Gremlin promotes retinal pigmentation epithelial (RPE) cell proliferation, migration and VEGF production via activating VEGFR2-Akt-mTORC2 signaling

Liu, Yuan; Chen, Zhijun; Cheng, Haixia; Chen, Juan; Qian, Jing

doi:10.18632/oncotarget.13518

Cited by 19 publications

(19 citation statements)

References 33 publications

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“…In agreement, staining of the tumor tissue with CD31 antibodies showed more staining and larger vessels in JP5/grem1 tumors (Figure 9B ). Gremlin-1 can signal through the VEGFR2 and it has also been recently linked to the regulation of VEGF expression in pigmentation epithelial cells [ 8 , 18 ]. Notably, VEGFA mRNA expression was decreased in gremlin-1 silenced mesothelioma cells and increased in JP5/grem1 cells as compared to the controls (Figure 9C ).…”

Section: Resultsmentioning

confidence: 99%

Gremlin-1 is a key regulator of the invasive cell phenotype in mesothelioma

et al. 2017

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Malignant mesothelioma originates from mesothelial cells and is a cancer type that aggressively invades into the surrounding tissue, has poor prognosis and no effective treatment. Gremlin-1 is a cysteine knot protein that functions by inhibiting BMP-pathway activity during development. BMP-independent functions have also been described for gremlin-1. We have previously shown high gremlin-1 expression in mesothelioma tumor tissue. Here, we investigated the functions of gremlin-1 in mesothelioma cell migration and invasive growth. Gremlin-1 promoted mesothelioma cell sprouting and invasion into three dimensional collagen and Matrigel matrices. The expression level of gremlin-1 was linked to changes in the expression of SNAI2, integrins, matrix metalloproteinases (MMP) and TGF-β family signaling - all previously associated with a mesenchymal invasive phenotype. Small molecule inhibitors of MMPs completely blocked mesothelioma cell invasive growth. In addition, inhibitors of TGF-β receptors significantly reduced invasive growth. This was associated with reduced expression of MMP2 but not SNAI2, indicating that gremlin-1 has both TGF-β pathway dependent and independent mechanisms of action. Results of in vivo mesothelioma xenograft experiments indicated that gremlin-1 overexpressing tumors were more vascular and had a tendency to send metastases. This suggests that by inducing a mesenchymal invasive cell phenotype together with enhanced tumor vascularization, gremlin-1 drives mesothelioma invasion and metastasis. These data identify gremlin-1 as a potential therapeutic target in mesothelioma.

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Section: Resultsmentioning

confidence: 99%

Gremlin-1 is a key regulator of the invasive cell phenotype in mesothelioma

et al. 2017

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“…Downstream activation of VEGFR2 includes ERK1/2, p38, Src and Akt pathways [8]. Seen in retinal pigment epithelial cells, GREMLIN, via VEGFR2, activates Akt-mTORC2 (mammalian target of rapamycin complex 2) signaling, and promotes cell proliferation, migration and VEGF production [63]. Commented above, PI3K is a key pathway in Nephrin signaling [37].…”

Section: Discussionmentioning

confidence: 99%

VEGFR2 Blockade Improves Renal Damage in an Experimental Model of Type 2 Diabetic Nephropathy

Lavoz

Rodrigues-Díez

Plaza

et al. 2020

JCM

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The absence of optimal treatments for Diabetic Nephropathy (DN) highlights the importance of the search for novel therapeutic targets. The vascular endothelial growth factor receptor 2 (VEGFR2) pathway is activated in experimental and human DN, but the effects of its blockade in experimental models of DN is still controversial. Here, we test the effects of a therapeutic anti-VEGFR2 treatment, using a VEGFR2 kinase inhibitor, on the progression of renal damage in the BTBR ob/ob (leptin deficiency mutation) mice. This experimental diabetic model develops histological characteristics mimicking the key features of advanced human DN. A VEGFR2 pathway-activation blockade using the VEGFR2 kinase inhibitor SU5416, starting after kidney disease development, improves renal function, glomerular damage (mesangial matrix expansion and basement membrane thickening), tubulointerstitial inflammation and tubular atrophy, compared to untreated diabetic mice. The downstream mechanisms involved in these beneficial effects of VEGFR2 blockade include gene expression restoration of podocyte markers and downregulation of renal injury biomarkers and pro-inflammatory mediators. Several ligands can activate VEGFR2, including the canonical ligands VEGFs and GREMLIN. Activation of a GREMLIN/VEGFR2 pathway, but not other ligands, is correlated with renal damage progression in BTBR ob/ob diabetic mice. RNA sequencing analysis of GREMLIN-regulated genes confirm the modulation of proinflammatory genes and related-molecular pathways. Overall, these data show that a GREMLIN/VEGFR2 pathway activation is involved in diabetic kidney disease and could potentially be a novel therapeutic target in this clinical condition.

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“…GREM1 increases hyperplasia and the invasiveness of synoviocytes via activation of ERK and Akt [47]. GREM1 activates the Akt signaling to promote proliferation, migration, and VEGF production in retinal pigmentation epithelial cells [48]. GREM1 utilizes both TGF-β/Smad and JNK/p38 MAPK signaling pathways to induce extracellular membrane proteins in human trabecular meshwork cells [49].…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that GREM1 can directly bind to VEGFR2 [51]. The GREM1-VEGFR2 pathway is involved in renal inflammation [52] and the proliferation of retinal pigmentation epithelial cells [48]. In addition, GREM1 induces EMT via VEGFR2 activation in tubular epithelial cells [36].…”

Section: Discussionmentioning

confidence: 99%

DHA inhibits Gremlin-1-induced epithelial-to-mesenchymal transition via ERK suppression in human breast cancer cells

et al. 2020

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Docosahexaenoic acid (DHA) is an omega-3 fatty acid abundant in fish oils. It is known to have an inhibitory effect on various diseases such as inflammation, diabetes, and cancer. Epithelial-to-mesenchymal transition (EMT) is a process that epithelial cells gain migratory property to become mesenchymal cells involved in wound healing, organ fibrosis, and cancer progression. Gremlin-1 (GREM1) is a bone morphogenetic protein antagonist known to play a role in EMT. However, the role of GREM1 in the induction of EMT in human breast cancer cells and the effect of DHA on GREM1-induced EMT remain unclear. Establishment of GREM1 knockdown cell lines was performed using lentiviral shRNAs. Expression of EMT markers was determined by qRT-PCR and Western blotting. Effect of GREM1 and/or DHA on cell migration was investigated using wound healing assay. The level of GREM1 expression in human breast cancer tissues was determined by Oncomine database mining. GREM1 induced the expression of genes including N-cadherin, vimentin, and Slug. GREM1 promoted the migration of human breast cancer cells. GREM1 enhanced the expression of phosphorylated extracellular signal-regulated kinase (p-ERK) and the ERK activation was involved in EMT. Interestingly, DHA reduced the expression of GREM1. DHA also inhibited the expression of mesenchymal cell-associated genes and cell migration induced by GREM1. Furthermore, DHA suppressed the expression of p-ERK induced by GREM1. These results indicate that GREM1-ERK axis plays a role in EMT in human breast cancer cells and DHA is a putative compound that can inhibit EMT by inhibiting GREM1 signal transduction.

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Gremlin promotes retinal pigmentation epithelial (RPE) cell proliferation, migration and VEGF production via activating VEGFR2-Akt-mTORC2 signaling

Cited by 19 publications

References 33 publications

Gremlin-1 is a key regulator of the invasive cell phenotype in mesothelioma

Gremlin-1 is a key regulator of the invasive cell phenotype in mesothelioma

VEGFR2 Blockade Improves Renal Damage in an Experimental Model of Type 2 Diabetic Nephropathy

DHA inhibits Gremlin-1-induced epithelial-to-mesenchymal transition via ERK suppression in human breast cancer cells

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