Overexpression of FOXM1 drives mycosis fungoides progression by regulating the cell cycle.

in Journal of dermatological science by Kecen Liu, Huizhong Wang, Jingyang Dang, Jiajia Zhu, Yujie Wen, Zhuojing Chen, Yang Wang, Jingru Sun

TLDR

  • FOXM1 overexpression is associated with poor prognosis in mycosis fungoides and its inhibition can impair cell proliferation and tumorigenicity.

Abstract

Mycosis fungoides (MF), the most prevalent variant of cutaneous T-cell lymphoma (CTCL), is characterized by the clonal proliferation of skin-homing CD4+ T lymphocytes. Forkhead box M1 (FOXM1) plays significant roles in the progression of various solid tumors. Its expression has been reported to diminish following treatment with Neosetophomone B in CTCL cells in vitro. However, the role of FOXM1 in the pathogenesis of MF remains unclear. To evaluate the expression pattern and underlying mechanism of FOXM1 in MF. FOXM1 expression in lesional skin samples was accessed via immunohistochemistry analyses. Inhibition of FOXM1 was performed through lenti-virus shRNA vector mediated gene knockdown and treatment with specific FOXM1 inhibitors (RCM1 and FDI-6). Furthermore, animal experiments were conducted to evaluate the effects of FOXM1 knockdown or treatment with FOXM1 inhibitors on tumor growth in vivo. Overexpression of FOXM1 was observed in MF with a stage-dependent pattern and poor prognosis. Inhibition of FOXM1 via either shRNA or specific inhibitors, significantly impaired MF cell proliferation by inducing cell cycle arrest and apoptosis, while also suppressing tumorigenicity in vitro and in vivo. Transcriptomic analysis revealed that FOXM1 suppression led to the downregulation of genes involved in cell cycle regulation, including CCNB2, CDK1, and E2F1. The overexpression of FOXM1 contributes significantly to the progression of MF primarily by regulating the cell cycle. Furthermore, FOXM1 may serve as a reliable prognostic biomarker and a promising therapeutic target for MF.

Overview

  • The study investigated the role of Forkhead box M1 (FOXM1) in the pathogenesis of mycosis fungoides (MF), a type of cutaneous T-cell lymphoma.
  • FOXM1 expression was evaluated in lesional skin samples through immunohistochemistry and its inhibition was performed through gene knockdown and treatment with specific inhibitors.
  • The study aimed to determine the relationship between FOXM1 expression and the progression of MF, and to assess its potential as a prognostic biomarker and therapeutic target.

Comparative Analysis & Findings

  • Overexpression of FOXM1 was observed in MF with a stage-dependent pattern and poor prognosis, suggesting a significant contribution to the progression of the disease.
  • Inhibition of FOXM1 via gene knockdown or specific inhibitors significantly impaired MF cell proliferation by inducing cell cycle arrest and apoptosis, while also suppressing tumorigenicity in vitro and in vivo.
  • Transcriptomic analysis revealed that FOXM1 suppression led to the downregulation of genes involved in cell cycle regulation, including CCNB2, CDK1, and E2F1, supporting the notion that FOXM1 regulates the cell cycle in MF.

Implications and Future Directions

  • The study suggests that FOXM1 could be a reliable prognostic biomarker for MF, allowing for earlier detection and interventions.
  • FOXM1 may serve as a promising therapeutic target for MF, offering a potential avenue for the development of novel treatment strategies.
  • Future studies should investigate the optimal methods for inhibiting FOXM1 in MF and explore its potential as a combination therapy with existing treatments.
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