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Genomic Insights into Oral Cancer Highlight Mutant SIGMAR1 as a Critical Target to Overcome Chemoresistance

Pablo Shimaoka Chagas1,2, Cristiana Bernadelli Garcia3, Andréia Machado Leopoldino3

  • 1Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. Do Café S/N, Ribeirão Preto, SP, 14040-903, Brazil. pablochagas@usp.br.

Biochemical Genetics
|April 21, 2025
PubMed

Insights

Sigma-1 receptor (SIGMAR1) mutations contribute to oral cancer drug resistance. Targeting SIGMAR1 may overcome chemoresistance, offering new therapeutic avenues for oral cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Oral cancer (OC) is an aggressive malignancy with limited treatment options.
  • Sigma-1 receptor (SIGMAR1) is implicated in cancer progression and drug resistance.
  • The specific role of SIGMAR1 in oral cancer pathogenesis and chemoresistance is not well-defined.

Purpose of the Study:

  • To investigate SIGMAR1 mutations, expression, and its association with drug resistance in oral cancer.
  • To identify novel SIGMAR1 alterations and their functional impact in OC.

Main Methods:

  • Analysis of 2008 oral cancer samples from TCGA Pan-Cancer Atlas for SIGMAR1 genetic alterations.
  • Sanger sequencing of the HN13 OC cell line to identify mutations.
  • Quantitative RT-PCR and Western blot to assess SIGMAR1 expression.
  • Assessment of HN13 cell sensitivity to cisplatin after SIGMAR1 silencing.

Main Results:

  • SIGMAR1 genetic alterations were found in 4% of oral cancer cases.
  • A novel heterozygous missense mutation (c.585C>G) in SIGMAR1 was identified in the HN13 cell line.
  • SIGMAR1 was overexpressed in HN13 cells compared to normal oral keratinocytes.
  • Silencing SIGMAR1 enhanced HN13 cell sensitivity to cisplatin, confirming its role in drug resistance.

Conclusions:

  • This study is the first to report the c.585C>G mutation in SIGMAR1 and its link to cisplatin resistance in oral cancer.
  • SIGMAR1 plays a crucial role in oral cancer pathogenesis and chemoresistance.
  • SIGMAR1 represents a potential therapeutic target for overcoming cisplatin resistance in oral cancer, paving the way for precision oncology.
Keywords:
Cancer therapy targetsCisplatin resistanceOral cancerSIGMAR1c.585C > G mutation

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