Hypoxia-induced PLOD2 promotes proliferation, migration and invasion via PI3K/Akt signaling in glioma

Song, Ye; Zheng, Shaoling; Wang, Jizhou; Long, Hao; Fang, Luxiong; Wang, Gang; Li, Zhiyong; Que, Tianshi; Liu, Yi B; Li, Yilei; Zhang, Xian; Fang, Weiyi; Qi, Songtao

doi:10.18632/oncotarget.16710

Cited by 85 publications

(78 citation statements)

References 40 publications

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“…Then, the biological functions of P4HA2 was examined. Similar with the findings in breast cancer [20], knockdown of P4HA2 was also found to inhibit glioma proliferation, migration and invasion in vitro and tumor xenograft growth in vivo. However, the underlying molecular mechanism is elusive.…”

Section: Discussionsupporting

confidence: 84%

“…Among the collagen receptors, the DDRs has been tightly associated with the PI3K/AKT signaling pathway, because of the C-terminal of DDR1 kinase domain contains the YELM binding motif for association with the p85 subunit of PI3K [36]. As previous literature has demonstrated that type I-IV collagens can all combine with DDRs [37,38] and deposited by P4HA2 [6,20] , we think at least the DDRs could theoretically mediate the collagen-dependent regulation of PI3K/AKT signaling pathway by P4HA2 in glioma, though it needs further confirmation. With the downregulation of collagen I, III and VI by P4HA2 silencing in glioma cells, a novel signal axis of P4HA2-collagen-PI3K/AKT pathway is proposed in contribution to glioma progression.…”

Section: Discussionmentioning

confidence: 99%

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P4HA2 is associated with prognosis, promotes proliferation, invasion, migration and EMT in glioma

Lin

Wei

et al. 2020

Preprint

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Running title: P4HA2 promotes glioma by collagen-PI3K/AKT pathway Highlights P4HA2 is overexpressed and correlated with poor prognosis in glioma.P4HA2 depletion inhibits glioma proliferation, migration, invasion and EMT-like phenotype in vitro and tumorigenesis in vivo.P4HA2 depletion attenuates the PI3K/AKT signaling pathway in a collagen-dependent manner. AbstractProlyl-4-hydroxylase subunit 2 (P4HA2), as a member of collagen modification enzymes, is induced under hypoxic conditions with essential roles in the collagen maturation, deposition as well as the remodeling of extracellular matrix(ECM).Mounting evidence has suggested that deregulation of P4HA2 is common in cancer.However, the expression pattern and molecular mechanisms of P4HA2 in glioma remain unknown. Here, we demonstrate that P4HA2 is overexpressed in glioma and inversely correlates with patient survival. Knockdown of P4HA2 inhibits proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT)-like phenotype of glioma cells in vitro and suppressed tumor xenograft growth in vivo. Mechanistically, bioinformatics analysis shows that ECM-receptor interaction and PI3K/AKT pathway are the most enriched pathways of the co-expressed genes with P4HA2. Furthermore, P4HA2 mRNA was positively correlated with mRNA expressions of a series of collagen genes, but not mRNA of PI3K or AKT1/2. Conversely, both the protein expressions of collagens and phosphorylated PI3K/AKT could be downregulated either by silencing of P4HA2 expression or inhibition of its prolyl hydroxylase. Moreover, the inhibitory effects on the migration, invasion and the EMT-related molecules by P4HA2 knockdown can be recapitulated by the Akt phosphorylation activator. Taken together, our findings for the first time reveal an oncogenic role of P4HA2 in the glioma malignancy. By regulating the expression of fibrillar collagens and the downstream PI3K/AKT signaling pathway, it may serve as a potential anti-cancer target for the treatment of glioma.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

P4HA2 is associated with prognosis, promotes proliferation, invasion, migration and EMT in glioma

Lin

Wei

et al. 2020

Preprint

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“…Akt activation promotes cellular growth and survival, and control of migration and invasion activities in GBM has been linked to activation of the PI3K/Akt pathway . We hypothesized that IL‐17A may facilitate PI3K/Akt pathway activation in U251 and U87 cells.…”

Section: Resultsmentioning

confidence: 99%

IL‐17A promotes cell migration and invasion of glioblastoma cells via activation of PI3K/AKT signalling pathway

Zheng

Diao

Wang

et al. 2018

J Cellular Molecular Medi

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Glioblastomas (GBMs) are the most common of both benign and malignant primary brain tumours, in which the inflammatory and immunologic abnormalities are involved. Interleukin‐17A (IL‐17A) plays an important role in various inflammatory diseases and cancers. Several recent studies revealed that the expression of IL‐17A was overexpressed in human GBMs tissue. However, the accurate role of IL‐17A in GBMs remains unclear. In this study, we aimed to explore the effect of IL‐17A on cell migration and invasion of GBMs and the mechanism by which the effects occurred. We found that exogenous IL‐17A promoted significantly cell migration and invasion abilities in two GBMs cell lines (U87MG and U251) in a time‐dependent manner. In addition, the protein expressions of PI3K, Akt and MMP‐2/9 were increased in the GBMs cells challenged by IL‐17A. Furthermore, a tight junction protein ZO‐1 was down‐regulated but Twist and Bmi1 were up‐regulated. Treatment with a PI3K inhibitor (LY294002) significantly reduced the abilities of both migration and invasion in U87MG and U251 cells. LY294002 treatment also attenuated the IL‐17A causing increases of protein levels of PI3K, AKT, MMP‐2/9, Twist and the decreases of protein level of ZO‐1 in the U87MG and U251 cells. Taken together, we concluded that IL‐17A promotes the GBM cells migration and invasion via PI3K/AKT signalling pathway. IL‐17A and its related signalling pathways may be potential therapeutic targets for GBM.

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“…In addition, we observed that A549 HxEVs were enriched in the golgi-expressed glycosylation enzyme alpha 6-mannosylglycoprotein 6-beta-N-acetylglucosaminyltransferase B (MGAT5B) which is a critical regulator of cancer cell-cell contact, EMT, and metastasis [32]. Furthermore, the α-ketoglutarate-dependent enzyme PLOD2 can hydroxylate pro-collagen within the ER and has been implicated in hypoxic cancer cell invasion in various experimental models [47][48][49][50][51][52]. Taken together, these data indicate that hypoxia stress stimulates cancer cell protein synthesis and EV distribution to induce diverse functional effects that likely extend beyond local survival strategies.…”

Section: Several Of These Proteins Have Been Reported In Other Contexmentioning

confidence: 99%

Microenvironmental Hypoxia Induces Dynamic Changes in Lung Cancer Synthesis and Secretion of Into Extracellular Vesicles

Tse

Tan

Park

et al. 2020

Preprint

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Background: Extracellular vesicles (EVs) mediate critical intercellular communication within healthy tissues, but are also exploited by tumour cells to promote angiogenesis, metastasis, and host immunosuppression under hypoxic stress. We hypothesize that oxygen starvation in developing tumours induces specific hypoxia-sensitive proteins for packing into small EVs to modulate its microenvironment for cancer progression and enhance malignancy. Methods: We employed a heavy isotope pulse/trace quantitative proteomic approach to study hypoxia-sensitive EVs proteins (HSEPs) in hypoxic A549 lung adenocarcinoma cells derived small EVs (<200 nm). Proteomics data mining and pathway analysis were used to reveal potential roles of the HSEPs in enhancing tumour cell progression and in modulating host immunity. Functional clustering was applied to study enhanced EVs biogenesis and secretion in hypoxic cancer cells. Subsequent biochemical functional assays were performed in A549 and H1299 lung cancer cells to validate the hypoxic cancer-derived EVs in promoting cancer progression.Results: Results revealed that hypoxia stimulated cancer cells to synthesize EVs proteins involved in enhancing tumour cell proliferation (NRSN2, WISP2, SPRX1, LCK), metastasis (GOLM1, STC1, MGAT5B), stemness (STC1, TMEM59), angiogenesis (ANGPTL4), and suppressing host immunity (CD70). In addition, functional clustering analyses revealed that tumour hypoxia was strongly associated with rapid synthesis and EV loading of lysosome-related hydrolases and membrane-trafficking proteins to enhance EVs secretion. Moreover, lung cancer-derived EVs were also enriched in signalling molecules capable of inducing epithelial-mesenchymal transition in recipient cancer cells to promote their migration and invasion. Conclusion: Together, these data indicate that lung cancer-derived EVs can act as paracrine/autocrine mediators of tumorigenesis and metastasis in hypoxic microenvironments. Tumour EVs may therefore offer novel opportunities for useful biomarkers discovery and therapeutic targeting of different cancer types and at different stages according to microenvironmental conditions.

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Hypoxia-induced PLOD2 promotes proliferation, migration and invasion via PI3K/Akt signaling in glioma

Cited by 85 publications

References 40 publications

P4HA2 is associated with prognosis, promotes proliferation, invasion, migration and EMT in glioma

P4HA2 is associated with prognosis, promotes proliferation, invasion, migration and EMT in glioma

IL‐17A promotes cell migration and invasion of glioblastoma cells via activation of PI3K/AKT signalling pathway

Microenvironmental Hypoxia Induces Dynamic Changes in Lung Cancer Synthesis and Secretion of Into Extracellular Vesicles

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