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PD-L1 promotes colorectal cancer stem cell expansion by activating HMGA1-dependent signaling pathways

Fang Wei1, Tong Zhang1, Shu-Chou Deng2

  • 1Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, China; Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, 510180, China.

Cancer Letters
|February 19, 2019
PubMed

Insights

Programmed death-ligand 1 (PD-L1) drives colorectal cancer stem cell (CSC) self-renewal by activating HMGA1 signaling. Targeting PD-L1 may offer new strategies against chemoresistant colorectal cancer (CRC).

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Programmed death-ligand 1 (PD-L1) inhibits T cell function, aiding tumor immune evasion.
  • The role of PD-L1 in colorectal cancer stem cells (CSCs) and chemoresistance is not well understood.

Purpose of the Study:

  • To investigate the effect of PD-L1 on colorectal CSCs and its underlying mechanisms.
  • To explore the correlation between PD-L1, CSC markers, and HMGA1 in clinical colorectal cancer (CRC) specimens.

Main Methods:

  • Assessed PD-L1 expression in colorectal CSCs and tumorspheres.
  • Manipulated PD-L1 expression to evaluate effects on CSC self-renewal and chemoresistance.
  • Investigated the interaction between PD-L1 and HMGA1, including downstream signaling pathways (PI3K/Akt, MEK/ERK).
  • Analyzed PD-L1, CSC markers, and HMGA1 expression in clinical CRC samples.

Main Results:

  • High PD-L1 expression was observed in CD133+CD44+ colorectal CSCs and tumorspheres.
  • Altering PD-L1 levels modulated CSC self-renewal, stemness gene expression, and tumorsphere formation.
  • PD-L1 expression increased in chemoresistant CRC cells and enhanced tumor formation in vivo.
  • PD-L1 directly interacted with HMGA1, activating PI3K/Akt and MEK/ERK pathways, promoting CSC expansion.
  • PD-L1 expression correlated with CSC markers and HMGA1 in clinical CRC specimens.

Conclusions:

  • PD-L1 plays a crucial role in maintaining colorectal CSC self-renewal through HMGA1-dependent signaling.
  • PD-L1 contributes to chemoresistance and tumorigenicity in colorectal cancer.
  • Targeting the PD-L1/HMGA1 axis presents a potential therapeutic strategy for colorectal cancer.
Keywords:
Cancer stem cells (CSCs)Colorectal cancer (CRC)HMGA1PD-L1

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