Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.
Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, People's Republic of China.
Cell Death Dis. 2019 Mar 18;10(4):261. doi: 10.1038/s41419-019-1497-1.
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 PD-L2 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.
已知作为共刺激分子的程序性死亡配体 2（PD-L2）通过与程序性死亡受体 1（PD-1）的相互作用导致 T 细胞耗竭，但对其肿瘤细胞内在信号的影响研究甚少。通过免疫组织化学检测 18 对原发性骨肉瘤组织和相应肺转移组织中的 PD-L2 表达。我们还研究了 PD-L2 敲低对骨肉瘤的体内外作用。在我们的研究中，根据免疫组织化学检测，PD-L2 表达在肺转移中高于原发性骨肉瘤。划痕和 Transwell 检测显示 PD-L2 敲低导致体外人骨肉瘤细胞迁移和侵袭的抑制。从机制上讲，我们证明 PD-L2 敲低通过使 RhoA-ROCK-LIMK2 信号失活、抑制上皮-间充质转化（EMT）和通过降低 beclin-1 表达抑制自噬，从而抑制迁移和侵袭。支持这些观察结果的是，beclin-1 敲低也抑制了 RhoA-ROCK-LIMK2 通路的激活，导致自噬抑制诱导的迁移和侵袭阻断。在裸鼠原位移植中，KHOS 细胞中 PD-L2 的耗竭显著减弱了体内肺转移的潜力。我们的研究揭示了 PD-L2 在骨肉瘤中具有促转移的功能机制。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，这可能代表骨肉瘤的一个潜在治疗靶点。
