Liu Tang, Yan Zuyun, Liu Yong, Choy Edwin, Hornicek Francis J, Mankin Henry, Duan Zhenfeng
Department of Orthopedics, the 2nd Xiangya Hospital of Central South University, Changsha, China.
Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, David Geffen School of Medicine at University of Los Angeles, Los Angeles, California, USA.
Cell Physiol Biochem. 2018;46(3):1218-1230. doi: 10.1159/000489072. Epub 2018 Apr 16.
BACKGROUND/AIMS: Metastasis is the major cause of death in patients with osteosarcoma. There is an urgent need to identify molecular markers that promote metastasis. Cluster of differentiation 44 is a receptor for hyaluronic acid (HA) and HA-binding has been proven to participate in various biological tumor activities, including tumor progression and metastasis.
We performed a meta-analysis to investigate the relationship between CD44 expression, survival, and metastasis in patients with osteosarcoma. We then utilized the CRISPR-Cas9 system to specifically silence CD44 in highly metastatic human osteosarcoma cells (MNNG/HOS and 143B) and further determined the functional effects of CD44 knockout in these cells.
The meta-analysis demonstrated that a high level of CD44 may predict poor survival and higher potential of metastasis in patients with osteosarcoma. The expression of CD44 in highly metastatic human osteosarcoma cell lines was efficiently blocked by CRISPR-Cas9. When CD44 was silenced, the proliferation and spheroid formation of these osteosarcoma cells was inhibited under 3-D culture conditions. Furthermore, the migratory and invasive functions were also impaired in these highly metastatic osteosarcoma cells.
These results suggest that developing new strategies to target CD44 in osteosarcoma may prevent metastasis and improve the clinical outcome of osteosarcoma patients.
背景/目的：转移是骨肉瘤患者死亡的主要原因。迫切需要鉴定促进转移的分子标志物。分化簇44是透明质酸（HA）的受体，并且已证明HA结合参与各种生物学肿瘤活动，包括肿瘤进展和转移。
我们进行了一项荟萃分析，以研究骨肉瘤患者中CD44表达、生存和转移之间的关系。然后，我们利用CRISPR-Cas9系统特异性沉默高转移性人骨肉瘤细胞（MNNG/HOS和143B）中的CD44，并进一步确定这些细胞中CD44基因敲除的功能影响。
荟萃分析表明，高水平的CD44可能预示骨肉瘤患者生存不良和转移潜力更高。CRISPR-Cas9有效阻断了高转移性人骨肉瘤细胞系中CD44的表达。当CD44沉默时，在三维培养条件下，这些骨肉瘤细胞的增殖和球状体形成受到抑制。此外，这些高转移性骨肉瘤细胞的迁移和侵袭功能也受到损害。
这些结果表明，开发针对骨肉瘤中CD44的新策略可能预防转移并改善骨肉瘤患者的临床结局。
