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Osteosarcoma cell intrinsic PD-L2 signals promote invasion and metastasis via the RhoA-ROCK-LIMK2 and autophagy pathways.

ABSTRACT: 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.

SUBMITTER: Ren T

PROVIDER: S-EPMC6423010 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Osteosarcoma cell intrinsic PD-L2 signals promote invasion and metastasis via the RhoA-ROCK-LIMK2 and autophagy pathways.

Ren Tingting T Zheng Bingxin B Huang Yi Y Wang Shidong S Bao Xing X Liu Kuisheng K Guo Wei W

Cell death & disease 20190318 4

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 el ...[more]

PMID: 30886151

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Project description:BackgroundErectile dysfunction (ED) occurs more frequently and causes a worse response to the first-line therapies in diabetics compared with nondiabetic men. Corpus cavernosum vascular dysfunction plays a pivotal role in the occurrence of diabetes mellitus ED (DMED). The aim of this study was to investigate the protective effects of glucagon-like peptide-1 (GLP-1) analog liraglutide on ED and explore the underlying mechanisms in vivo and in vitro.MethodsType 1 diabetes was induced in rats by streptozotocin, and the apomorphine test was for screening the DMED model in diabetic rats. Then they were randomly treated with subcutaneous injections of liraglutide (0.3 mg/kg/12 h) for 4 weeks. Erectile function was assessed by cavernous nerve electrostimulation. The corpus cavernosum was used for further study. In vitro, effects of liraglutide were evaluated by primary corpus cavernosum smooth muscle cells (CCSMCs) exposed to low or high glucose (HG)-containing medium with or without liraglutide and GLP-1 receptor (GLP-1R) inhibitor. Western blotting, fluorescent probe, immunohistochemistry, and relevant assay kits were performed to measure the levels of target proteins.ResultsAdministration of liraglutide did not significantly affect plasma glucose and body weights in diabetic rats, but improved erectile function, reduced levels of NADPH oxidases and ROS production, downregulated expression of Ras homolog gene family (RhoA) and Rho-associated protein kinase (ROCK) 2 in the DMED group dramatically. The liraglutide treatment promoted autophagy further and restored expression of GLP-1R in the DMED group. Besides, cultured CCSMCs with liraglutide exhibited a lower level of oxidative stress accompanied by inhibition of the RhoA/ROCK pathway and a higher level of autophagy compared with HG treatment. These beneficial effects of liraglutide effectively reversed by GLP-1R inhibitor.ConclusionLiraglutide exerts protective effects on ED associated with the regulation of smooth muscle dysfunction, oxidative stress and autophagy, independently of a glucose- lowering effect. It provides new insight into the extrapancreatic actions of liraglutide and preclinical evidence for a potential treatment for DMED.

Dataset Information

Osteosarcoma cell intrinsic PD-L2 signals promote invasion and metastasis via the RhoA-ROCK-LIMK2 and autophagy pathways.

Publications

Osteosarcoma cell intrinsic PD-L2 signals promote invasion and metastasis via the RhoA-ROCK-LIMK2 and autophagy pathways.

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