Glioma-derived LRIG3 interacts with NETO2 in tumor-associated macrophages to modulate microenvironment and suppress tumor growth

Li, Youwei; Wang, Wei; Hou, Xiaoshuang; Huang, Wenda; Zhang, Po; He, Yue; Wang, Baofeng; Duan, Qiuhong; Mao, Feng; Guo, Dongsheng

doi:10.1038/s41419-023-05555-z

Cited by 8 publications

(2 citation statements)

References 57 publications

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“…Although we have demonstrated that CD58 and sCD58 activate AKT signaling pathway, it is not clear how sCD58 increases the phosphorylation level of AKT. Interestingly, LRIG3 and sLRIG3 can regulate the MET/PI3K/Akt pathway in GBM [ 42 ], and further study found sLRIG3 also binds to the transmembrane protein NETO2 to activate the NF-kB pathway in GBM [ 43 ]. TELO2, a cofactor of phosphatidylinositol 3-kinase-related kinases, has been reported to bind to RICTOR as the mTORC2 complex and promote CRC cell progression through the AKT pathway [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

CD58 acts as a tumor promotor in hepatocellular carcinoma via activating the AKT/GSK-3β/β-catenin pathway

Wang,

Cao,

Cao

et al. 2023

J Transl Med

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Background Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide because of rapid progression and high incidence of metastasis or recurrence. Accumulating evidence shows that CD58-expressing tumor cell is implicated in development of various cancers. The present study aimed to reveal the functional significance of CD58 in HCC progression and the underlying mechanisms. Methods Immunohistochemical staining (IHC), and western blotting were used to detect the expression of CD58 in HCC tissues and cells. The levels of sCD58 (a soluble form of CD58) in the cell supernatants and serum were assessed by ELISA. CCK-8, colony formation, and xenograft assays were used to detect the function of CD58 on proliferation in vitro and in vivo. Transwell assay and sphere formation assay were performed to evaluate the effect of CD58 and sCD58 on metastasis and self-renewal ability of HCC cells. Western blotting, immunofluorescence (IF), TOP/FOP Flash reporter assay, and subcellular fractionation assay were conducted to investigate the molecular regulation between CD58/sCD58 and AKT/GSK-3β/β-catenin axis in HCC cells. Results CD58 was significantly upregulated in HCC tissues. Elevation of CD58 expression correlated with more satellite foci and vascular invasion, and poorer tumor-free and overall survival in HCC patients. Higher sCD58 levels were in HCC patients' serum compared to healthy individuals. Functionally, CD58 promotes the proliferation of HCC cells in vitro and in vivo. Meanwhile, CD58 and sCD58 induce metastasis, self-renewal and pluripotency in HCC cells in vitro. Mechanistically, CD58 activates the AKT/GSK-3β/β-catenin signaling pathway by increasing phosphorylation of AKT or GSK3β signaling, promoting expression of Wnt/β-catenin target proteins and TCF/LEF-mediated transcriptional activity. Furthermore, AKT activator SC-79 or inhibitor LY294002 abolished the inhibitory effect of CD58 silencing on the proliferation, metastasis, and stemness of HCC cells. Conclusions Taken together, CD58 promotes HCC progression and metastasis via activating the AKT/GSK-3β/β-catenin pathway, suggesting that CD58 is a novel prognostic biomarker and therapeutic target for HCC. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

CD58 acts as a tumor promotor in hepatocellular carcinoma via activating the AKT/GSK-3β/β-catenin pathway

Wang,

Cao,

Cao

et al. 2023

J Transl Med

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“…To directly observe tumor growth, 150 mg/kg d -Luciferin (Shanghai Yuanye) was injected intraperitoneally into anesthetized mice, and tumor growth images were acquired by an in vivo imaging system (IVIS) after 5 min. All mice were imaged in second week and weekly measured until the first mouse developed neurological symptoms, then killed when neurological symptoms occurred 12 , 13 .…”

Section: Methodsmentioning

confidence: 99%

YANK2 activated by Fyn promotes glioma tumorigenesis via the mTOR-independent p70S6K activation pathway

Shi,

Cheng,

Wang

et al. 2024

Sci Rep

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Glioma, particularly glioblastomas (GBM), is incurable brain tumor. The most targeted receptor tyrosine kinase (RTKs) drugs did not bring benefit to GBM patients. The mechanism of glioma growth continues to be explored to find more effective treatment. Here, we reported that Ser/Thr protein kinase YANK2 (yet another kinase 2) is upregulated in glioma tissues and promotes the growth and proliferation of glioma in vitro and in vivo. Further, we confirmed that oncogene Fyn directly activated YANK2 through phosphorylation its Y110, and Fyn-mediated YANK2 phosphorylation at Y110 site promotes glioma growth by increasing its stability. Finally, YANK2 was proved to be a novel upstream kinase of p70S6K and promotes glioma growth by directly phosphorylating p70S6K at T389. Taken together, we found a new mTOR-independent p70S6K activation pathway, Fyn-YANK2-p70S6K, which promotes glioma growth, and YANK2 is a potential oncogene and serves as a novel therapeutic target for glioma.

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GPR65 contributes to constructing immunosuppressive microenvironment in glioma

Fan,

Liu,

Zhang

et al. 2024

Neurosurg Rev

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Glioma, especially glioblastoma patients, present highly heterogeneous and immunosuppressive microenvironment, leading to their poor response to treatment and survival. Targeting the tumor microenvironment is considered a promising therapeutic strategy. M2 macrophages are highly infiltrated in glioma tissue, even up to 50% of the total number of bulk tissue cells. Here, we identified GPR65 as the hub gene of the M2 macrophage-related module in glioma through WGCNA analysis. The expression and prognosis analysis suggested that GPR65 was positively correlated with the malignancy and poor prognosis of glioma, and the heterogeneity analysis found that GPR65 was highly expressed in the vascular proliferation area of glioma, which matched the spatial expression characteristics of M2 macrophages. We further verified that GPR65 was highly expressed in macrophages but not tumor cells in the glioma microenvironment by single-cell data analysis and immunofluorescence. Most importantly, we found that inhibition of GPR65 was sufficient to reduce macrophages’ polarization response to glioma cell and break the malignant cooperation with glioma cells. Our study reports the expression characteristics and malignant behavior of GPR65 in the glioma microenvironment, which provides a new alternative target of treatment to glioma microenvironment. Supplementary Information The online version contains supplementary material available at 10.1007/s10143-024-02633-4.

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Glioma-derived LRIG3 interacts with NETO2 in tumor-associated macrophages to modulate microenvironment and suppress tumor growth

Cited by 8 publications

References 57 publications

CD58 acts as a tumor promotor in hepatocellular carcinoma via activating the AKT/GSK-3β/β-catenin pathway

CD58 acts as a tumor promotor in hepatocellular carcinoma via activating the AKT/GSK-3β/β-catenin pathway

YANK2 activated by Fyn promotes glioma tumorigenesis via the mTOR-independent p70S6K activation pathway

GPR65 contributes to constructing immunosuppressive microenvironment in glioma

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