Dataset Information

Knockdown of PPARδ Induces VEGFA-Mediated Angiogenesis via Interaction With ERO1A in Human Colorectal Cancer.

ABSTRACT: Angiogenesis is an important mechanism underlying the development and metastasis of colorectal cancer (CRC) and has emerged as a therapeutic target for metastatic CRC (mCRC). Our recent studies found that Peroxisome proliferator-activated receptor β/δ/D (PPARδ) regulates vascular endothelial growth factor A(VEGFA) secretion and the sensitivity to bevacizumab in CRC. However, its exact effect and underlying mechanisms remain unidentified. In this study, we showed that PPARδ expression was inversely associated with the microvascular density in human CRC tissues. Knockdown of PPARδ enhanced VEGFA expression in HCT116 cells and HUVEC angiogenesis in vitro; these phenomena were replicated in the experimental in vivo studies. By tandem mass tag (TMT)-labeling proteomics and chromatin immunoprecipitation sequencing (ChIP-seq) analyses, endoplasmic reticulum oxidoreductase 1 alpha (ERO1A) was screened and predicted as a target gene of PPARδ. This was verified by exploring the effect of coregulation of PPARδ and ERO1A on the VEGFA expression in HCT116 cells. The results revealed that PPARδ induced VEGFA by interacting with ERO1A. In conclusion, our results suggest that knockdown of PPARδ can promote CRC angiogenesis by upregulating VEGFA through ERO1A. This pathway may be a potential target for mCRC treatment.

SUBMITTER: Luo W

PROVIDER: S-EPMC8546184 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Knockdown of PPARδ Induces VEGFA-Mediated Angiogenesis <i>via</i> Interaction With ERO1A in Human Colorectal Cancer.

Luo Wenjun W He Diao D Zhang Jianhao J Ma Zida Z Chen Keling K Lv Zhaoying Z Fan Chuanwen C Yang Lie L Li Yuan Y Zhou Zongguang Z

Frontiers in oncology 20211012

Angiogenesis is an important mechanism underlying the development and metastasis of colorectal cancer (CRC) and has emerged as a therapeutic target for metastatic CRC (mCRC). Our recent studies found that Peroxisome proliferator-activated receptor β/δ/D (PPARδ) regulates vascular endothelial growth factor A(VEGFA) secretion and the sensitivity to bevacizumab in CRC. However, its exact effect and underlying mechanisms remain unidentified. In this study, we showed that PPARδ expression was inverse ...[more]

PMID: 34712608

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Project description:BackgroundCancer stem cells are a small subpopulation of cells which are responsible for tumor metastasis, angiogenesis, drug resistance etc. 5-Fluorouracil (5FU), a common therapeutic drug used in colorectal cancer treatment is reported to enrich CSCs, tumor recurrence and induces severe organ toxicities resulting in poor clinical outcome in patients. Therefore, we introduced a natural flavonoid Orientin in combination with 5FU to mitigate the CSC mediated angiogenesis and induced toxicities.MethodsTumorosphere generation, flow cytometry, immunofluorescence assay, and western blotting were performed by using 5FU and Orientin individually and both treated colorectal cells and CSCs. In silico study was carried out to check the interaction between HIF1α and Orientin. In ovo chorioallantoic membrane (CAM) assay and tube formation assay using HUVECs were performed to monitor CSC mediated angiogenesis. In vivo CT26 syngeneic mice model was used to validate in silico and ex vivo results.ResultsWe found that 5FU treatment significantly increased the CD44+/CD133+ CSC population. In contrast, this CSC population in CSC enriched spheres (CES) derived from HCT116 cells were decreased by combination of Orientin and 5FU. Decrease of CSC's stemness properties was also noted, as evidenced by the downregulation of NANOG, SOX2 and OCT4. This new therapeutic strategy also inhibited CSC mediated angiogenesis by downregulating 5FU induced ROS, NO and LPO in those tumorospheres. Combination of Orientin and 5FU significantly reduced CSC mediated angiogenesis in HUVEC and CAM. Additionally, in silico study predicted that Orientin can bind to the PAS domain of HIF1α, a crucial factor for promoting angiogenesis. Expression of HIF1α and VEGFA were also decreased when the CESs were exposed to the combinatorial treatment. Additionally, we found that treatment with 5FU alone resulted reduction in tumor volume but it enriched CSCs and produced nephrotoxicity and hepatotoxicity in vivo. Combined treatment also considerably reduced the CD44+/CD133+ CSC population and hindered angiogenesis in a therapeutic in vivo model in BALB/c mice.ConclusionsThis novel treatment strategy of "Orientin with 5FU" is likely to improve the efficiency of conventional chemotherapy and may suppress disease recurrence in colorectal cancer by limiting CSC mediated angiogenesis.

Dataset Information

Knockdown of PPARδ Induces VEGFA-Mediated Angiogenesis via Interaction With ERO1A in Human Colorectal Cancer.

Publications

Knockdown of PPARδ Induces VEGFA-Mediated Angiogenesis <i>via</i> Interaction With ERO1A in Human Colorectal Cancer.

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