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m6A-Modified SNRPA Controls Alternative Splicing of ERCC1 Exon 8 to Induce Cisplatin Resistance in Lung

Weina Fan1,2, Jian Huang1, Fanglin Tian1

  • 1The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150081, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|November 18, 2024
PubMed

Insights

SNRPA gene regulates cisplatin resistance in lung adenocarcinoma. Targeting SNRPA may enhance chemotherapy sensitivity and improve patient outcomes.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • Alternative splicing (AS) contributes to cancer progression and drug resistance.
  • Platinum-based chemotherapy is a common treatment for lung adenocarcinoma (LUAD).
  • Mechanisms of chemotherapy resistance in LUAD, particularly involving AS, require further elucidation.

Purpose of the Study:

  • To investigate the role of SNRPA, a spliceosome-related gene, in platinum chemotherapy resistance in LUAD.
  • To explore the molecular mechanisms by which SNRPA influences cisplatin resistance and DNA repair.
  • To evaluate SNRPA as a potential therapeutic target for enhancing chemosensitivity in LUAD.

Main Methods:

  • CRISPR/Cas9 and shRNA were used for SNRPA knockout and knockdown in LUAD cells.
  • Gene Ontology (GO) analysis was performed to identify SNRPA-associated functions.
  • Western blotting and siRNA were employed to study ERCC1-XPF complex formation and specific isoforms.

Main Results:

  • SNRPA knockout/knockdown reversed cisplatin resistance in LUAD cells; overexpression enhanced resistance.
  • SNRPA is linked to DNA damage repair pathways, influencing ERCC1 exon 8 skipping and ERCC1-XPF complex formation.
  • IGF2BP and ELAVL1 proteins bind to SNRPA mRNA, with ELAVL1 promoting cisplatin resistance and DNA repair.

Conclusions:

  • SNRPA plays a critical role in mediating platinum-based drug resistance in LUAD.
  • Targeting SNRPA or its associated pathways (e.g., ELAVL1, ERCC1 isoforms) offers a novel strategy to overcome cisplatin resistance.
  • Modulating SNRPA function could improve chemosensitivity and patient prognosis in LUAD.
Keywords:
DNA repairELAVL1ERCC1SNRPAalternative splicingcisplatin resistance

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