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.
Highlights
Colorectal cancer (CRC) is the third most common malignant tumor and the second highest cause of cancer-associated death worldwide, with estimated more than 1.8 million new patients as well as over 800,000 deaths in 2018 [1]
We identified that knockdown of Peroxisome proliferator-activated receptor b/d/D (PPARd) promoted colorectal cancer (CRC) angiogenesis both in vitro and in vivo
Mechanistic studies showed that knockdown of PPARd induced angiogenesis by upregulating vascular endothelial growth factor A (VEGFA) via endoplasmic reticulum oxidoreductase 1 alpha (ERO1A) in CRC cells
Summary
Colorectal cancer (CRC) is the third most common malignant tumor and the second highest cause of cancer-associated death worldwide, with estimated more than 1.8 million new patients as well as over 800,000 deaths in 2018 [1]. Combining antiangiogenic drugs with established chemotherapeutic regimens has increased the median overall survival of mCRC patients from 12 months in the mid-1990s to almost 30 months [6, 7]. These antiangiogenic drugs fail to elicit long-lasting clinical responses in most patients due to primary or acquired resistance [8,9,10]. The underlying mechanisms of therapeutic resistance remain unclear This gap in knowledge is partly a result of the poor understanding of the molecular mechanisms of altered angiogenesis in the tumor microenvironment. It is imperative to explore the complex angiogenic mechanisms of CRC to provide more potential targets for the development of therapeutic treatments
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