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<p>Uveal melanoma (UM) is the most common intraocular tumor, and despite being rare, it accounts for nearly 13% of melanoma-related deaths. Indeed, patients with metastatic disease have typically survival rates of less than one year, with little improvement over the past few decades. Although <i>TP53</i> mutations are uncommon in UM, recent findings highlight a dysfunctional p53 pathway in this cancer. Given its crucial role in mediating DNA damage responses, we analyzed the p53 protein functionality and downstream target activation in a panel of UM cell lines in response to standard-of-care treatments (i.e., cisplatin and proton-beam irradiation). Although most of the analyzed cells retained a wild-type p53, we observed a wide range of p53 protein stabilization and targets’ activation. Recently, p53 isoforms have been recognized as modifiers of p53 activity, and their biology and functions depend on cellular context. We observed that UM cells express a broad spectrum of p53 isoforms, including Δ160p53α and Δ133p53β and the longer variants Δ40p53β and p53β. Interestingly, the down-regulation of the short p53 isoforms (Δ133/Δ160) revealed their contribution to promoting cell growth and in mitigating cell death triggered by standard-of-care therapies. Moreover, we verified the wild-type p53 status in a panel of 32 UM cases and analyzed the expression levels of p53 isoforms. Our results indicated a correlation between higher expression levels of Δ40p53α or Δ133p53γ isoforms and the development of more aggressive cancers. Our findings suggest that shorter p53 isoforms can promote cancer aggressiveness and therapy resistance, thereby providing crucial insights into UM pathogenesis.</p>

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Exploring p53 isoforms: unraveling heterogeneous p53 tumor suppressor functionality in uveal melanoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月5日

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  • Laura Bartolomei,
  • Yari Ciribilli,
  • Samuele Brugnara,
  • Francesco Reggiani,
  • Gian Mario Moretta,
  • Mariangela Petito,
  • Elisa Marcaccini,
  • Marianna Ambrosio,
  • Carlo Mosci,
  • Ulrich Pfeffer,
  • Adriana Amaro,
  • Paola Monti,
  • Alessandra Bisio

摘要

Uveal melanoma (UM) is the most common intraocular tumor, and despite being rare, it accounts for nearly 13% of melanoma-related deaths. Indeed, patients with metastatic disease have typically survival rates of less than one year, with little improvement over the past few decades. Although TP53 mutations are uncommon in UM, recent findings highlight a dysfunctional p53 pathway in this cancer. Given its crucial role in mediating DNA damage responses, we analyzed the p53 protein functionality and downstream target activation in a panel of UM cell lines in response to standard-of-care treatments (i.e., cisplatin and proton-beam irradiation). Although most of the analyzed cells retained a wild-type p53, we observed a wide range of p53 protein stabilization and targets’ activation. Recently, p53 isoforms have been recognized as modifiers of p53 activity, and their biology and functions depend on cellular context. We observed that UM cells express a broad spectrum of p53 isoforms, including Δ160p53α and Δ133p53β and the longer variants Δ40p53β and p53β. Interestingly, the down-regulation of the short p53 isoforms (Δ133/Δ160) revealed their contribution to promoting cell growth and in mitigating cell death triggered by standard-of-care therapies. Moreover, we verified the wild-type p53 status in a panel of 32 UM cases and analyzed the expression levels of p53 isoforms. Our results indicated a correlation between higher expression levels of Δ40p53α or Δ133p53γ isoforms and the development of more aggressive cancers. Our findings suggest that shorter p53 isoforms can promote cancer aggressiveness and therapy resistance, thereby providing crucial insights into UM pathogenesis.