ESE3 Inhibits Pancreatic Cancer Metastasis by Upregulating E-Cadherin

Zhao, Tiansuo; Jiang, Wenna; Wang, Xiuchao; Wang, Hongwei; Chen, Zheng; Li, Yang; Sun, Yan; Huang, Chongbiao; Han, Zhi Bo; Yang, Shengyu; Jia, Zhiliang; Xie, Keping; Ren, He; Hao, Jihui

doi:10.1158/0008-5472.can-16-2170

Cited by 51 publications

(43 citation statements)

References 42 publications

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“…Our previously data demonstrated tumoral ESE3 inhibits PDAC EMT and metastasis by transcriptionally up-regulating E-cadherin (Zhao et al, 2017) . Interestingly, although ESE3 expression was down-regulated in PDAC cells, we observed robust upregulation of ESE3 in PSC in PDAC tissues when compared to normal pancreatic tissue ( Fig.…”

Section: Ese3 Was Overexpressed In Activated Pscmentioning

confidence: 85%

“…In pancreatic cancer, our previous investigation identified ESE3 as a tumor suppressor. ESE3 overexpression in tumor cells transcriptionally up-regulates E-cadherin to prevent EMT and metastasis (Zhao et al, 2017) . Moreover, ESE3 overexpression in PDAC cells down-regulates TGFβ1 and GM-CSF (Liu et al, 2019) to inhibit Treg induction and MDSC accumulation, which in turn increase sensitivity to immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

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Tumor-stromal IL-1β/ NFκB / ESE3 Signaling Axis Drives Pancreatic Cancer Fibrosis, Chemoresistance, and Poor Prognosis

Hao

Zhao

Xiao

et al. 2020

Preprint

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Pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrosis and pancreatic ductal adenocarcinoma (PDAC) progression. The mechanisms controlling PSC activation is not completely understood. Here we investigated the role of ESE3 (Epithelium-Specific ETS factor 3) in PSC activation. We discovered that in PDAC patients ESE3 expression was increased in PSC while decreased in tumor cells. ESE3 overexpression in PSC promoted PSC activation. Condition medium from ESE3-overexprssing PSC promotes PDAC cell migration, chemoresistance, tumor growth and fibrosis. ESE3 directly induced the transcription of α-SMA, Collagen 1 and IL-1β by binding to ESE3 binding sites on their promoters to activate PSC. On the other hand, IL-1β upregulates ESE3 in PSC through NFκB activation and ESE3 is required for PSC activation by tumor cell derived IL-1β. Clinical data showed ESE3 upregulation in PSC was positively correlated with tumor size, pTNM stage, CA19-9, CEA and CA242 level in serum. ESE3 overexpression in PSC was an independent negative prognostic factor for disease-free survival and overall survival among PDAC patients. Inhibition of the IL-1β/ ESE3 (PSC)/ IL-1β positive feedback loop represents a promising therapeutic strategy to reduce tumor fibrosis and increase chemotherapeutic efficacy in PDAC.

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Section: Ese3 Was Overexpressed In Activated Pscmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Tumor-stromal IL-1β/ NFκB / ESE3 Signaling Axis Drives Pancreatic Cancer Fibrosis, Chemoresistance, and Poor Prognosis

Hao

Zhao

Xiao

et al. 2020

Preprint

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“…E-cadherin is a key factor in cell-cell adhesion. The destruction of E-cadherin is thought to be one of the first steps in metastasis, playing critical roles in tumor metastasis [21,[31][32][33]. Recent reports have shown that a decrease in E-cadherin is strongly associated with metastasis and poor clinical prognosis and suggested that targeting E-cadherin could be a promising therapeutic approach for metastatic CRC [34].…”

Section: Discussionmentioning

confidence: 99%

Death Domain-Associated Protein Promotes Colon Cancer Metastasis through Direct Interaction with ZEB1

Liu¹,

Guo

Zhu³

et al. 2020

J. Cancer

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Background: Death domain-associated protein (DAXX) is a tumor suppressor and its loss has been found in a variety of cancer types. Dysregulation of DAXX is strongly correlated with cancer metastasis. However, the role and functions of DAXX in colorectal cancer (CRC) metastasis are not fully understood. Methods: We validated the mRNA and protein expression of DAXX in CRC specimens and CRC cell lines using real-time reverse transcription-PCR and Western blot, respectively. The overexpression plasmids of ZEB1 and E-cadherin and the siRNAs for DAXX and ZEB1 knockdown were constructed to study the impact of these factors on cells. Wound-healing assay and Transwell assay were performed to examine the cell motility and cell migration and invasion abilities, respectively. Luciferase assay was performed to assess the E-cadherin promoter activity. Immunoprecipitation assay was performed to investigate the interaction between proteins. The rescue experiment was carried out to verify whether the effect of DAXX on E-cadherin expression is depended on ZEB1. Results: DAXX expression was lower in liver metastases than in primary colon cancer tissues. Our results demonstrated that DAXX directly interacted with ZEB1 and suppressed its inhibitory effect on promoter activity of E-cadherin through a ZEB1-dependent manner, and thus suppresses the cell motility, migration, and invasion of CRC cell lines. Conclusion: In sum, these findings supported that the loss of DAXX is associated with cancer cell metastases in CRC. ZEB1-mediated transcriptional suppression of E-cadherin is a possible mechanism. DAXX/ZEB-1 pathway could be a potential therapeutic target for preventing cancer metastasis in CRC.

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“…Therefore, we investigated whether Peer-reviewed version available at Cancers 2019, 11, 942; doi:10.3390/cancers11070942 of a tool to circumvent the pro-tumour M2 addicted immune suppressive-environment [44]. Secondly, due to the differential E-cadherin expression, PANC-1 can be controlled in their invasive phenotype [45]. Conversely, the absence of E-cadherin modulation might contribute to the MIAPaCa-2 relative decreased sensitivity to XAV-939.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Comparison Between the Lymph Node-Positive and Negative Reveals a Peculiar Immune-microenvironment Signature and a Theranostic Role for WNT Targeting in Pancreatic Ductal Adenocarcinoma: A Pilot Study

Argentiero¹,

Summa²,

Fonte³

et al. 2019

Preprint

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Over the past several years there has been much debate with regards to the prognostic and clinical significance of pancreatic ductal adenocarcinoma (PDAC) with lymph nodes metastasis. The PDAC gene-expression knowledge and the biologic alterations underlying the lymph node involvement convey a clinical implication in dealing with the theranostic window.To this end, we provide an original bioinformatic dissection of the gene-expression differences of PDAC according to the nodal involvement from a large public available dataset. Comprehensive transcriptomic analysis from 143 RNA-seq patient’s derived samples indicated that WNT increased activation and a peculiar immune-microenvironment identify subjects with nodal involvement.In frame of this thinking, we validated the WNT pathway role in increasing the likelihood of lymphatic dissemination in vitro. Moreover, we demonstrated for the first time in a PDAC model the potential therapeutic window that XAV-939, a specific WNT pathway inhibitor, has in re-educating a tumour permissive immune system. Finally, we outline the potential implication on bystander molecular drivers exerted by WNT molecular inhibition, providing a picture of the proteomic oncogenic landscape changes elicited by XAV-939 on PDAC cells and their clinical implication. Our findings hold the promise to identify novel immune-based therapeutic strategies targeting WNT to enhance PDAC cytotoxicity and restore anti-PDAC immunity in nodes-positive disease.

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ESE3 Inhibits Pancreatic Cancer Metastasis by Upregulating E-Cadherin

Cited by 51 publications

References 42 publications

Tumor-stromal IL-1β/ NFκB / ESE3 Signaling Axis Drives Pancreatic Cancer Fibrosis, Chemoresistance, and Poor Prognosis

Tumor-stromal IL-1β/ NFκB / ESE3 Signaling Axis Drives Pancreatic Cancer Fibrosis, Chemoresistance, and Poor Prognosis

Death Domain-Associated Protein Promotes Colon Cancer Metastasis through Direct Interaction with ZEB1

Gene Expression Comparison Between the Lymph Node-Positive and Negative Reveals a Peculiar Immune-microenvironment Signature and a Theranostic Role for WNT Targeting in Pancreatic Ductal Adenocarcinoma: A Pilot Study

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