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TCF7L1 regulates cytokine response and neuroendocrine differentiation of prostate cancer
- Source :
- Oncogenesis, Vol 10, Iss 11, Pp 1-11 (2021)
- Publication Year :
- 2021
- Publisher :
- Nature Publishing Group, 2021.
-
Abstract
- Abstract Neuroendocrine differentiation (NED) is associated with WNT signaling activation and can be significantly observed after failure of androgen-deprivation therapy (ADT) for prostatic adenocarcinomas. Cytokine signaling is stimulated in NED prostate cancer; however, how ADT-upregulated WNT signaling promotes activation of cytokine signaling and contributes to NED of prostate cancer is poorly understood. In this study, we identified ADT-mediated upregulation of transcription factor 7 like 1 (TCF7L1), which increases the cytokine response and enhances NED of prostate cancer through interleukin (IL)-8/C-X-C motif chemokine receptor type 2 (CXCR2) signaling activation. ADT induced the secretion of WNT4 which upon engagement of TCF7L1 in prostate cancer cells, enhanced IL-8 and CXCR2 expressions. TCF7L1 directly binds to the regulatory sequence region of IL-8 and CXCR2 through WNT4 activation, thus upregulating IL-8/CXCR2 signaling-driven NED and cell motility. Analysis of prostate tissue samples collected from small-cell neuroendocrine prostate cancer (SCPC) and castration-resistant prostate cancer (CRPC) tumors showed an increased intensity of nuclear TCF7L1 associated with CXCR2. Our results suggest that induction of WNT4/TCF7L1 results in increased NED and malignancy in prostate cancer that is linked to dysregulation of androgen receptor signaling and activation of the IL-8/CXCR2 pathway.
- Subjects :
- Neoplasms. Tumors. Oncology. Including cancer and carcinogens
RC254-282
Subjects
Details
- Language :
- English
- ISSN :
- 21579024
- Volume :
- 10
- Issue :
- 11
- Database :
- Directory of Open Access Journals
- Journal :
- Oncogenesis
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.99d5960710964c0a90f14edae6b01add
- Document Type :
- article
- Full Text :
- https://doi.org/10.1038/s41389-021-00371-6