Dataset Information

Thalidomide targets EGFL6 to inhibit EGFL6/PAX6 axis-driven angiogenesis in small bowel vascular malformation.

ABSTRACT: BACKGROUND:Small bowel vascular malformation disease (SBVM) is the most common cause of obscure gastrointestinal bleeding (OGIB). Several studies suggested that EGFL6 was able to promote the growth of tumor endothelial cells by forming tumor vessels. To date, it remains unclear how EGFL6 promotes pathological angiogenesis in SBVM and whether EGFL6 is a target of thalidomide. METHODS:We took advantage of SBVM plasma and tissue samples and compared the expression of EGFL6 between SBVM patients and healthy people via ELISA and Immunohistochemistry. We elucidated the underlying function of EGFL6 in SBVM in vitro and by generating a zebrafish model that overexpresses EGFL6, The cycloheximide (CHX)-chase experiment and CoIP assays were conducted to demonstrate that thalidomide can promote the degradation of EGFL6 by targeting CRBN. RESULTS:The analysis of SBVM plasma and tissue samples revealed that EGFL6 was overexpressed in the patients compared to healthy people. Using in vitro and in vivo assays, we demonstrated that an EMT pathway triggered by the EGFL6/PAX6 axis is involved in the pathogenesis of SBVM. Furthermore, through in vitro and in vivo assays, we elucidated that thalidomide can function as anti-angiogenesis medicine through the regulation of EGFL6 in a proteasome-dependent manner. Finally, we found that CRBN can mediate the effect of thalidomide on EGFL6 expression and that the CRBN protein interacts with EGFL6 via a Lon N-terminal peptide. CONCLUSION:Our findings revealed a key role for EGFL6 in SBVM pathogenesis and provided a mechanism explaining why thalidomide can cure small bowel bleeding resulting from SBVM.

SUBMITTER: Tang CT

PROVIDER: S-EPMC7671996 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Thalidomide targets EGFL6 to inhibit EGFL6/PAX6 axis-driven angiogenesis in small bowel vascular malformation.

Tang Chao-Tao CT Zhang Qing-Wei QW Wu Shan S Tang Ming-Yu MY Liang Qian Q Lin Xiao-Lu XL Gao Yun-Jie YJ Ge Zhi-Zheng ZZ

Cellular and molecular life sciences : CMLS 20200201 24

<h4>Background</h4>Small bowel vascular malformation disease (SBVM) is the most common cause of obscure gastrointestinal bleeding (OGIB). Several studies suggested that EGFL6 was able to promote the growth of tumor endothelial cells by forming tumor vessels. To date, it remains unclear how EGFL6 promotes pathological angiogenesis in SBVM and whether EGFL6 is a target of thalidomide.<h4>Methods</h4>We took advantage of SBVM plasma and tissue samples and compared the expression of EGFL6 between SB ...[more]

PMID: 32008086

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Project description:Rationale: Angiogenesis and osteogenesis are highly coupled processes which are indispensable to bone repair. However, the underlying mechanism(s) remain elusive. To bridge the gap in understanding the coupling process is crucial to develop corresponding solutions to abnormal bone healing. Epidermal growth factor-like protein 6 (EGFL6) is an angiogenic factor specifically and distinctively up-regulated during osteoblast differentiation. In contrast with most currently known osteoblast-derived coupling factors, EGFL6 is highlighted with little or low expression in other cells and tissues. Methods: In this study, primary bone marrow mesenchymal stem cells (MSCs) and osteoblastic cell line (MC3T3-E1) were transduced with lentiviral silencing or overexpression constructs targeting EGFL6. Cells were induced by osteogenic medium, followed by the evaluation of mineralization as well as related gene and protein expression. Global and conditional knockout mice were established to examine the bone phenotype under physiological condition. Furthermore, bone defect models were created to investigate the outcome of bone repair in mice lacking EGFL6 expression. Results: We show that overexpression of EGFL6 markedly enhances osteogenic capacity in vitro by augmenting bone morphogenic protein (BMP)-Smad and MAPK signaling, whereas downregulation of EGFL6 diminishes osteoblastic mineralization. Interestingly, osteoblast differentiation was not affected by the exogenous addition of EGFL6 protein, thereby indicating that EGFL6 may regulate osteoblastic function in an intracrine manner. Mice with osteoblast-specific and global knockout of EGFL6 surprisingly exhibit a normal bone phenotype under physiological conditions. However, EGFL6-deficiency leads to compromised bone repair in a bone defect model which is characterized by decreased formation of type H vessels as well as osteoblast lineage cells. Conclusions: Together, these data demonstrate that EGFL6 serves as an essential regulator to couple osteogenesis to angiogenesis during bone repair.

Dataset Information

Thalidomide targets EGFL6 to inhibit EGFL6/PAX6 axis-driven angiogenesis in small bowel vascular malformation.

Publications

Thalidomide targets EGFL6 to inhibit EGFL6/PAX6 axis-driven angiogenesis in small bowel vascular malformation.

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