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Thalidomide suppresses angiogenesis and immune evasion via lncRNA FGD5-AS1/miR-454-3p/ZEB1 axis-mediated VEGFA

Yang Xia1, Wei-Cheng Wang2, Wen-Hao Shen2

  • 1Department of Oncology, Taizhou Clinical Medical School of Nanjing Medical University; Taizhou People's Hospital, Taizhou, 225300, Jiangsu Province, China; Department of Radiotherapy, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China.

Chemico-Biological Interactions
|September 14, 2021
PubMed
Abstract

Insights

Thalidomide effectively inhibits non-small cell lung cancer (NSCLC) growth by targeting the FGD5-AS1/miR-454-3p/ZEB1 pathway. This mechanism reduces tumor angiogenesis and enhances anti-tumor immunity, offering a new therapeutic strategy for NSCLC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Non-small cell lung cancer (NSCLC) is the most common type of lung cancer.
  • Understanding the molecular targets of anti-cancer drugs is crucial for improving treatment efficacy.
  • Thalidomide's role in NSCLC tumorigenesis requires further investigation.

Purpose of the Study:

  • To investigate the anti-tumor effects of thalidomide in non-small cell lung cancer (NSCLC).
  • To elucidate the molecular mechanisms underlying thalidomide's action in NSCLC.
  • To identify potential therapeutic targets within the NSCLC tumor microenvironment.

Main Methods:

  • Establishment of an A549 xenograft nude mouse model to evaluate thalidomide's therapeutic effects.
  • Assessment of FGD5-AS1 expression in NSCLC tissues and cell lines.
  • In vitro assays including CCK-8, transwell, and tube formation assays to evaluate cell viability, invasion, and angiogenesis.
  • Flow cytometry to analyze CD8+ T cell activity.
  • Luciferase reporter, RIP, and ChIP assays to investigate the FGD5-AS1/miR-454-3p/ZEB1 regulatory network.

Main Results:

  • Thalidomide treatment reduced tumor growth, angiogenesis, and increased CD8+ T cell ratios in vivo.
  • Elevated FGD5-AS1 expression correlated with poorer survival in NSCLC patients.
  • Knockdown of FGD5-AS1 suppressed cancer cell proliferation, invasion, and angiogenesis, and also affected CD8+ T cell apoptosis.
  • Thalidomide's anti-tumor activity in NSCLC was mediated through targeting FGD5-AS1.
  • FGD5-AS1 acts as a sponge for miR-454-3p, upregulating ZEB1, PD-L1, and VEGFA.
  • Reversal of thalidomide's effects was observed with simultaneous overexpression of FGD5-AS1 and silencing of miR-454-3p.

Conclusions:

  • Thalidomide inhibits NSCLC angiogenesis and immune evasion.
  • The mechanism involves the FGD5-AS1/miR-454-3p/ZEB1 axis.
  • Regulation of VEGFA expression and the PD-1/PD-L1 checkpoint is key to thalidomide's efficacy.
Keywords:
AngiogenesisEMTImmune evasionThalidomideVEGFAlncRNA FGD5-AS1/miR-454–3p/ZEB1 axis

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