Cancers (Jan 2024)

The Role of SOX2 and SOX9 in Radioresistance and Tumor Recurrence

  • Silvia Barbosa,
  • Natalia Koerich Laureano,
  • Wahyu Wijaya Hadiwikarta,
  • Fernanda Visioli,
  • Mahnaz Bonrouhi,
  • Kinga Pajdzik,
  • Cristina Conde-Lopez,
  • Christel Herold-Mende,
  • Gustavo Eidt,
  • Renan Langie,
  • Marcelo Lazzaron Lamers,
  • Fabian Stögbauer,
  • Jochen Hess,
  • Ina Kurth,
  • Adriana Jou

DOI
https://doi.org/10.3390/cancers16020439
Journal volume & issue
Vol. 16, no. 2
p. 439

Abstract

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Head and neck squamous cell carcinoma (HNSCC) exhibits considerable variability in patient outcome. It has been reported that SOX2 plays a role in proliferation, tumor growth, drug resistance, and metastasis in a variety of cancer types. Additionally, SOX9 has been implicated in immune tolerance and treatment failures. SOX2 and SOX9 induce treatment failure by a molecular mechanism that has not yet been elucidated. This study explores the inverse association of SOX2/SOX9 and their distinct expression in tumors, influencing the tumor microenvironment and radiotherapy responses. Through public RNA sequencing data, human biopsy samples, and knockdown cellular models, we explored the effects of inverted SOX2 and SOX9 expression. We found that patients expressing SOX2LowSOX9High showed decreased survival compared to SOX2HighSOX9Low. A survival analysis of patients stratified by radiotherapy and human papillomavirus brings additional clinical relevance. We identified a gene set signature comprising newly discovered candidate genes resulting from inverted SOX2/SOX9 expression. Moreover, the TGF-β pathway emerges as a significant predicted contributor to the overexpression of these candidate genes. In vitro findings reveal that silencing SOX2 enhances tumor radioresistance, while SOX9 silencing enhances radiosensitivity. These discoveries lay the groundwork for further studies on the therapeutic potential of transcription factors in optimizing HNSCC treatment.

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