Suppression of the Epidermal Growth Factor-like Domain 7 and Inhibition of Migration and Epithelial-Mesenchymal Transition in Human Pancreatic Cancer PANC-1 Cells

Wang, Yunliang; Dong, Fenglin; Yang, Jian; Li, Zhi; Zhi, Qiaoming; Zhao, Xin; Yang, Yong; Li, Dechun; Shen, Xinyong; Zhou, Jin

doi:10.7314/apjcp.2015.16.9.4065

Cited by 10 publications

(11 citation statements)

References 21 publications

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“…Afterwards, the expression of EGFL7 was reported to be differentially altered in a number of tumor types and it was stated that it may contribute to the initiation and progression of cancers [18,19,20,21,22]. In our previous study, we knocked down EGFL7 expression by RNA interference and found that highly expressed EGFL7 promoted the migration of PANC-1 cells and acted through the transcription factors snail and slug to induce EMT in pancreatic cancer [35]. In another study on pancreatic cancer, we demonstrated that silencing of the EGFL7 expression had a strong inhibitory effect on the tubular formation of microvessels through downregulation of the protein levels of VEGF and Ang-2 [17].…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Induces Multidrug Resistance via Enhancement of Epidermal Growth Factor-Like Domain 7 Expression in Non-Small Lung Cancer Cells

Shen

Zhi²,

Wang³

et al. 2017

Chemotherapy

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Chemotherapy is widely used in non-small cell lung cancer (NSCLC) treatment, yet multidrug resistance (MDR) is a major chemotherapeutic obstacle in both resectable and advanced NSCLC. Epidermal growth factor-like domain 7 (EGFL7), also known as vascular endothelial stain, is an endothelial cell-derived secreted factor that regulates vascular tube formulation. The aim of this study was to investigate the potential relationships between EGFL7 and MDR in NSCLC cells. We first obtained the CDDP-based MDR phenotype cell line A549/CDDP by repeated exposure to a proper concentration of CDDP (cisplatin) from original A549 cells. These A549/CDDP cells, which maintained relative high levels of EGFL7 and P-glycoprotein (P-gp), were resistant to other chemotherapy drugs, such as carboplatin (CBP), paclitaxel (TAX), and gemcitabine (GEM) (p < 0.05). We also found that hypoxia significantly reduced the chemosensitivity of NSCLC cells, and hypoxia-induced MDR was mediated by P-gp and EGFL7 (p < 0.05). EGFL7 was veryy relevant to NSCLC cell MDR, and downregulation of EGFL7 could significantly increase the chemosensitivity of NSCLC cells (p < 0.05). Thus, our findings first indicate that hypoxia induced NSCLC cell MDR at least partly by enhancing the expression of EGFL7 protein. EGFL7 might be a feasible target for reversing hypoxia-mediated MDR in NSCLC cells and a promising biomarker for predicting the development of MDR in NSCLC patients on chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Hypoxia Induces Multidrug Resistance via Enhancement of Epidermal Growth Factor-Like Domain 7 Expression in Non-Small Lung Cancer Cells

Shen

Zhi²,

Wang³

et al. 2017

Chemotherapy

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“…Epidermal growth factor (EGF)-like (EGFL) family proteins contain multiple EGF repeats and trigger multiple biological functions, including angiogenesis, proliferation, apoptosis, cell cycle regulation, migration, and invasion via binding to their receptors. [6][7][8] Recently, EGF-like proteins, such as EGFL7 and Heparin-binding-EGF, have been shown to play a role in carcinogenesis. 8,9 EGFL6, also called MAEG, is an approximately 60 kDa secreted protein with EGF structural homology located on the human Xp22 chromosome.…”

mentioning

confidence: 99%

“…[6][7][8] Recently, EGF-like proteins, such as EGFL7 and Heparin-binding-EGF, have been shown to play a role in carcinogenesis. 8,9 EGFL6, also called MAEG, is an approximately 60 kDa secreted protein with EGF structural homology located on the human Xp22 chromosome. 6,10,11 EGFL6 has been detected in several tissue samples and cell types, including hair follicles, endothelium, and cancer cells.…”

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confidence: 99%

EGFL6 promotes cell proliferation in colorectal cancer via regulation of the WNT/β‐catenin pathway

Zhang

Tang

et al. 2019

Molecular Carcinogenesis

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Epidermal growth factor‐like protein 6 (EGFL6) serves as an exocrine protein promoting proliferation and migration during carcinogenesis in ovarian cancer. However, its function and mechanisms in colorectal cancer (CRC) have not been completely explored. To investigate the role of EGFL6 in CRC cell growth, in vitro CCK8, colony formation assays, flow cytometric analysis of the cell cycle and apoptosis, and an in vivo tumor xenograft model were utilized. Additionally, Western blotting and luciferase reporter assays were used to investigate the underlying mechanisms of EGFL6 function on the WNT/β‐catenin signaling pathway. Immunohistochemical staining showed that EGFL6 is overexpressed in CRCs and this overexpression was highly correlated with advanced T classification, N classification, distant metastasis, and poor survival. Knocking down EGFL6 in CRC cell lines induced the inhibition of cell growth, cell cycle arrest at the G0/G1 phase, and apoptosis. Further, knockdown of EGFL6 blocked WNT/β‐catenin signaling as measured by Western blotting and luciferase reporter assay. Results also showed that recombinant EGFL6 (rEGFL6) induced β‐catenin in a concentration‐ and time‐dependent manner. Further experiments showed that administration of rEGFL6 to cell cultures with EGFL6 knocked down or treated with the WNT/β‐catenin inhibitor ICG‐001 increased β‐catenin and its downstream protein CyclinD1. The CCK8 assay showed that EGFL6 promoted CRC cell growth partly by the promotion of TCF7L2 expression. These findings suggest that EGFL6 plays a crucial role in the progression of CRC by regulation of the WNT/β‐catenin signaling pathway.

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“…In addition, many preclinical and clinical studies have implicated EGFL7 in cancer development and metastasis, with high EGFL7 expression in many epithelial cancers commonly observed. Furthermore, EGFL7 is known to modulate tumor metastasis through the EGFR‐Akt‐Snail pathway in gastric cancer (Luo et al, ), PC (Wang, Dong et al, ), and immune evasion in breast cancer (Delfortrie et al, ; Pannier et al, ). Several studies have also shown the association between miR‐126 and regulation of VEGF/EGFL7 in several metastatic cancers, thus revealing exciting molecular insights on tumourigenesis and metastasis in these cancers.…”

Section: Resultsmentioning

confidence: 99%

EGFL7: Master regulator of cancer pathogenesis, angiogenesis and an emerging mediator of bone homeostasis

Hong

Kuek

Shi

et al. 2018

Journal Cellular Physiology

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Epidermal growth factor-like domain-containing protein 7 (EGFL7), a member of the epidermal growth factor (EGF)-like protein family, is a potent angiogenic factor expressed in many different cell types. EGFL7 plays a vital role in controlling vascular angiogenesis during embryogenesis, organogenesis, and maintaining skeletal homeostasis. It regulates cellular functions by mediating the main signaling pathways (Notch, integrin) and EGF receptor cascades. Accumulating evidence suggests that Egfl7 plays a crucial role in cancer biology by modulating tumor angiogenesis, metastasis, and invasion. Dysregulation of Egfl7 has been frequently found in several types of cancers, such as malignant glioma, colorectal carcinoma, oral and oesophageal cancers, gastric cancer, hepatocellular carcinoma, pancreatic cancer, breast cancer, lung cancer, osteosarcoma, and acute myeloid leukemia. In addition, altered expression of miR-126, a microRNA associated with Egfl7, was found to play an important role in oncogenesis. More recently, our study has shown that EGFL7 is expressed in both the osteoclast and osteoblast lineages and promotes endothelial cell activities via extracellular signal-regulated kinase (ERK), signal transducer and activator of transcription 3 (STAT3), and integrin signaling cascades, indicative of its angiogenic regulation in the bone microenvironment. Thus, understanding the role of EGFL7 may provide novel insights into the development of improved diagnostics and therapeutic treatment for cancers and skeletal pathological disorders, such as ischemic osteonecrosis and bone fracture healing.

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Suppression of the Epidermal Growth Factor-like Domain 7 and Inhibition of Migration and Epithelial-Mesenchymal Transition in Human Pancreatic Cancer PANC-1 Cells

Cited by 10 publications

References 21 publications

Hypoxia Induces Multidrug Resistance via Enhancement of Epidermal Growth Factor-Like Domain 7 Expression in Non-Small Lung Cancer Cells

Hypoxia Induces Multidrug Resistance via Enhancement of Epidermal Growth Factor-Like Domain 7 Expression in Non-Small Lung Cancer Cells

EGFL6 promotes cell proliferation in colorectal cancer via regulation of the WNT/β‐catenin pathway

EGFL7: Master regulator of cancer pathogenesis, angiogenesis and an emerging mediator of bone homeostasis

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