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Silencing CTNND1 mediates triple-negative breast cancer bone metastasis via upregulating CXCR4/CXCL12 axis and neutrophils infiltration in bone

Lin, Qun, Fang, Xiaolin, Liang, Gehao, Luo, Qing, Cen, Yinghuan, Shi, Yu, Jia, Shijie, Li, Juanmei, Yang, Wenqian, Sanders, Andrew J., Gong, Chang and Jiang, Wenguo 2021. Silencing CTNND1 mediates triple-negative breast cancer bone metastasis via upregulating CXCR4/CXCL12 axis and neutrophils infiltration in bone. Cancers 13 (22) , 5703. 10.3390/cancers13225703

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Abstract

Bone metastasis from triple-negative breast cancer (TNBC) frequently results in poorer prognosis than other types of breast cancer due to the delay in diagnosis and intervention, lack of effective treatments and more skeletal-related complications. In the present study, we identified CTNND1 as a most reduced molecule in metastatic bone lesion from TNBC by way of high throughput sequencing of TNBC samples. In vivo experiments revealed that knockdown of CTNND1 enhanced tumor cells metastasis to bones and also increased neutrophils infiltration in bones. In vitro, we demonstrated that knockdown of CTNND1 accelerated epithelial–mesenchymal transformation (EMT) of tumor cells and their recruitment to bones. The involvement by CTNND1 in EMT and bone homing was achieved by upregulating CXCR4 via activating the PI3K/AKT/HIF-1αpathway. Moreover, TNBC cells with reduced expression of CTNND1 elicited cytotoxic T-cells responses through accelerating neutrophils infiltration by secreting more GM-CSF and IL-8. Clinically, patients with triple-negative breast cancer and lower level of CTNND1 had shorter overall survival (OS) and distant metastasis-free survival (DMFS). It was concluded that downregulation of CTNND1 played a critical role in facilitating bone metastasis of TNBC and that CTNND1 might be a potential biomarker for predicting the risk of bone metastases in TNBC.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: MDPI
ISSN: 2072-6694
Funders: RealCan Fellowship, Cardiff China Medical Scholarship, the National Key R&D Program of China (2017YFC1309103 and 2017YFC1309104); the National Natural Science Foundation of China (81672594, 81772836, 81872139 and 82072907); Clinical Innovation Project of Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory, 2018GZR0201004); Sun Yat-Sen Memorial Hospital cultivation project for clinical research (SYS-C-201805); Key Projects of The National Natural Science Foundation of China (51861125203); Project of The Beijing Xisike Clinical Oncology Research Foundation (Y
Date of First Compliant Deposit: 15 November 2021
Date of Acceptance: 4 November 2021
Last Modified: 07 Jan 2022 02:17
URI: https://orca.cardiff.ac.uk/id/eprint/145515

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