Hypoxia-Mediated Up-Regulation of Pim-1 Contributes to Solid Tumor Formation
Hypoxia-Mediated Up-Regulation of Pim-1 Contributes to Solid Tumor Formation
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DOI：
10.2353/ajpath.2009.080972
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发表时间：
2009-07-01
影响因子：
6
通讯作者：
Lee, Mong-Hong
中科院分区：
文献类型：
--
作者：
Chen, Jian;Kobayashi, Masanobu;Lee, Mong-Hong
肿瘤缺氧直接促进基因组不稳定性并促进细胞存活，导致肿瘤具有更具侵袭性的表型。原癌基因pim-1通过磷酸化靶蛋白来调节细胞凋亡和细胞周期。Pim-1的过表达可引起基因组不稳定性并促进淋巴瘤发生。目前尚不清楚Pim-1是否参与实体瘤中低氧介导的肿瘤存活。在这里，我们表明，缺氧可以稳定Pim-1通过阻止其泛素介导的蛋白酶体降解，并可以导致Pim-1从细胞质易位到细胞核。重要的是，Pim-1的过表达仅在低氧条件下增加NIH 3 T3细胞转化，表明低氧条件下的Pim-1表达可能涉及实体瘤的转化过程。此外，通过引入显性负性Pim-1来阻断Pim-1功能可使胰腺癌细胞对缺氧条件下葡萄糖剥夺诱导的凋亡重新敏感。Pim-1的短干扰RNA的引入也使癌细胞在缺氧条件下对葡萄糖剥夺再敏感，而Pim-1的强制过表达导致实体瘤细胞变得对葡萄糖剥夺具有抗性。此外，显性阴性Pim-1降低胰腺癌细胞和HeLa异种移植小鼠模型中的致瘤性。总之，我们的研究表明，Pim-1在体内实体瘤形成中起着独特的作用，这意味着Pim-1可能是癌症治疗的新靶点。(Am《病理学杂志》，2009年，第175页。400-411; DOI：10.2353/ajpath.2009.080972）
Tumor hypoxia directly promotes genomic instability and facilitates cell survival, resulting in tumors with a more aggressive phenotype. The proto-oncogene pim-1 regulates apoptosis and the cell cycle by phosphorylating target proteins. Overexpression of Pim-1 can cause genomic instability and contribute to lymphomagenesis. It is not clear whether Pim-1 is involved in hypoxia-mediated tumor survival in solid tumors. Here, we show that hypoxia can stabilize Pim-1 by preventing its ubiquitin-mediated proteasomal degradation and can cause Pim-1 translocation from the cytoplasm to the nucleus. importantly, overexpression of Pim-1 increases NIH3T3 cell transformation exclusively under hypoxic conditions, suggesting that Pim-1 expression under hypoxia may be implicated in the transformation process of solid tumors. Also, blocking Pim-1 function by introduction of dominant negative Pim-1 resensitizes pancreatic cancer cells to apoptosis induced by glucose-deprivation under hypoxia. introduction of short interfering RNAs for Pim-1 also resensitizes; cancer cells to glucose deprivation under hypoxic conditions, while forced overexpression of Pim-1 causes solid tumor cells to become resistant to glucose deprivation. Moreover, dominant negative Pim-1 reduces tumorigenicity in pancreatic cancer cells and HeLa xenograft mouse models. Together, our studies indicate that Pim-1 plays a distinct role in solid tumor formation in vivo, implying that Pim-1 may be a novel target for cancer therapy. (Am J Pathol 2009, 175.-400-411; DOI: 10.2353/ajpath.2009.080972)