The p53 Target Gene Siva Enables Non-Small Cell Lung Cancer Development
Menée sur des lignées cellulaires et à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, indépendamment du gène p53, le gène SIVA favorise le développement d'un cancer du poumon non à petites cellules
Although p53 transcriptional activation potential is critical for its ability to suppress cancer, the specific target genes involved in tumor suppression remain unclear. Siva is a p53 target gene essential for p53-dependent apoptosis, although it can also promote proliferation through inhibition of p53 in some settings. Thus, the role of SIVA in tumorigenesis remains unclear. Here, we seek to define the contribution of SIVA to tumorigenesis by generating Siva conditional knockout mice. Surprisingly, we find that SIVA loss inhibits non-small cell lung cancer (NSCLC) development, suggesting that SIVA facilitates tumorigenesis. Similarly, SIVA knockdown in mouse and human NSCLC cell lines decreases proliferation and transformation. Consistent with this pro-tumorigenic role for SIVA, high-level SIVA expression correlates with reduced NSCLC patient survival. SIVA acts independently of p53, and instead, stimulates mTOR signaling and metabolism in NSCLC cells. Thus, SIVA enables tumorigenesis in a p53-independent manner, revealing a potential new cancer therapy target.