Dataset Information

The role of anlotinib-mediated EGFR blockade in a positive feedback loop of CXCL11-EGF-EGFR signalling in anaplastic thyroid cancer angiogenesis.

ABSTRACT:

Background

Hypoxia-induced angiogenesis functions importantly in anaplastic thyroid cancer (ATC) progression. However, the therapeutic potential of broad-spectrum anti-angiogenic agent remains undefined. Anlotinib conventionally targets VEGFR, FGFR and PDGFR. Here, a novel role of anlotinib on ATC angiogenesis was illustrated.

Methods

Molecular expressions were established via tissue microarray. Multiple assays (tubule formation, 3D sprouting and chicken chorioallantoic membrane model) were used for angiogenic evaluation. Panels of molecular screening were achieved by antibody and PCR arrays. The loop binding motif of EGFR for homology modelling was prepared using Maestro.

Results

Anlotinib could dose- and time-dependently inhibit cell viability under normoxia and hypoxia and could repress hypoxia-activated angiogenesis more efficiently in vitro and in vivo. CXCL11 and phospho-EGFR were hypoxia-upregulated with a positive correlation. The cancer-endothelium crosstalk could be mediated by the positive CXCL11-EGF-EGFR feedback loop, which could be blocked by anlotinib directly targeting EGFR via a dual mechanism by simultaneous inhibitory effects on cancer and endothelial cells. The AKT-mTOR pathway was involved in this regulatory network.

Conclusions

The newly identified CXCL11-EGF-EGFR signalling provided mechanistic insight into the interaction between cancer and endothelial cells under hypoxia, and EGFR was a novel target. Anlotinib may be the encouraging therapeutic candidate in ATC.

SUBMITTER: Liang J

PROVIDER: S-EPMC8328993 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Publications

The role of anlotinib-mediated EGFR blockade in a positive feedback loop of CXCL11-EGF-EGFR signalling in anaplastic thyroid cancer angiogenesis.

Liang Juyong J Jin Zhijian Z Kuang Jie J Feng Haoran H Zhao Qiwu Q Yang Zheyu Z Zhan Ling L Shen Baiyong B Yan Jiqi J Cai Wei W Cheng Xi X Qiu Weihua W

British journal of cancer 20210604 3

<h4>Background</h4>Hypoxia-induced angiogenesis functions importantly in anaplastic thyroid cancer (ATC) progression. However, the therapeutic potential of broad-spectrum anti-angiogenic agent remains undefined. Anlotinib conventionally targets VEGFR, FGFR and PDGFR. Here, a novel role of anlotinib on ATC angiogenesis was illustrated.<h4>Methods</h4>Molecular expressions were established via tissue microarray. Multiple assays (tubule formation, 3D sprouting and chicken chorioallantoic membrane m ...[more]

PMID: 34088989

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Project description:BackgroundAngiogenesis plays a critical role in the progression of glioma. Previous studies have indicated that RNA-binding proteins (RBPs) interact with RNAs and participate in the regulation of the malignant behaviors of tumors. As a type of endogenous non-coding RNAs, circular RNAs (circRNAs) are abnormally expressed in various cancers and are involved in diverse tumorigeneses including angiogenesis.MethodsThe expression levels of FUS, circ_002136, miR-138-5p, SOX13, and SPON2 were determined using quantitative real-time PCR (qRT-PCR) and western blot. Transient cell transfection was performed using the Lipofectamine 3000 reagent. The RNA-binding protein immunoprecipitation (RNA-IP) and the RNA pull-down assays were used to detect the interaction between FUS and circ_002136. The dual-luciferase reporter assay system was performed to detect the binding sites of circ_002136 and miR-138-5p, miR-138-5p and SOX13. The chromatin immunoprecipitation (ChIP) assays were used to examine the interactions between transcription factor SOX13 and its target proteins .ResultsWe demonstrated that down-regulation of FUS or circ_002136 dramatically inhibited the viability, migration and tube formation of U87 glioma-exposed endothelial cells (GECs). MiR-138-5p was down-regulated in GECs and circ_002136 functionally targeted miR-138-5p in an RNA-induced silencing complex (RISC). Inhibition of circ_002136, combined with the restoration of miR-138-5p, robustly reduced the angiogenesis of GECs. As a target gene of miR-138-5p, SOX13 was overexpressed in GECs and was proved to be involved in circ_002136 and miR-138-5p-mediated angiogenesis in gliomas. In addition, we found that SOX13 was directly associated with and activated the SPON2 promoter, thereby up-regulating the expression of SPON2 at the transcriptional level. Knockdown of SPON2 suppressed the angiogenesis in GECs. More important, SOX13 activated the FUS promoter and increased its expression, forming a feedback loop.ConclusionOur data suggests that the feedback loop of FUS/circ_002136/miR-138-5p/SOX13 played a crucial role in the regulation of angiogenesis in glioma. This also provides a potential target and an alternative strategy for combined glioma therapy.

Dataset Information

The role of anlotinib-mediated EGFR blockade in a positive feedback loop of CXCL11-EGF-EGFR signalling in anaplastic thyroid cancer angiogenesis.

Background

Methods

Results

Conclusions

Publications

The role of anlotinib-mediated EGFR blockade in a positive feedback loop of CXCL11-EGF-EGFR signalling in anaplastic thyroid cancer angiogenesis.

Similar Datasets

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