lncRNA316686对NGFR的调控机制研究

The cause of dopamine agonist-resistant prolactinomas is primarily due to a decrease in D2R and NGFR on tumor cell surface. Although studies have shown that NGF prompts D2R expression by activating NF-κB, the mechanisms underlying the regulation of NGFR expression remain unclear. Recent studies show that long non-coding RNAs (lncRNA) are essential regulators for a number of biological processes and diseases. Our previous studies showed that lncRNA316686 might involve in regulating NGFR expression by screening of lncRNA and mRNA common expressive profile microarray and that there was a significant differential NGFR and lncRNA316686 expression in dopamine-sensitive and -resistant prolactinomas by RT-PCR analysis. In this proposed study, we will further confirm whether NGFR is regulated by lncRNA316686 and then identify the molecular mechanisms underlying the regulation of NGFR expression in prolactinoma cell line. Next, we will determine whether targeted interventions can reverse the resistance to dopamine agonist in vitro and in vivo. We expect that lncRNA316686 can control NGFR expression level, which may, at least in part, diminish the resistance to dopamine agonists in prolactinoma. Meanwhile, lncRNA316686 can be used as a molecular biomarker for prolactinoma's sensitivity to dopamine agonist therapy and thus guide the clinical pharmacotherapy. If successful, the findings from this study will give us insight into the molecular mechanism of dopamine agonists-resistant prolactinomas and provide us a new avenue for treatment of dopamine-resistant prolactinomas.

垂体泌乳素腺瘤细胞表面D2R和NGFR数量的减少被认为是肿瘤耐药的主要原因，NGF通过与其受体NGFR结合激活NF-κB来促使D2R表达，但对NGFR的调控机制未明。长链非编码RNA（lncRNA）是最近发现的在多种生物学过程以及疾病中起重要调控作用的非编码RNA。本课题前期采用lncRNA和mRNA芯片共表达谱分析筛选并用RT-PCR方法验证泌乳素腺瘤药物治疗中NGFR相关的lncRNA316686。本课题将进一步在细胞水平验证lncRNA316686对NGFR的调控及机制，同时体外和体内靶向干预观察逆转耐药效果，以期在lncRNA水平调控NGFR表达，从而逆转耐药泌乳素腺瘤对药物治疗的反应性，同时lncRNA316686可以作为泌乳素腺瘤药物治疗敏感性的生物学分子指标从而指导临床用药。如果实验成功，将为临床解决耐药泌乳素腺瘤的治疗难题奠定实验基础。