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Please use this identifier to cite or link to this item:
http://ir.nhri.org.tw/handle/3990099045/16419
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| Title: | Epithelial cell adhesion molecule induces induces Wnt receptor transcription to promote colorectal cancer progression |
| Authors: | Wu, HC;Panda, SS;Lee, CC;Shen, CN;Li, WS;Hsieh, HP |
| Contributors: | Institute of Biotechnology and Pharmaceutical Research |
| Abstract: | Epithelial cell adhesion molecule (EpCAM) has been widely studied as a tumour antigen due to its expression in varieties of solid tumours. Moreover, the glycoprotein contributes to critical cancer-associated cellular functionalities via its extraceullar (EpEX) and intraceullar (EpICD) domains. In colorectal cancerb (CRC), EpCAM has been implicated in the Wnt signaling pathway, as EpICD and B-Catenin are coordinately translocated to the nucleus. Once in the nucleus, EpICD transcriptionally regulates EpCAM target genes. Here, we studied the role of EpCAM in colorectal cancer (CRC) stemness. We found that the EpEX-induced Wnt signaling activated TACE and γ-secretase enzymes to augment shedding of EpEX and EpICD, establishing a positive feedback loop. Importantly, we show that the EpICD interacted with the promoters of Wnt receptors (FZD6 and LRP5/6) thus upregulated their transcriptional activity inducing Wnt signaling. Furthermore, activation of Wnt-pathway-associated kinases in the β-Catenin destruction complex (GSK3β and CK1) induced γ-secretase activity to augment EpICD shedding, establishing a positive-feedback loop. Our EpCAM-neutralizing antibody (EA2-6) and a porcupine inhibitor (LGK974) each partially attenuated acncer stemness, while their combination abolished stemness-related endpoints, induced apoptosis in vitro and markedly diminished tumour progression in animal moedls of human CRC. From these findings, we conclued that EpCAM stimulates Wnt signaling to promote cancer stemness, and the combination of EpAb2-6 and porcupine inhibitors may represent an effective CRC treatment, including for KRAS-mutant cancers. Thus. the mechanistic insights gained from our study may be useful to improve existin treatments or to develop novel anticancer therapeutics. |
| Date: | 2024-11 |
| Relation: | Asia-Pacific Journal of Clinical Oncology. 2024 Nov;20:121. |
| Link to: | https://doi.org/10.1111/ajco.14117 |
| JIF/Ranking 2023: | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=&DestApp=IC2JCR |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:001352150600154 |
| Appears in Collections: | [謝興邦] 會議論文/會議摘要
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| ISI001352150600154.pdf | 107Kb | Adobe PDF | 24 | View/Open |
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