MD, PhD, Laboratory of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 37 Guoxue Xiang, Chengdu, Sichuan 610041, People's Republic of China.
Mol Cancer Res. 2014 Jan;12(1):101-10. doi: 10.1158/1541-7786.MCR-13-0136. Epub 2013 Aug 21.
Small cell lung cancer (SCLC) is a rapidly progressing, incurable cancer that frequently spreads to bone. New insights are needed to identify therapeutic targets to prevent or retard SCLC metastatic progression. Human SCLC SBC-5 cells in mouse xenograft models home to skeletal and nonskeletal sites, whereas human SCLC SBC-3 cells only pervade nonskeletal sites. Because microRNAs (miRNA) often act as tumor regulators, we investigated their role in preclinical models of SCLC. miRNA expression profiling revealed selective and reduced expression of miRNA (miR)-335 and miR-29a in SBC-5 cells, compared with SBC-3 cells. In SBC-5 cells, miR-335 expression correlated with bone osteolytic lesions, whereas miR-29a expression did not. Overexpression of miR-335 in SBC-5 cells significantly reduced cell migration, invasion, proliferation, colony formation, and osteoclast induction in vitro. Importantly, in miR-335 overexpressing SBC-5 cell xenografts (n = 10), there were minimal osteolytic lesions in the majority of mice and none in three mice. Expression of RANK ligand (RANKL) and insulin-like growth factor-I receptor (IGF-IR), key mediators of bone metastases, were elevated in SBC-5 as compared with SBC-3 cells. Mechanistically, overexpression of miR-335 in SBC-5 cells reduced RANKL and IGF-IR expression. In conclusion, loss of miR-335 promoted SCLC metastatic skeletal lesions via deregulation of IGF-IR and RANKL pathways and was associated with metastatic osteolytic skeletal lesions.
These preclinical findings establish a need to pursue the role of miR-335 in human SCLC with metastatic skeletal disease.
小细胞肺癌（SCLC）是一种快速进展、无法治愈的癌症，经常扩散到骨骼。需要新的见解来确定治疗靶点，以预防或延缓 SCLC 转移进展。在小鼠异种移植模型中，人 SCLC SBC-5 细胞归巢到骨骼和非骨骼部位，而人 SCLC SBC-3 细胞仅渗透非骨骼部位。由于 microRNAs（miRNA）通常作为肿瘤调节剂发挥作用，我们研究了它们在 SCLC 临床前模型中的作用。miRNA 表达谱分析显示，与 SBC-3 细胞相比，SBC-5 细胞中 miRNA（miR）-335 和 miR-29a 的表达具有选择性和降低。在 SBC-5 细胞中，miR-335 的表达与骨溶骨性病变相关，而 miR-29a 的表达则没有。在 SBC-5 细胞中过表达 miR-335 可显著降低细胞迁移、侵袭、增殖、集落形成和体外破骨细胞诱导。重要的是，在 miR-335 过表达 SBC-5 细胞异种移植（n = 10）中，大多数小鼠的溶骨性病变很少，三例小鼠中没有。与 SBC-3 细胞相比，SBC-5 细胞中 RANK 配体（RANKL）和胰岛素样生长因子-I 受体（IGF-IR）的表达升高，这是骨转移的关键介质。从机制上讲，在 SBC-5 细胞中过表达 miR-335 可降低 RANKL 和 IGF-IR 的表达。总之，miR-335 的缺失通过调节 IGF-IR 和 RANKL 途径促进 SCLC 转移性骨骼病变，并与转移性溶骨性骨骼病变相关。
这些临床前发现确立了在具有转移性骨骼疾病的人类 SCLC 中探索 miR-335 作用的必要性。
