Van Nostrand Jeanine L, Brisac Alice, Mello Stephano S, Jacobs Suzanne B R, Luong Richard, Attardi Laura D
Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
Department of Biology, Ecole Normale Supérieure de Lyon, Lyon, France.
Cancer Discov. 2015 Jun;5(6):622-35. doi: 10.1158/2159-8290.CD-14-0921. Epub 2015 Mar 26.
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 protumorigenic 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.
These findings collectively reveal a novel role for the p53 target gene SIVA both in regulating metabolism and in enabling tumorigenesis, independently of p53. Importantly, these studies further identify SIVA as a new prognostic marker and as a potential target for NSCLC cancer therapy.
尽管p53的转录激活潜能对其抑制癌症的能力至关重要，但参与肿瘤抑制的具体靶基因仍不清楚。SIVA是p53依赖性凋亡所必需的一个p53靶基因，不过在某些情况下它也可通过抑制p53来促进增殖。因此，SIVA在肿瘤发生中的作用仍不清楚。在此，我们通过构建Siva条件性敲除小鼠来确定SIVA对肿瘤发生的作用。令人惊讶的是，我们发现SIVA缺失会抑制非小细胞肺癌（NSCLC）的发展，这表明SIVA促进肿瘤发生。同样，在小鼠和人NSCLC细胞系中敲低SIVA会降低细胞增殖和转化能力。与SIVA的这种促肿瘤作用一致，高水平的SIVA表达与NSCLC患者生存率降低相关。SIVA独立于p53发挥作用，相反，它会刺激NSCLC细胞中的mTOR信号传导和代谢。因此，SIVA以一种不依赖p53的方式促进肿瘤发生，揭示了一个潜在的新癌症治疗靶点。
这些发现共同揭示了p53靶基因SIVA在调节代谢以及在不依赖p53的情况下促进肿瘤发生方面的新作用。重要的是，这些研究进一步确定SIVA是一种新的预后标志物以及NSCLC癌症治疗的潜在靶点。
