BCL-9调控IκBα介导NF-κB通路过度激活对肝癌骨转移及骨破坏的作用机制研究

Liver cancer is one of the most common malignant tumors of digestive system with extremely high morbidity and mortality. It is a kind of bone-seeking tumors, with high rate of bone metastasis. Bone metastasis would be associated with a series skeletal related events (SRE) such as pathological fracture, neurologic compression, and even paralysis. SRE would affect the quality of life and survival period of patients with advanced liver cancer. By the high throughput sequencing, we found a transcriptional coregulators named BCL-9 was highly expressed in bone metastasis samples of liver cancer. The ability of HepG2 and SMMC-7721 cells’ proliferation, migration and angiogenesis would be promoted by BCL-9 over-expression, while reduced by BCL-9 knock-down. By using mouse tibial tumor model, we found that the bone destruction and osteoclast precursor cells differentiation were suppressed when BCL-9 was knocked-out in HepG2 cells. Further, we found that BCL-9 could interact with IκBα, which is a key inhibitor of NF-κB pathway, and lead to excessive activation of NF-κB pathway. Currently, the relationship between BCL-9 and bone metastasis and bone destruction had not been reported. Based on the large number of bone metastasis samples of liver cancer, we intend to illustrate the mechanism of the regulation of BCL9 on the IκBα-mediated excessive activation of NF-κB pathway in bone metastasis and destruction of liver cancer. We hope to provide theoretical basis for the treatment of bone metastasis of liver cancer.

肝癌是我国发病率和死亡率最高的消化系统恶性肿瘤之一，属亲骨性肿瘤，易发生骨转移。肝癌骨转移常导致病理性骨折、神经压迫甚至瘫痪等并发症，严重影响患者生存质量和生存期。项目组利用高通量测序等手段发现一种转录辅助因子BCL-9在肝癌骨转移灶中显著高表达；过表达BCL-9后肝癌细胞的增殖、迁移及诱导血管生成能力均显著增强，反之则减弱；利用小鼠胫骨荷瘤模型，我们发现敲除BCL-9后显著降低了肝癌细胞的骨破坏能力及诱导破骨前体细胞分化成熟能力；进一步研究发现BCL-9与NF-κB通路抑制因子IκBα有显著的相互作用，并影响NF-κB通路的活性及下游靶基因的表达。目前，BCL-9与肝癌骨转移及骨破坏的关系尚未见报到。项目组拟从大量肝癌骨转移标本及病例入手，在分子、细胞和动物水平阐明BCL-9调控IκBα介导NF-κB通路过度激活在肝癌骨转移及骨破坏中的关键机制，为治疗肝癌骨转移提供新的理论依据和药物靶点

肝癌是我国发病率和死亡率最高的消化系统恶性肿瘤之一，易发生骨转移。肝癌骨转移常导致病理性骨折、神经压迫甚至瘫痪等并发症，严重影响患者生存质量和生存期。项目组结合临床优势，利用高通量测序发现BCL-9在肝癌骨转移灶中显著高表达；过表达BCL-9后肝癌细胞的增殖、迁移及诱导血管生成能力均显著增强，反之则减弱；敲除BCL-9后显著降低了肝癌细胞的骨破坏能力及诱导破骨前体细胞分化成熟能力；进一步研究发现BCL-9与NF-κB通路抑制因子IκBα有显著的相互作用，并影响NF-κB通路的活性及下游靶基因的表达。同时在本项目的经费支持下，本课题组建立了病人特异性的肝癌骨转移的PDX以及PDO的模型，并且进行了前期的药物耐药性分析实验。综上所述，项目组在完成从BCL-9调控IκBα介导NF-κB通路过度激活在肝癌骨转移及骨破坏中的关键机制的基础上，同时建立了基于PDX以及PDO模型的病人特异性的肝癌骨转移的临床样本库，为将来的临床研究以及药物研发提供了良好的平台。