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Alginate microspheres encapsulating hox transcript antisense RNA siRNA regulate the Hedgehog-Gli1 pathway to

Guojie Lu1, Huiling Zhong1, Jianwei Gao1

  • 1Department of Cardiothoracic Surgery, The Affiliated Panyu Central Hospital of Guangzhou Medical University, Guangzhou, China.

Journal of Biomaterials Applications
|January 23, 2024
PubMed

Insights

This study shows that HOTAIR siRNA, delivered via sodium alginate microspheres, effectively overcomes EGFR-TKIs resistance in non-small cell lung cancer by inhibiting the Hedgehog-Gli1 pathway. This approach offers a promising strategy for enhancing cancer treatment efficacy.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biotechnology

Background:

  • Long non-coding RNA HOTAIR and Hedgehog-Gli1 pathway are implicated in cancer progression and drug resistance.
  • The role of HOTAIR in EGFR-TKIs resistance in non-small cell lung cancer (NSCLC) is not fully understood.
  • Developing strategies to overcome acquired resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs) is crucial for improving patient outcomes.

Purpose of the Study:

  • To investigate the role of HOTAIR in the development of EGFR-TKIs resistance in NSCLC.
  • To evaluate the efficacy of HOTAIR siRNA encapsulated in sodium alginate microspheres (SA/HOTAIR siRNA) in overcoming gefitinib resistance.
  • To explore the modulation of the Hedgehog-Gli1 signaling pathway by HOTAIR in EGFR-TKIs resistant cells.

Main Methods:

  • Preparation of sodium alginate microspheres encapsulating HOTAIR siRNA using an electrospray method.
  • In vitro assessment of SA/HOTAIR siRNA's effect on proliferation, migration, invasion, and apoptosis in gefitinib-resistant PC9/GR cells.
  • In vivo evaluation of SA/HOTAIR siRNA's anti-tumor effects and impact on the Hedgehog-Gli1 pathway in animal models.
  • Analysis of HOTAIR expression in NSCLC patients undergoing EGFR-TKIs treatment.

Main Results:

  • Sodium alginate microspheres exhibited good biocompatibility, high encapsulation efficiency, and enhanced siRNA silencing.
  • HOTAIR siRNA significantly inhibited PC9/GR cell proliferation, migration, and invasion, while promoting apoptosis.
  • SA/HOTAIR siRNA demonstrated superior efficacy compared to HOTAIR siRNA alone in inhibiting cellular and tumor functions.
  • HOTAIR siRNA suppressed tumor growth, downregulated the Hedgehog-Gli1 pathway and anti-apoptotic proteins in vivo.
  • Pre-treatment HOTAIR expression levels in serum and urine could predict EGFR-TKIs treatment efficacy in NSCLC patients.

Conclusions:

  • HOTAIR siRNA effectively mitigates acquired resistance to EGFR-TKIs by inhibiting the Hedgehog-Gli1 pathway.
  • SA/HOTAIR siRNA represents a reliable and long-lasting drug delivery system for combating acquired EGFR-TKIs resistance.
  • Monitoring HOTAIR expression may serve as a predictive biomarker for EGFR-TKIs treatment response in NSCLC.
Keywords:
Hox transcript antisense RNAepidermal growth factor receptor tyrosine kinase inhibitorsgefitinib resistancehedgehog-GLi1non-small cell lung cancersodium alginate microspheres

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