探讨HOTAIR参与蟾毒灵抗前列腺癌骨转移作用的研究

There is no effective treatment for Castration-Resistant Prostate Cancer in west medicine. Previous study found that migration of prostate cancer cells PC3 and DU145 was significantly inhibited by bufalin, gene expression profiling revealed HOTAIR expression was significantly down-regulated after treated with bufalin, further experiments suggested that HOTAIR expression levels were positively correlated to the invasive ability of prostate cancer cells. Clinical samples confirmed that the HOTAIR levels in prostate cancer tissues were significantly higher than in benign prostate hyperplasia, and the levels in bone metastatic lesions higher than in primary lesions. The HOTAIR levels in serum from prostate cancer patients were higher than from normal control. This study put forward the hypothesis that "The prostate cancer cells regulate the microenvironment of bone by secreting exosome, Bufalin inhibits prostate cancer bone metastasis by down-regulating HOTAIR", this study is aimed to 1) explore the mechanisms of the effect of HOTAIR on osteoblasts and osteoclasts; 2) explore the mechanisms of the effect of bufalin on prostate cancer cells by inhibiting HOTAIR; 3) validate the mechanisms in animal models; 4) analyze the relationship between HOTAIR expression in clinical samples and clinical prognosis. This study may provide a basis to use bufalin for the treatment of prostate cancer, and clarify the mechanisms of HOTAIR in regulating bone metastasis.

去势抵抗性前列腺癌目前西医缺乏有效治疗手段。前期研究应用中药提取物蟾毒灵处理去势抵抗性前列腺癌细胞PC3和DU145，发现细胞迁移能力显著下降，对比用药前后LncRNA表达谱发现HOTAIR表达显著下调，上调/下调前列腺癌细胞HOTAIR表达，发现细胞侵袭能力与HOTAIR表达正相关，临床标本证实前列腺癌组织HOTAIR水平明显高于前列腺增生组织，且骨转移灶高于原发灶，患者血清HOTAIR水平高于正常体检人群。故本研究提出“前列腺癌细胞通过外分泌HOTAIR调控骨转移微环境，蟾毒灵通过抑制该通路抑制前列腺癌骨转移”的假说，本研究拟：1）探寻HOTAIR调节成骨、破骨细胞功能的机制；2）探寻蟾毒灵抑制前列腺癌外分泌HOTAIR的机制；3）动物模型验证该机制；4）临床标本分析HOTAIR表达与临床预后相关性。本研究为蟾毒灵治疗前列腺癌提供理论依据，并探索HOTAIR参与肿瘤骨转移的调控机制。

前列腺癌骨转移严重威男性健康和生命，总体疗效不佳，迫切需要探索寻找新的治疗策略。本研究证实蟾毒灵通过HOTAIR/miR-520b/FGFR1轴调控前列腺癌细胞侵袭转移，此外，前列腺癌细胞外分泌的HOTAIR通过调节成骨细胞OPG-Rankl的表达，促进破骨细胞RANK信号通路的激活，从而促进骨转移发生。临床研究发现前列腺癌骨转移组织中HOTAIR及FGFR1表达均显著高于前列腺癌原发灶，血清HOTAIR水平与骨代谢指标呈正相关，血清HOTAIR可作为前列腺癌骨转移患者的可靠生物标记物。总之，本研究首次发现HOTAIR促进前列腺癌骨转移的作用，并提示蟾毒灵具有治疗该疾病的临床应用前景。