ELF3 promotes epithelial–mesenchymal transition by protecting ZEB1 from miR-141-3p-mediated silencing in hepatocellular carcinoma

Zheng, Longbo; Xu, Meifeng; Xu, Junjie; Wu, Ke; Qian, Fang; Liang, Yuelong; Zhou, Shengde; Cen, Dong; Ji, Lin; Han, Wei; Cai, Xiujun

doi:10.1038/s41419-018-0399-y

Cited by 86 publications

(66 citation statements)

References 49 publications

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“…This suggests that SARC evolved from precursor conventional UC carrying these mutations and that mutations in these genes may drive the progression process. Several of the genes that are frequently mutated in conventional UC, including ARID1A , KDM6A , EP300 , ELF3 , and CREBBP , were not mutated in SARC, and these genes are involved in chromatin remodeling (Dutto et al, 2018; Ler et al, 2017; Skulte et al, 2014; Tang et al, 2013; Wang et al, 2017; Zheng et al, 2018). In general, as a group, chromatin-remodeling genes were not mutated in SARC.…”

Section: Resultsmentioning

confidence: 99%

Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

et al. 2019

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SUMMARY Sarcomatoid urothelial bladder cancer (SARC) displays a high propensity for distant metastasis and is associated with short survival. We report a comprehensive genomic analysis of 28 cases of SARC and 84 cases of conventional urothelial carcinoma (UC), with the TCGA cohort of 408 muscle- invasive bladder cancers serving as the reference. SARCs show a distinct mutational landscape, with enrichment of TP53, RB1, and PIK3CA mutations. They are related to the basal molecular subtype of conventional UCs and could be divided into epithelial-basal and more clinically aggressive mesenchymal subsets on the basis of TP63 and its target gene expression levels. Other analyses reveal that SARCs are driven by downregulation of homotypic adherence genes and dysregulation of the EMT network, and nearly half exhibit a heavily infiltrated immune phenotype. Our observations have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer.

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Section: Resultsmentioning

confidence: 99%

Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

et al. 2019

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“…25 In our study, treatment of SKOV3 cells in vivo with IgG-8311 led to the upregulation of genes that characterize an epithelial phenotype (CDH1, SLIT2), while reducing the expression of genes associated with a mesenchymal phenotype (ITGA3, ELF3). [26][27][28] Moreover, evidence is mounting in favor of cancer stem cells (CSCs) activating EMT as a mechanism of intrinsic drug resistance. 29 During EOC progression, SMAD3-dependent TGF-β signaling promotes EMT and the proportion of cells expressing stemness markers (CD44+/CD117+) via transglutaminase 2 (TG2).…”

Section: Discussionmentioning

confidence: 99%

Blockade of TGF-β signaling with novel synthetic antibodies limits immune exclusion and improves chemotherapy response in metastatic ovarian cancer models

et al. 2018

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Blockade of TGF-β signaling with novel synthetic antibodies limits immune exclusion and improves chemotherapy response in metastatic ovarian cancer models, OncoImmunology, 8:2, e1539613, ABSTRACT Epithelial ovarian cancer (EOC) is a leading cause of cancer-related death in women. EOC is often diagnosed at late stages, with peritoneal metastases and ascites production. Current surgery and platinum-based chemotherapy regimes fail to prevent recurrence in most patients. High levels of Transforming growth factor-β (TGF-β) within ascites has been linked to poor prognosis. TGF-β signaling promotes epithelial-mesenchymal transition (EMT) in EOC tumor cells, and immune suppression within the tumor microenvironment, with both contributing to chemotherapy resistance and metastasis. The goal of this study was to develop specific synthetic inhibitory antibodies to the Type II TGF-β receptor (TGFBR2), and test these antibodies in EOC cell and tumor models. Following screening of a phage-displayed synthetic antigen-binding fragment (Fab) library with the extracellular domain of TGFBR2, we identified a lead inhibitory Fab that suppressed TGF-β signaling in mouse and human EOC cell lines. Affinity maturation of the lead inhibitory Fab resulted in several derivative Fabs with increased affinity for TGFBR2 and efficacy as suppressors of TGF-β signaling, EMT and EOC cell invasion. In EOC xenograft and syngeneic tumor models, blockade of TGFBR2 with our lead antibodies led to improved chemotherapy response. This correlated with reversal of EMT and immune exclusion in these tumor models with TGFBR2 blockade. Together, these results describe new inhibitors of the TGF-β pathway that improve antitumor immunity, and response to chemotherapy in preclinical EOC models. ARTICLE HISTORY

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“…After two-month sorafenib treatment, tumors were regarded to be sorafenib resistant. Subcutaneous tumor models were constructed according to a previous report 30 . Pieces from one sorafenib resistant tumor were implanted to axillary areas in 4-week-old BALB/C nude mice.…”

Section: Mir-486-3p Could Suppress Cell Proliferation and Contribute mentioning

confidence: 99%

miR-486-3p mediates hepatocellular carcinoma sorafenib resistance by targeting FGFR4 and EGFR

Lin

Wan

et al. 2020

Cell Death Dis

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HCC is a common malignancy worldwide and surgery or reginal treatments are deemed insufficient for advancedstage disease. Sorafenib is an inhibitor of many kinases and was shown to benefit advanced HCC patients. However, resistance emerges soon after initial treatment, limiting the clinical benefit of sorafenib, and the mechanisms still remain elusive. Thus, this study aims to investigate the mechanisms of sorafenib resistance and to provide possible targets for combination therapies. Through miRNA sequencing, we found that miR-486-3p was downregulated in sorafenib resistant HCC cell lines. Cell viability experiments showed increased miR-486-3p expression could induce cell apoptosis while miR-486-3p knockdown by CRISPR-CAS9 technique could reduce cell apoptosis in sorafenib treatment. Clinical data also indicated that miR-486-3p level was downregulated in tumor tissue compared with adjacent normal tissue in HCC patients. Mechanism dissections showed that FGFR4 and EGFR were the targets of miR-486-3p, which was verified by luciferase reporter assay. Importantly, FGFR4 or EGFR selective inhibitor could enhance sorafenib efficacy in the resistant cells. Moreover, in vivo sorafenib resistant model identified that over-expressing miR-486-3p by lentivirus injection could overcome sorafenib resistance by significantly suppressing tumor growth in combination with the treatment of sorafenib. In conclusion, we found miR-486-3p was an important mediator regulating sorafenib resistance by targeting FGFR4 and EGFR, thus offering a potential target for HCC treatment.

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ELF3 promotes epithelial–mesenchymal transition by protecting ZEB1 from miR-141-3p-mediated silencing in hepatocellular carcinoma

Cited by 86 publications

References 49 publications

Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

Blockade of TGF-β signaling with novel synthetic antibodies limits immune exclusion and improves chemotherapy response in metastatic ovarian cancer models

miR-486-3p mediates hepatocellular carcinoma sorafenib resistance by targeting FGFR4 and EGFR

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