The p53 Target Gene SIVA Enables Non-Small Cell Lung Cancer Development.
The p53 Target Gene SIVA Enables Non-Small Cell Lung Cancer Development.
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DOI：
10.1158/2159-8290.cd-14-0921
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发表时间：
2015-06
期刊：
影响因子：
28.2
通讯作者：
Attardi LD
中科院分区：
文献类型：
--
作者：
Van Nostrand JL;Brisac A;Mello SS;Jacobs SB;Luong R;Attardi LD
尽管p53转录激活潜力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 依赖性细胞凋亡所必需的 p53 靶基因，尽管它在某些情况下也可以通过抑制 p53 来促进增殖。因此，SIVA 在肿瘤发生中的作用仍不清楚。在这里，我们试图通过生成 Siva 条件敲除小鼠来确定 SIVA 对肿瘤发生的贡献。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，小鼠和人类 NSCLC 细胞系中的 SIVA 敲低会降低增殖和转化。与 SIVA 的促肿瘤作用一致，高水平 SIVA 表达与 NSCLC 患者生存率降低相关。 SIVA 的作用独立于 p53，而是刺激 NSCLC 细胞中的 mTOR 信号传导和代谢。因此，SIVA 能够以不依赖于 p53 的方式发生肿瘤，揭示了潜在的新癌症治疗靶点。
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.