value.