Human fibulin-3 protein variant expresses anti-cancer effects in the malignant glioma extracellular compartment in intracranial xenograft models

Li, Yanyan; Hu, Yuan; Liu, Chuanjin; Wang, Qingyue; Han, Xiaoxiao; Han, Yong; Xie, Xiumin; Chen, Xiong-Hui; Li, Xiang; Siegel, Eric R.; Afrasiabi, Kambiz; Linskey, Mark E.; Zhou, Youxin; Zhou, Yihong

doi:10.18632/oncotarget.22344

Cited by 8 publications

(11 citation statements)

References 21 publications

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“…[33][34][35][36] However, in human gliomas, EFEMP1 was significantly up-regulated and promoted tumor cell motility and invasion with elevated expression and activity of matrix metalloproteases, such as MMP-2, MMP-9, ADAMTS-5 and ADAM17. [37][38][39] In conclusion, there are reports for prooncogenic and anti-oncogenic roles for EFEMP2, and more in-depth research is needed in the future.…”

Section: Discussionmentioning

confidence: 96%

<p>EFEMP2 Suppresses the Invasion of Lung Cancer Cells by Inhibiting Epithelial-Mesenchymal Transition (EMT) and Down-Regulating MMPs</p>

Song¹,

Li²,

Liu³

et al. 2020

OTT

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Background: Epidermal growth factor-containing fibulin-like extracellular matrix protein 2 (EFEMP2), also known as fibulin-4, MBP1 and UPH1, is an extracellular matrix protein associated with a variety of tumors. The purpose of this study was to investigate the prognostic value and the function of EFEMP2 in lung cancer. Methods: The mRNA and protein expression of EFEMP2 in lung normal and cancer tissues, lung cancer cell lines (A549, H460, H1299 and H1650) and normal epithelial cell line BEAS-2B were evaluated by immunohistochemistry, RT-qPCR and Western blotting. The Public databases (Oncomine and Kaplan-Meier plotter) were used to investigate the prognostic value of EFEMP2 in lung cancer. RNA interference (RNAi) and overexpression transfection were performed to detect the effects of EFEMP2 up-or down-regulation on lung normal and cancer cell proliferation, invasion and metastasis in vitro and in vivo. Results: EFEMP2 was lowly expressed in lung cancer tissues and cells, and its low expression was associated with malignant phenotype and poor prognosis of lung cancer. The same conclusion had been drawn from the Public databases. EFEMP2 overexpression significantly inhibited the invasion of lung cancer cells, hampered the process of EMT, and decreased the expression and activity of MMP2 and MMP9, while EFEMP2 knockdown remarkably enhanced the invasion of lung cancer cells, promoted EMT, and increased the expression and activity of MMP2 and MMP9. Conclusion: The low expression of EFEMP2 was detected in lung cancer and was positively correlated with the poor prognosis of patients. EFEMP2 was a tumor suppressor gene that inhibited the progress of lung cancer, which suggested a new research objective for the future studies.

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Section: Discussionmentioning

confidence: 96%

<p>EFEMP2 Suppresses the Invasion of Lung Cancer Cells by Inhibiting Epithelial-Mesenchymal Transition (EMT) and Down-Regulating MMPs</p>

Song¹,

Li²,

Liu³

et al. 2020

OTT

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“…5 The same multifaceted tumor suppression mechanisms of ZR30 were found in treated GBM cell lines and primary cultures, as also shown by induction of h-fibulin-3-v expression in GBM cells. 4,5 Initially, EFEMP1 was reported to have a role in antiangiogenesis. 6 The cell context-dependent dual function of EFEMP1 in cancer appears to complicate its role in tumor vascularization.…”

Section: Introductionmentioning

confidence: 63%

“…23,24 We have shown ZR30's effect on inhibition of extracellular activation of MMP2 and attenuation of phosphorylation of AKT in both types of glioma cells with high expression of NOTCH1 or EGFR. 5 Along with suppression of GBM cell ETD, these findings suggest at least 3 convergent, but independent, mechanisms of action of ZR30 in suppression of GBM vascularization.…”

Section: Zr30 Does Not Affect Gbm Cell Growth In Vitromentioning

confidence: 82%

“…ZR30 used in this study was provided by Ziren Research. It was made by an in vitro cell‐free system based on the sequence of the h‐fibulin‐3‐v, excluding the signal peptide, as detailed previously …”

Section: Methodsmentioning

confidence: 99%

“…Each BALB/c nude mouse (SPF level, 5-6 weeks old, female; Shanghai SLAC Laboratory Animal Co.) was implanted with a guide cannula in the right frontal lobe, and then 3 μL glioma cells (9:1 mixture of 51A-GFP and 51B-RFP, a total of 1 × 10 5 cells) was injected through the guide cannula, as described previously. 5 Nineteen days after cell implantation, 5 μL PBS or ZR30 (180 ng/μL) was injected through the guide cannula into the cell implantation site. Two weeks after treatment, right hemispheres were removed from both groups of mice and processed for immunohistochemistry using primary Ab of anti-CD31 (ab182981; Abcam), as detailed previously.…”

Section: Intracranial Human Gbm Xenografts and Immunohistochemistrymentioning

confidence: 99%

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Dual antivascular function of human fibulin‐3 variant, a potential new drug discovery strategy for glioblastoma

Luo

Cen

et al. 2020

Cancer Science

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The ECM protein EFEMP1 (fibulin‐3) is associated with all types of solid tumor through its cell context‐dependent dual function. A variant of fibulin‐3 was engineered by truncation and mutation to alleviate its oncogenic function, specifically the proinvasive role in glioblastoma multiforme (GBM) cells at stem‐like state. ZR30 is an in vitro synthesized 39‐kDa protein of human fibulin‐3 variant. It has a therapeutic effect in intracranial xenograft models of human GBM, through suppression of epidermal growth factor receptor/AKT and NOTCH1/AKT signaling in GBM cells and extracellular MMP2 activation. Glioblastoma multiforme is highly vascular, with leaky blood vessels formed by tumor cells expressing endothelial cell markers, including CD31. Here we studied GBM intracranial xenografts, 2 weeks after intratumoral injection of ZR30 or PBS, by CD31 immunohistochemistry. We found a 70% reduction of blood vessel density in ZR30‐treated xenografts compared with that of PBS‐treated ones. Matrigel plug assays showed the effect of ZR30 on suppressing angiogenesis. We further studied the effect of ZR30 on genes involved in endothelial transdifferentiation (ETD), in 7 primary cultures derived from 3 GBMs under different culture conditions. Two GBM cultures formed mesh structures with upregulation of ETD genes shortly after culture in Matrigel Matrix, and ZR30 suppressed both. ZR30 also downregulated ETD genes in two GBM cultures with high expression of these genes. In conclusion, multifaceted tumor suppression effects of human fibulin‐3 variant include both suppression of angiogenesis and vasculogenic mimicry in GBM.

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Relationship between expression of XRCC1 and tumor proliferation, migration, invasion, and angiogenesis in glioma

et al. 2018

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Human fibulin-3 protein variant expresses anti-cancer effects in the malignant glioma extracellular compartment in intracranial xenograft models

Cited by 8 publications

References 21 publications

<p>EFEMP2 Suppresses the Invasion of Lung Cancer Cells by Inhibiting Epithelial-Mesenchymal Transition (EMT) and Down-Regulating MMPs</p>

<p>EFEMP2 Suppresses the Invasion of Lung Cancer Cells by Inhibiting Epithelial-Mesenchymal Transition (EMT) and Down-Regulating MMPs</p>

Dual antivascular function of human fibulin‐3 variant, a potential new drug discovery strategy for glioblastoma

Relationship between expression of XRCC1 and tumor proliferation, migration, invasion, and angiogenesis in glioma

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