EHF promotes colorectal carcinoma progression by activating TGF‐β1 transcription and canonical TGF‐β signaling

Wang, Lan; Ai, Mei-Ling; Nie, Miaoting; Zhao, Li; Deng, Guangxu; Hu, Shasha; Han, Yue; Zeng, Weiting; Wang, Yiqing; Yang, Mei; Wang, Shuang

doi:10.1111/cas.14444

Cited by 20 publications

(14 citation statements)

References 39 publications

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“…FBN1, produced by fibroblasts, is an important structural factor of the extracellular matrix, which provides great support to connective tissues [43, 44]. As reported earlier, FBN1 mediated stretching of ligaments, skin, and blood vessels; supported rigid tissues, including muscle, nerve, and lens of the eyes; and regulated TGF‐β bioavailability [45], which induced epithelial‐to‐mesenchymal transition (EMT) in cancers of epithelial origin, thereby stimulating molecular and phenotypical changes that resulted in prometastatic characteristics [46, 47]. Moreover, the activation of TGF‐β is reported to enhance invasion of ovarian cancer [48].…”

Section: Discussionmentioning

confidence: 99%

The Fibrillin‐1/VEGFR2/STAT2 signaling axis promotes chemoresistance via modulating glycolysis and angiogenesis in ovarian cancer organoids and cells

Wang

Chen

Zuo

et al. 2022

Cancer Communications

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Background Chemotherapy resistance is a primary reason of ovarian cancer therapy failure; hence it is important to investigate the underlying mechanisms of chemotherapy resistance and develop novel potential therapeutic targets. Methods RNA sequencing of cisplatin‐resistant and ‐sensitive (chemoresistant and chemosensitive, respectively) ovarian cancer organoids was performed, followed by detection of the expression level of fibrillin‐1 (FBN1) in organoids and clinical specimens of ovarian cancer. Subsequently, glucose metabolism, angiogenesis, and chemosensitivity were analyzed in structural glycoprotein FBN1‐knockout cisplatin‐resistant ovarian cancer organoids and cell lines. To gain insights into the specific functions and mechanisms of action of FBN1 in ovarian cancer, immunoprecipitation, silver nitrate staining, mass spectrometry, immunofluorescence, Western blotting, and Fӧrster resonance energy transfer‐fluorescence lifetime imaging analyses were performed, followed by in vivo assays using vertebrate model systems of nude mice and zebrafish. Results FBN1 expression was significantly enhanced in cisplatin‐resistant ovarian cancer organoids and tissues, indicating that FBN1 might be a key factor in chemoresistance of ovarian cancer. We also discovered that FBN1 sustained the energy stress and induced angiogenesis in vitro and in vivo, which promoted the cisplatin‐resistance of ovarian cancer. Knockout of FBN1 combined with treatment of the antiangiogenic drug apatinib improved the cisplatin‐sensitivity of ovarian cancer cells. Mechanistically, FBN1 mediated the phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) at the Tyr1054 residue, which activated its downstream focal adhesion kinase (FAK)/protein kinase B (PKB or AKT) pathway, induced the phosphorylation of signal transducer and activator of transcription 2 (STAT2) at the tyrosine residue 690 (Tyr690), promoted the nuclear translocation of STAT2, and ultimately altered the expression of genes associated with STAT2‐mediated angiogenesis and glycolysis. Conclusions The FBN1/VEGFR2/STAT2 signaling axis may induce chemoresistance of ovarian cancer cells by participating in the process of glycolysis and angiogenesis. The present study suggested a novel FBN1‐targeted therapy and/or combination of FBN1 inhibition and antiangiogenic drug for treating ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

The Fibrillin‐1/VEGFR2/STAT2 signaling axis promotes chemoresistance via modulating glycolysis and angiogenesis in ovarian cancer organoids and cells

Wang

Chen

Zuo

et al. 2022

Cancer Communications

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“…EHF belongs to the ETS TF family as the core GGAA/T motif 26,27 . Previous studies have shown that aberrant expression of EHF may contribute to cell proliferation in several cancer types 28‐31 . It has also been reported that EHF overexpression is caused by copy number alteration and binding to the promoter region located in the HER family in GC 32 .…”

Section: Discussionmentioning

confidence: 99%

Activation of EHF via STAT3 phosphorylation by LMP2A in Epstein‐Barr virus–positive gastric cancer

Okabe

Usui

et al. 2021

Cancer Science

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Epstein‐Barr virus (EBV) is associated with approximately 10% of gastric cancers (GCs). We previously showed that EBV infection of gastric epithelial cells induces aberrant DNA methylation in promoter regions, which causes silencing of critical tumor suppressor genes. Here, we analyzed gene expressions and active histone modifications (H3K4me3, H3K4me1, and H3K27ac) genome‐widely in EBV‐positive GC cell lines and in vitro EBV‐infected GC cell lines to elucidate the transcription factors contributing to tumorigenesis through enhancer activation. Genes associated with “signaling of WNT in cancer” were significantly enriched in EBV‐positive GC, showing increased active β‐catenin staining. Genes neighboring activated enhancers were significantly upregulated, and EHF motif was significantly enriched in these active enhancers. Higher expression of EHF in clinical EBV‐positive GC compared with normal tissue and EBV‐negative GC was confirmed by RNA‐seq using The Cancer Genome Atlas cohort, and by immunostaining using our cohort. EHF knockdown markedly inhibited cell proliferation. Moreover, there was significant enrichment of critical cancer pathway–related genes (eg, FZD5) in the downstream of EHF. EBV protein LMP2A caused upregulation of EHF via phosphorylation of STAT3. STAT3 knockdown was shown to inhibit cellular growth of EBV‐positive GC cells, and the inhibition was rescued by EHF overexpression. Our data highlighted the important role of EBV infection in gastric tumorigenesis via enhancer activation.

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confidence: 99%

Circular RNA: A promising new star for the diagnosis and treatment of colorectal cancer

Zhang

Sun

et al. 2021

Cancer Medicine

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Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive tract, and morbidity and mortality rank third and second in malignant tumors. [1][2][3] Currently, early screening for CRC can effectively improve the survival rate of patients with CRC, but approximately 25% of CRC patients develop metastatic disease from an early stage. [4][5][6] Therefore, a promising field of antimetastatic therapy lies in the targeted inhibition of cancer cells with high metastatic potential from the primary site. 7,8 Recently, there has been a qualitative leap in tumor medical technology, such as the application of laparoscopic surgery, nano-assembly technology, PET/ CT imaging technology, and dynamic network biomarker (DNB), etc. 9-11 However, the cure rate and survival rate of CRC are still very low, mainly lacking new drug treatment targets and biomarkers for the treatment of CRC. 12 According to the research of circular RNAs in the CRC field, circular RNAs are expected to be therapeutic targets

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EHF promotes colorectal carcinoma progression by activating TGF‐β1 transcription and canonical TGF‐β signaling

Cited by 20 publications

References 39 publications

The Fibrillin‐1/VEGFR2/STAT2 signaling axis promotes chemoresistance via modulating glycolysis and angiogenesis in ovarian cancer organoids and cells

The Fibrillin‐1/VEGFR2/STAT2 signaling axis promotes chemoresistance via modulating glycolysis and angiogenesis in ovarian cancer organoids and cells

Activation of EHF via STAT3 phosphorylation by LMP2A in Epstein‐Barr virus–positive gastric cancer

Circular RNA: A promising new star for the diagnosis and treatment of colorectal cancer

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