FOXF1 promotes angiogenesis and accelerates bevacizumab resistance in colorectal cancer by transcriptionally activating VEGFA

Wang, Shuyang; Xiao, Zihan; Hong, Zexuan; Jiao, Hong-Li; Zhu, Shirley; Zhao, Yali; Bi, Jiaxin; Qiu, Jun-Feng; Zhang, Dan; Yan, Junyu; Zhang, Lingjie; Huang, Chengmei; Li, Tingting; Li, Liang; Liao, Wenting; Ye, Yaping; Ding, Yan‐Qing

doi:10.1016/j.canlet.2018.09.026

Cited by 49 publications

(33 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further rescue experiments con rmed that ETV5-mediated CCL2 secretion by CRC cells promoted bevacizumab resistance in a manner of paracrine activation effect in HUVECs. Therefore, when the ETV5 + CRCs received bevacizumab treatment, the secreted CCL2 signaling pathway continued to activate angiogenesis-related pathway in HUVECs, such as PI3K/AKT and p38/MAPK signaling pathways, which resulted in angiogenesis [8]. Our resulted con rmed that ETV5-mediated secretion of CCL2 played a crucial role in bevacizumab resistance.…”

Section: Discussionsupporting

confidence: 52%

See 1 more Smart Citation

Targeting tumor cell-derived CCL2 as a strategy to overcome bevacizumab resistance in ETV5+ colorectal cancer

Feng

Liu

Liang

et al. 2020

Preprint

View full text Add to dashboard Cite

Background ETV5 mediated angiogenesis was dependent on PDGF-BB/PDGFR-β/Src/STAT3/VEGFA pathway in colorectal cancer (CRC) in our previous study. However, whether ETV5 affects effect of antiangiogenic therapy in CRC requires further investigation. Methods GSEA analysis and a series of experiments were performed to identify the critical candidate gene involved in bevacizumab resistance, and further explored whether the treatment targeting the candidate gene enhanced bevacizumab sensitivity in vitro and in vivo. Results ETV5 could directly bind to VEGFA promoter and promote translation of VEGFA. However, by in vitro and in vivo experiments, ETV5 actually accelerated anti-VEGF therapy (bevacizumab) resistance. GSEA analysis and further assays confirmed that ETV5 could promote angiogenesis by enhancing secretion of another tumor angiogenesis factor CCL2 in CRC cells, which resulted in bevacizumab resistance. ETV5 induced VEGFA and CCL2 were mutually independent to induce angiogenesis by activating PI3K/AKT and p38/MAPK signaling pathways in human umbilical vein endothelial cells. In CRC tissues, ETV5 protein level was positively associated with CD31, CCL2, VEGFA protein expression. CRC patients with high expression of ETV5/VEGFA or ETV5/CCL2 showed inferior prognosis than other patients. Combination of anti-CCL2 and anti-VEGFA (Bevacizumab) treatment could more effectively inhibited tumor angiogenesis and growth than single treatment did in CRCs with high expression of ETV5 (ETV5 + CRCs). Conclusions Our results not only revealed ETV5 as a novel biomarker for antiangiogenic therapy, but also indicated a potential combined therapy strategy by simultaneously targeting CCL2 and VEGFA in ETV5 + CRC.

show abstract

Section: Discussionsupporting

confidence: 52%

“…Bevacizumab, a clinically used antiangiogenic drug, can speci cally target VEGFA and then inhibit VEGF-VEGFR signaling [6]. Bevacizumab plus chemotherapy is the rst-line treatment option for metastatic CRC [6][7][8]. Nonetheless, some CRC patients are resistant to Bevacizumab, and the overall response rate is limited [9].…”

Section: Introductionmentioning

confidence: 99%

Targeting tumor cell-derived CCL2 as a strategy to overcome bevacizumab resistance in ETV5+ colorectal cancer

Feng

Liu

Liang

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…20 Numerous studies reveal that many gene alterations are involved in the initiation and progression of CRC. 4,21,22 ADHFE1 is a transcriptional differentially expressed gene (DEG) that was identified using CRC mRNA sequencing data from The Cancer Genome Atlas (TCGA) and GEO. ADHFE1 is mapped to human chromosome 8q13.1 and encodes the protein which belongs to the iron-activated alcohol dehydrogenase family.…”

Section: Discussionmentioning

confidence: 99%

<p>Hypermethylation Of ADHFE1 Promotes The Proliferation Of Colorectal Cancer Cell Via Modulating Cell Cycle Progression</p>

Hu¹,

Ma²,

Zhang³

et al. 2019

OTT

View full text Add to dashboard Cite

Background: Colorectal cancer (CRC) is one of the most common malignancies worldwide. Studies have demonstrated that epigenetic modifications play essential roles in the development of CRC. ADHFE1 is a differentially expressed gene that has been reported to be hypermethylated in CRC. However, the role and mechanism of ADHFE1 in the proliferation of CRC remain unclear. Materials and methods: ADHFE1 expression was analyzed in CRC tissues by IHC and qRT-PCR, and the relationship between ADHFE1 expression and the clinicopathological parameters was analyzed. Cell proliferation were assessed by the in vitro and in vivo experimental models. GSEA assay was performed to explore the mechanism of ADHFE1 in the proliferation of CRC. Flow cytometry and Western blot were used to detect the activation of the cell cycle signaling. Bisulfite genomic sequence (BSP) assay was used to test the methylation degree of ADHFE1 gene promoter in CRC tissues. Results: Here, we verified that ADHFE1 was down-regulated and hypermethylated in CRC tissues. The down-regulation of ADHFE1 was correlated with poor differentiation and advanced TNM stage of CRC patients. And ADHFE1 expression restored when the CRC cell line SW620 was treated with the demethylating agent 5-Aza-CdR. Overexpression of ADHFE1 inhibited the proliferation of CRC, while ADHFE1 knockdown promoted the proliferation of CRC cells in vitro and in vivo. Moreover, ADHFE1 overexpression could induce a significant G1-S cell cycle arrest in CRC cells and vice versa. Conclusion: Hypermethylation of ADHFE1 might promote cell proliferation by modulating cell cycle progression in CRC, potentially providing a new therapeutic target for CRC patients.

show abstract

“…RT-QPCR(Realtime-Quantitative reverse transcription polymerase chain reaction) and Western blot were done as previously described [33]. RT-QPCR primers were designed using Primer 5.0 software.…”

Section: Rt-qpcr and Western Blot Analysesmentioning

confidence: 99%

Downregulation of Siah1 promotes colorectal cancer cell proliferation and migration by regulating AKT and YAP ubiquitylation and proteasome degradation

et al. 2020

Self Cite

View full text Add to dashboard Cite

Background: Colorectal cancer (CRC) is one of the most common malignant tumors in the world. Siah E3 ubiquitin protein ligase 1 (Siah1) has been identified as a tumor suppressor gene and plays an important role in the development of malignant tumors. However, the potential role and molecular mechanism of Siah1 in the development and progression of CRC is still unclear. Methods: To explore the role and molecular mechanism of Siah1 in the development and progression of CRC, we examined the expression of Siah1 in CRC tissue samples and analyzed its association with progression and prognosis in CRC. In addition, overexpression and knockdown of Siah1 was used to investigate its activity in CRC cells. We also use bioinformatics to analyze and verify the significant roles of Siah1 in critical signaling pathways of CRC. Results: We found that the expression of Siah1 was significantly downregulated in CRC tissues, and low expression of Siah1 was associated with aggressive TNM staging and poor survival of CRC patients. Moreover, we revealed that overexpression of Siah1 in CRC cells markedly inhibited CRC cell proliferation and invasion in vitro and in vivo, while knockdown of Siah1 enhanced CRC cell proliferation and invasion. Furthermore, we found that Siah1 prohibited cell proliferation and invasion in CRC partially through promoting AKT (the serine-threonine protein kinase) and YAP (yes associated protein) ubiquitylation and proteasome degradation to regulate the activity of MAPK(mitogen-activated protein kinase 1), PI3K-AKT (phosphatidylinositol 3-kinase-the serine-threonine protein kinase) and Hippo signaling pathways. Conclusions: These findings suggested that Siah1 is a novel potential prognostic biomarker and plays a tumor suppressor role in the development and progression of CRC.

show abstract

FOXF1 promotes angiogenesis and accelerates bevacizumab resistance in colorectal cancer by transcriptionally activating VEGFA

Cited by 49 publications

References 43 publications

Targeting tumor cell-derived CCL2 as a strategy to overcome bevacizumab resistance in ETV5+ colorectal cancer

Targeting tumor cell-derived CCL2 as a strategy to overcome bevacizumab resistance in ETV5+ colorectal cancer

<p>Hypermethylation Of ADHFE1 Promotes The Proliferation Of Colorectal Cancer Cell Via Modulating Cell Cycle Progression</p>

Downregulation of Siah1 promotes colorectal cancer cell proliferation and migration by regulating AKT and YAP ubiquitylation and proteasome degradation

Contact Info

Product

Resources

About