Repulsive guidance molecule B inhibits metastasis and is associated with decreased mortality in non-small cell lung cancer

Li, Jin; Ye, Lin; Shi, Xiaoshun; Chen, Jingyi; Feng, Fenglan; Chen, Yaoqi; Xiao, Yiren; Shen, Jianfei; Peng, Li; Jiang, Wen Guo; He, Jianxing

doi:10.18632/oncotarget.7463

Cited by 17 publications

(12 citation statements)

References 41 publications

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“…RGMb, a secondary receptor for PD-L2 18 , is a member of the repulsive guidance molecule (RGM) family that includes RGMa, RGMb, and RGMc 37 , and is expressed in the nervous system, macrophages, and other cells of the immune system 37 , 38 . Moreover, RGMb is also reported to be expressed in some tumors and has varying roles 39 – 41 . Previous studies show that RGMb is associated with tumorigenesis, immunoregulation, and cell-to-cell adhesion, and has an important role in the RGMb-neogenin-RhoA signaling pathway 19 , 42 – 45 .…”

Section: Discussionmentioning

confidence: 99%

“…Some studies have shown the expression and interaction of RGMb/neogenin, RGMb/BMPs, or neogenin/BMPs, and most of the researches on RGMb/neogenin mainly focus on the nervous system 19 – 21 , 46 , 47 . RGMb is also reported to be expressed in some tumors such as breast cancer, colorectal cancer, and lung cancer, and has varying roles; 39 – 41 abnormal expression of neogenin has been found in pancreatic carcinoma, colon cancer, esophageal squamous cell carcinoma, gliomas, and breast cancer; 50 BMP and its receptors are also implicated with many cancers 22 . However, the systematic study for BBRN expression in tumor is rare.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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“…; Li et al. ; Muller et al. ), most publications to date have focused on experimental model systems (Matsunaga et al.…”

Section: Discussionmentioning

confidence: 99%

Variation in the repulsive guidance molecule family in human populations

Rotwein

2019

Physiol Rep

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Repulsive guidance molecules, RGMA, RGMB, and RGMC, are related proteins discovered independently through different experimental paradigms. They are encoded by single copy genes in mammalian and other vertebrate genomes, and are ~50% identical in amino acid sequence. The importance of RGM actions in human physiology has not been realized, as most research has focused on non‐human models, although mutations in RGMC are the cause of the severe iron storage disorder, juvenile hemochromatosis. Here I show that repositories of human genomic and population genetic data can be used as starting points for discovery and for developing new testable hypotheses about each of these paralogs in human biology and disease susceptibility. Information was extracted, aggregated, and analyzed from the Ensembl and UCSC Genome Browsers, the Exome Aggregation Consortium, the Genotype‐Tissue Expression project portal, the cBio portal for Cancer Genomics, and the National Cancer Institute Genomic Data Commons data site. Results identify extensive variation in gene expression patterns, substantial alternative RNA splicing, and possible missense alterations and other modifications in the coding regions of each of the three genes, with many putative mutations being detected in individuals with different types of cancers. Moreover, selected amino acid substitutions are highly prevalent in the world population, with minor allele frequencies of up to 37% for RGMA and up to 8% for RGMB. These results indicate that protein sequence variation is common in the human RGM family, and raises the possibility that individual variants will have a significant population impact on human physiology and/or disease predisposition.

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“…ID1 inhibits the activation of E12/E47. It is predicted that ID1 dependent pancreatic cancers could be sensitive to specific ID1 small-molecule inhibitors [ 153 ]. The potential benefit of gefitinib in suppressing ID1 in K-Ras mutant NSCLC also warrants investigation.…”

Section: Transforming Growth Factor-β Signaling In K-ras Mutationmentioning

confidence: 99%

Non-Small-Cell Lung Cancer Signaling Pathways, Metabolism, and PD-1/PD-L1 Antibodies

Santarpía

Aguilar

Chaib

et al. 2020

Cancers

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Treatment of advanced (metastatic) non-small-cell lung cancer (NSCLC) is currently mainly based on immunotherapy with antibodies against PD-1 or PD-L1, alone, or in combination with chemotherapy. In locally advanced NSCLC and in early resected stages, immunotherapy is also employed. Tumor PD-L1 expression by immunohistochemistry is considered the standard practice. Response rate is low, with median progression free survival very short in the vast majority of studies reported. Herein, numerous biological facets of NSCLC are described involving driver genetic lesions, mutations ad fusions, PD-L1 glycosylation, ferroptosis and metabolic rewiring in NSCLC and lung adenocarcinoma (LUAD). Novel concepts, such as immune-transmitters and the effect of neurotransmitters in immune evasion and tumor growth, the nascent relevance of necroptosis and pyroptosis, possible new biomarkers, such as gasdermin D and gasdermin E, the conundrum of K-Ras mutations in LUADs, with the growing recognition of liver kinase B1 (LKB1) and metabolic pathways, including others, are also commented. The review serves to charter diverse treatment solutions, depending on the main altered signaling pathways, in order to have effectual immunotherapy. Tumor PDCD1 gene (encoding PD-1) has been recently described, in equilibrium with tumor PD-L1 (encoded by PDCD1LG1). Such description explains tumor hyper-progression, which has been reported in several studies, and poises the fundamental criterion that IHC PD-L1 expression as a biomarker should be revisited.

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Repulsive guidance molecule B inhibits metastasis and is associated with decreased mortality in non-small cell lung cancer

Cited by 17 publications

References 41 publications

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

Variation in the repulsive guidance molecule family in human populations

Non-Small-Cell Lung Cancer Signaling Pathways, Metabolism, and PD-1/PD-L1 Antibodies

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