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Published on: September 28, 2018
Protein tyrosine phosphatase receptor-type δ acts as a negative regulator suppressing breast cancer
Xiaotang Yu1, Fan Zhang2, Jun Mao1
1Department of Pathology and Forensic Medicine, Dalian Medical University, Dalian 116044, PR China.
Abstract:
Protein tyrosine phosphatase receptor-type δ (PTPRD) is frequently inactivated in human cancers. This study investigated the role of PTPRD in the regulation of stemness, epithelial-mesenchymal transition (EMT), and migration and invasion in breast cancer cells. In vitro, PTPRD silencing using siRNA enhanced the stem cell-like properties of breast cancer cells, including their mammosphere- and holoclone-forming abilities, and it promoted tumorigenicity in vivo. PTPRD knockdown also increased the CD44+/CD24- breast cancer stem cell (BCSC) population and the expression of the stem cell markers ALDH1 and OCT4. It also promoted migration and invasion by breast cancer cell, EMT, and activation of signal transducer and activator of transcription 3 (STAT3). BCSCs expressed low levels of PTPRD, displayed mesenchymal phenotypes, and were more sensitive to IL-6-mediated STAT3 activation than non-BCSCs. PTPRD expression was upregulated by IL-6 in breast cancer cells, thereby establishing a negative feedback circuit by which IL-6 induced canonical STAT3 phosphorylation and transiently upregulated PTPRD, which in turn dephosphorylated STAT3 and prevented downstream signaling via the IL-6/STAT3 cascade. These data suggest that therapies aimed at restoring or enhancing PTPRD expression may be effective in controlling breast cancer progression and metastasis.
Insights
Restoring Protein tyrosine phosphatase receptor-type δ (PTPRD) may combat breast cancer. PTPRD loss enhances cancer stem cells, migration, and metastasis by activating STAT3 signaling.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Protein tyrosine phosphatase receptor-type δ (PTPRD) is frequently inactivated in human cancers.
- Dysregulation of PTPRD is implicated in cancer progression.
Purpose of the Study:
- To investigate the role of PTPRD in regulating breast cancer stemness, epithelial-mesenchymal transition (EMT), and metastasis.
- To elucidate the molecular mechanisms underlying PTPRD's function in breast cancer.
Main Methods:
- PTPRD silencing using siRNA in breast cancer cells.
- Assessment of stem cell properties (mammosphere, holoclone formation, CD44+/CD24- population, stem cell markers ALDH1, OCT4).
- Evaluation of migration, invasion, EMT, and STAT3 signaling pathway activation.
- Analysis of PTPRD expression in breast cancer stem cells (BCSCs) and its regulation by IL-6.
Main Results:
- PTPRD silencing enhanced stem cell-like properties, promoted tumorigenicity, increased BCSCs, and upregulated stem cell markers.
- PTPRD knockdown promoted cell migration, invasion, EMT, and STAT3 activation.
- BCSCs exhibited low PTPRD levels and mesenchymal phenotypes.
- IL-6 upregulated PTPRD, creating a negative feedback loop that dephosphorylated STAT3.
Conclusions:
- PTPRD plays a crucial role in suppressing breast cancer stemness, EMT, and metastasis.
- Restoring PTPRD expression may represent a therapeutic strategy to control breast cancer progression and metastasis by inhibiting the IL-6/STAT3 pathway.
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