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Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development
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MTHFD2 promotes PD-L1 expression via activation of the JAK/STAT signalling pathway in bladder cancer

Linzhi Li1, Yunlong Zhang1, Weimin Hu1

  • 1Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China.

Journal of Cellular and Molecular Medicine
|July 22, 2023
PubMed

Insights

Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) drives bladder cancer (BC) progression and immune evasion. Targeting MTHFD2 may offer new therapeutic strategies by inhibiting PD-L1 expression via the JAK/STAT pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Bladder cancer (BC) treatment faces challenges with high recurrence and progression rates despite combination chemotherapy.
  • Novel therapeutic targets are crucial for improving BC patient outcomes.
  • Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is implicated in tumorigenesis and immune evasion in various cancers, but its role in BC is uncharacterized.

Purpose of the Study:

  • To investigate the expression, prognostic significance, and protumoral functions of MTHFD2 in bladder cancer.
  • To elucidate the mechanism by which MTHFD2 upregulates programmed death-ligand 1 (PD-L1) expression in BC.

Main Methods:

  • Analysis of publicly available databases for MTHFD2 expression and correlation with clinical features and prognosis in BC.
  • In vitro and in vivo experiments to assess the effects of MTHFD2 on BC cell growth, migration, invasion, tumorigenicity, and apoptosis.
  • Investigation of the correlation between MTHFD2 expression, immune infiltration, PD-L1 levels, and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway.
  • Assessment of MTHFD2 and PD-L1 expression changes following interferon gamma treatment and MTHFD2 knockdown.
  • Evaluation of the impact of JAK/STAT pathway activation on MTHFD2 knockdown effects in BC cells.

Main Results:

  • High MTHFD2 expression in BC correlates with adverse clinical features and poor prognosis.
  • MTHFD2 promotes BC cell growth, migration, invasion, and tumorigenicity while reducing apoptosis in vitro and in vivo.
  • MTHFD2 expression is linked to increased immune infiltration, elevated PD-L1 levels, and activation of the JAK/STAT pathway in BC.
  • Interferon gamma treatment upregulates MTHFD2, PD-L1, and JAK/STAT pathway proteins, while MTHFD2 knockdown decreases their expression.
  • JAK/STAT pathway activation partially counteracts the effects of MTHFD2 knockdown on BC cells.

Conclusions:

  • MTHFD2 plays a significant protumoral role in bladder cancer.
  • MTHFD2 promotes BC progression and immune evasion by upregulating PD-L1 expression.
  • The MTHFD2-mediated upregulation of PD-L1 occurs through the activation of the JAK/STAT signaling pathway.
  • MTHFD2 represents a potential therapeutic target for bladder cancer treatment.
Keywords:
MTHFD2PD-L1bladder cancer (BC)malignant phenotypepoor prognosis

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