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TCF7L1 regulates cytokine response and neuroendocrine differentiation of prostate cancer

Yu-Ching Wen1,2,3, Yen-Nien Liu4, Hsiu-Lien Yeh5

  • 1Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.

Oncogenesis
|November 20, 2021
PubMed

Insights

Androgen-deprivation therapy failure in prostate cancer activates WNT4/TCF7L1 signaling, increasing Interleukin-8/CXCR2 expression. This promotes neuroendocrine differentiation and malignancy, driving prostate cancer progression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Urology

Background:

  • Neuroendocrine differentiation (NED) in prostate cancer is linked to WNT signaling activation, particularly after androgen-deprivation therapy (ADT) failure.
  • The precise mechanisms by which ADT-induced WNT signaling promotes cytokine signaling and contributes to NED remain unclear.

Purpose of the Study:

  • To elucidate the role of ADT-upregulated WNT signaling in activating cytokine signaling and driving prostate cancer NED.
  • To identify key molecular players involved in the transition to a neuroendocrine phenotype following ADT.

Main Methods:

  • Investigated the expression and function of transcription factor 7 like 1 (TCF7L1) in prostate cancer cells under ADT conditions.
  • Analyzed the impact of WNT4 and TCF7L1 on Interleukin-8 (IL-8) and CXCR2 expression.
  • Examined the binding of TCF7L1 to regulatory regions of IL-8 and CXCR2.
  • Assessed TCF7L1 and CXCR2 levels in clinical samples of small-cell prostate cancer and castration-resistant prostate cancer.

Main Results:

  • ADT upregulates TCF7L1, which enhances cytokine response and promotes NED via IL-8/CXCR2 signaling.
  • ADT induces WNT4 secretion, leading to TCF7L1 engagement and increased IL-8 and CXCR2 expression.
  • TCF7L1 directly binds to IL-8 and CXCR2 regulatory regions, upregulating IL-8/CXCR2-driven NED and cell motility.
  • Clinical samples show increased nuclear TCF7L1 and CXCR2 in neuroendocrine and castration-resistant prostate cancer.

Conclusions:

  • WNT4/TCF7L1 induction drives NED and malignancy in prostate cancer by dysregulating androgen receptor signaling and activating the IL-8/CXCR2 pathway.
  • Targeting the WNT4/TCF7L1/IL-8/CXCR2 axis may offer therapeutic strategies for advanced prostate cancer.

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