MicroRNA分子信号网络调控肺癌骨转移的继续研究

Lung cancer is the major cause of malignancy-related death worldwide. The skeleton is one of the most common sites of metastasis in patients with lung cancer. It has been reported that 39-82% of patients with advanced lung cancer develop bone metastasis. Currently, the molecular mechanism is largely unknown and no curative therapy exists for bone metastasis. Under the grant support from the NSFC, we have established the novel cellular model and xenograft animal model for bone metastasis in lung cancer. We found that miRNA (miR)-335 was down-regulated in SBC-5 cells, which could metastasize to bone in mouse xenograft models. Overexpression of miR-335 in SBC-5 cells significantly reduced cell migration, invasion, proliferation, colony formation, and osteoclast induction in vitro, as well as osteolytic lesions in mouse xenograft models. Mechanistically, loss of miR-335 promoted lung cancer metastatic skeletal lesions via deregulation of IGF-IR and RANKL pathways and was associated with metastatic osteolytic skeletal lesions. We also found the expression level of miR-21 was significantly higher in the cellular lyses and culture medium from SBC-5 cells, as well as in the serum from patients with lung cancer bone metastasis. Inhibition of miR-21 significantly reduced abnormal osteoclastgenesis induced by SBC-5 cells. We hypothesize that a specific miRNA network majorly consisted of miR-335 and miR-21 regulates bone metastasis in lung cancer. We will continue to determine this specific miRNA network and to investigate the molecular mechanism under its regulations. Understanding the pathological roles of miRNAs in bone metastasis will provide new insights not only into basic mechanisms of the disease but also, will likely suggest strategies to develop therapies and paired diagnostic biomarkers.

肺癌是最常见恶性肿瘤之一，肺癌转移为病人死亡的主要原因，骨转移为肺癌转移的主要形式之一，发生率高达39%-82%。骨转移发生机理尚不清楚，也无有效防治方法。申请者在国家自然科学基金的资助下，建立了肺癌骨转移的新型细胞和动物模型，发现miR-335在具骨转移特性的肺癌细胞中呈低表达，而恢复miR-335的表达可抑制肺癌骨转移的发生，证实miR-335靶向作用于RANKL和IGF-IR而调控肺癌骨转移的发生发展；同时发现miR-21在具骨转移特性的肺癌细胞内和上清、肺癌骨转移患者的血清中呈高表达，阻断miR-21信号将抑制肺癌细胞所介导的破骨细胞形成。申请者设想以miR-335和miR-21为中心的miRNA分子信号网络协同调控肺癌骨转移的发生发展，拟继续研究并揭示此分子信号网络及其病理作用，为肺癌骨转移的早期诊断、预后判断及靶向治疗提供理论依据。

肺癌是最常见恶性肿瘤之一，肺癌转移为病人死亡的主要原因，骨转移为肺癌转移的主要形式之一，发生率高达39%-82%。骨转移发生机理尚不清楚，也无有效防治方法。本项目围绕血液中游离的miR-21是否调控及通过什么机制调控肺癌骨转移发生发展这一关键问题，从基础研究和临床研究两方面开展研究。通过细胞研究发现miR-21在有骨转移特性的肺癌细胞株SBC-5细胞内表达明显增高，培养上清中的游离miR-21水平明显增高；通过临床研究发现肺癌患者血浆miR-21水平与肺癌骨转移的发生和转归密切相关、与破骨细胞的功能活化显著相关；在机制方面，发现游离miR-21不但可促进单核细胞系分化为破骨细胞，也可促进肺癌患者原代单核细胞向破骨细胞分化，PTEN为游离miR-21调控单核细胞向破骨细胞分化的靶基因，TRAP 和MMP-9基因的高表达为游离miR-21/PTEN促进单核/破骨细胞功能的结果，这三个基因共同参与了游离miR-21调控单核/破骨细胞功能的信号网络。通过研究证实了肺癌患者血浆miR-21水平有望作为血清学标志物用于肺癌骨转移的早期筛查和疗效判断指标。