Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China.
Sci Rep. 2017 Apr 7;7:46238. doi: 10.1038/srep46238.
To discover tumor-associated proteins in osteosarcoma, a quantitative proteomic analysis was performed to identify proteins that were differentially expressed between osteosarcoma and human osteoblastic cells. Through clinical screening and a functional evaluation, chromosome segregation 1-like (CSE1L) protein was found to be related to the growth of osteosarcoma cells. To date, little is known about the function and underlying mechanism of CSE1L in osteosarcoma. In the present study, we show that knockdown of CSE1L inhibits osteosarcoma growth in vitro and in vivo. By co-immunoprecipitation and RNA-seq analysis, CSE1L was found to interact with mutS homolog 6 (MSH6) and function as a positive regulator of MSH6 protein in osteosarcoma cells. A rescue study showed that decreased growth of osteosarcoma cells by CSE1L knockdown was reversed by MSH6 overexpression, indicating that the activity of CSE1L was an MSH6-dependent function. In addition, depletion of MSH6 hindered cellular proliferation in vitro and in vivo. Notably, CSE1L expression was correlated with MSH6 expression in tumor samples and was associated with poor prognosis in patients with osteosarcoma. Taken together, our results demonstrate that the CSE1L-MSH6 axis has an important role in osteosarcoma progression.
为了在骨肉瘤中发现肿瘤相关蛋白，我们进行了定量蛋白质组学分析，以鉴定在骨肉瘤和人成骨细胞之间差异表达的蛋白。通过临床筛选和功能评估，发现染色体分离 1 样蛋白（CSE1L）与骨肉瘤细胞的生长有关。迄今为止，关于 CSE1L 在骨肉瘤中的功能和潜在机制知之甚少。在本研究中，我们表明 CSE1L 的敲低抑制了骨肉瘤在体外和体内的生长。通过共免疫沉淀和 RNA-seq 分析，发现 CSE1L 与 mutS 同源物 6（MSH6）相互作用，并在骨肉瘤细胞中作为 MSH6 蛋白的正调节剂发挥作用。挽救研究表明，通过 CSE1L 敲低降低骨肉瘤细胞的生长被 MSH6 过表达逆转，表明 CSE1L 的活性是一种依赖于 MSH6 的功能。此外，MSH6 的耗竭抑制了体外和体内的细胞增殖。值得注意的是，CSE1L 表达与肿瘤样本中 MSH6 表达相关，并与骨肉瘤患者的不良预后相关。总之，我们的结果表明 CSE1L-MSH6 轴在骨肉瘤进展中具有重要作用。
