Abstract
In our previous study, ETV5 mediated-angiogenesis was demonstrated to be dependent upon the PDGF-BB/PDGFR-β/Src/STAT3/VEGFA pathway in colorectal cancer (CRC). However, the ability of ETV5 to affect the efficacy of anti-angiogenic therapy in CRC requires further investigation. Gene set enrichment analysis (GSEA) and a series of experiments were performed to identify the critical candidate gene involved in Bevacizumab resistance. Furthermore, the ability of treatment targeting the candidate gene to enhance Bevacizumab sensitivity in vitro and in vivo was investigated. Our results revealed that ETV5 directly bound to the VEGFA promoter to promote translation of VEGFA. However, according to in vitro and in vivo experiments, ETV5 unexpectedly accelerated antiVEGF therapy (Bevacizumab) resistance. GSEA and additional assays confirmed that ETV5 could promote angiogenesis by inducing the secretion of another tumor angiogenesis factor (CCL2) in CRC cells to facilitate Bevacizumab resistance. Mechanistically, ETV5 upregulated CCL2 by activating STAT3 to facilitate binding with the CCL2 promoter. ETV5 induced-VEGFA translation and CCL2 secretion were mutually independent mechanisms, that induced angiogenesis by activating the PI3K/AKT and p38/MAPK signaling pathways in human umbilical vein endothelial cells (HUVECs). In CRC tissues, ETV5 protein levels were positively associated with CD31, CCL2, and VEGFA protein expression. CRC patients possessing high expression of ETV5/VEGFA or ETV5/CCL2 exhibited a poorer prognosis compared to that of other patients. Combined antiCCL2 and antiVEGFA (Bevacizumab) treatment could inhibit tumor angiogenesis and growth more effectively than single treatments in CRCs with high expression of ETV5 (ETV5+ CRCs). In conclusion, our results not only revealed ETV5 as a novel biomarker for anti-angiogenic therapy, but also indicated a potential combined therapy strategy that involved in targeting of both CCL2 and VEGFA in ETV5+ CRC.
Highlights
Colorectal cancer (CRC) is one of the most common cancers worldwide, and its morbidity and mortality rank third among all cancers[1]
Our previous study found that PDGF-BB could activate vascular endothelial growth factor A (VEGFA) expression via the PDGFR-β/Src/STAT3 pathway in CRC19, and our present results indicated that E26 transformation-specific variant 5 (ETV5) could upregulate VEGFA via transcriptional activation of VEGFA in CRC
chorioallantoic membrane (CAM) assays were performed and the results indicated that the HT29/shETV5 group treated with a combination of recombinant human CC-chemokine ligand 2 (CCL2), and VEGFA protein exhibited a higher level of angiogenesis than that exhibited by those groups exposed to individual treatments of recombinant human CCL2 or VEGFA protein
Summary
Colorectal cancer (CRC) is one of the most common cancers worldwide, and its morbidity and mortality rank third among all cancers[1]. Despite advancements in the Angiogenesis is a hallmark process in the oncogenesis of CRC3–5, and vascular endothelial growth factor A (VEGFA) and its receptors (VEGFR-1/VEGFR-2) play dominant roles in the regulation of this complex process. Attenuation of VEGF-VEGFR signaling can disrupt vascularization, and this has been considered as a promising therapeutic strategy for CRC6. Bevacizumab, a clinically used anti-angiogenic drug, can target VEGFA to inhibit VEGF–VEGFR signaling[6]. Official journal of the Cell Death Differentiation Association. Feng et al Cell Death and Disease (2020)11:916 is the first-line treatment for metastatic CRC6–8. Some CRC patients are resistant to Bevacizumab, and the overall response rate is limited[9]. Exploration of mechanisms of resistance to anti-angiogenic treatments will be beneficial for identification of potential targets, that can be exploited to overcome Bevacizumab resistance in CRC
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