Osteosarcoma cell intrinsic PD-L2 signals promote invasion and metastasis via the RhoA-ROCK-LIMK2 and autophagy pathways
Osteosarcoma cell intrinsic PD-L2 signals promote invasion and metastasis via the RhoA-ROCK-LIMK2 and autophagy pathways
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骨肉瘤细胞内在的PD-L2信号通过RhoA-ROCK-LIMK2和自噬途径促进侵袭和转移
DOI：
10.1038/s41419-019-1497-1
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发表时间：
2019-03-18
影响因子：
9
通讯作者：
Guo, Wei
中科院分区：
文献类型：
--
作者：
Ren, Tingting;Zheng, Bingxin;Guo, Wei
程序性死亡配体-2（PD-L2）是一种共刺激分子，通过与程序性死亡1（PD-1）受体相互作用，参与T细胞耗竭，但其对肿瘤细胞内源性信号的影响研究较少。采用免疫组化法检测18对原发骨肉瘤组织及配对肺转移组织中PD-L2的表达。我们还研究了PD-L2敲低对骨肉瘤的体外和体内影响。在我们的研究中，PD-L2表达升高肺转移瘤相比，原发性骨肉瘤根据免疫组化检测。创伤愈合和transwell实验表明PD-L2基因敲低可抑制人骨肉瘤细胞的迁移和侵袭。从机制上讲，我们证明了PDL 2敲低通过灭活RhoA-ROCK-LIMK 2信号传导、抑制上皮-间充质转化（EMT）和通过降低beclin-1表达抑制自噬来减弱迁移和侵袭。为了支持这些观察结果，beclin-1敲低也抑制了RhoA-ROCK-LIMK 2通路的激活，导致自噬抑制诱导的迁移和侵袭阻断。通过裸鼠原位移植，KHOS细胞中PD-L2的耗尽显著减弱体内肺转移潜能。我们的研究揭示了PD-L2在骨肉瘤中的促转移功能机制。此外，我们证明了PD-L2对自噬的调节作用，以及自噬与骨肉瘤转移之间的关系，这可能是骨肉瘤的潜在治疗靶点。
Known as co-stimulatory molecule, programmed death ligand-2 (PD-L2) contributes to T-cell exhaustion by interaction with programmed death-1 (PD-1) receptor, but its tumor cell-intrinsic signal effects have been little investigated. PD-L2 expression was detected by immunohistochemistry in 18 pairs of primary osteosarcoma tissues and matching lung metastasis tissues. We also investigated the effects of PD-L2 knockdown on osteosarcoma both in vitro and in vivo. In our study, PD-L2 expression was elevated in lung metastases compared with primary osteosarcoma according to an immunohistochemistry assay. Wound-healing and transwell assays revealed that PD-L2 knockdown leaded to inhibition of migration and invasion of human osteosarcoma cells in vitro. Mechanistically, we demonstrated that PDL2 knockdown attenuated migration and invasion by inactivating RhoA-ROCK-LIMK2 signaling, suppressing epithelial-mesenchymal transition (EMT), and inhibiting autophagy by decreasing beclin-1 expression. In support of these observations, beclin-1 knockdown also inhibited activation of the RhoA-ROCK-LIMK2 pathway, leading to autophagy inhibition-induced blockade of migration and invasion. Depletion of PD-L2 in KHOS cells markedly weakens pulmonary metastatic potential in vivo by orthotopic transplantation of nude mice. Our study reveals a pro-metastatic functional mechanism for PD-L2 in osteosarcoma. Furthermore, we demonstrate a regulatory role for PD-L2 on autophagy, as well as a relationship between autophagy and metastasis in osteosarcoma, which may represent a potential therapeutic target for osteosarcoma.