Oncogenic KRAS and BRAF differentially regulate hypoxia-inducible factor-1alpha and -2alpha in colon cancer.
Oncogenic KRAS and BRAF differentially regulate hypoxia-inducible factor-1alpha and -2alpha in colon cancer.
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DOI：
10.1158/0008-5472.can-09-2213
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发表时间：
2009-11-01
期刊：
影响因子：
11.2
通讯作者：
Chung DC
中科院分区：
文献类型：
--
作者：
Kikuchi H;Pino MS;Zeng M;Shirasawa S;Chung DC
KRAS和BRAF突变在人类结肠癌中经常观察到。这些突变以一种互斥的方式发生，每一种突变都与独特的生物学特征有关。我们之前证明了K-ras可以与缺氧相互作用，激活多种信号通路。许多缺氧反应是由缺氧诱导因子-1α (HIF-1α)和HIF-2α介导的，我们试图确定突变体KRAS和BRAF在结肠癌细胞中诱导HIF-1α和HIF-2α的作用。突变体K-ras在Caco2细胞中的异位表达仅增强了HIF-1α的缺氧诱导，而突变体BRAF同时增强了HIF-1α和HIF-2α。在DLD1和HCT116细胞中敲除或敲低KRAS突变体只会损伤HIF-1α的缺氧诱导。HIF-1α mRNA水平在有和没有KRAS突变的细胞中是相似的。然而，在KRAS突变的细胞中，HIF-1α蛋白的合成率更高，这被PI3K抑制剂LY294002抑制。相反，在HT29细胞中敲低突变体BRAF抑制HIF-1α和HIF-2α。尽管BRAF可以调节HIF-1α和HIF-2α的mRNA水平，但敲除BRAF或使用MEK抑制剂PD98059治疗仅会损害HIF-2α的翻译。我们的数据显示，致癌的KRAS和BRAF突变对结肠癌中HIF-1α和HIF-2α的缺氧诱导有不同的调节，这可能是结肠肿瘤中KRAS和BRAF突变的表型差异的潜在原因。
KRAS and BRAF mutations are frequently observed in human colon cancers. These mutations occur in a mutually exclusive manner, and each is associated with distinctive biological features. We previously demonstrated that K-ras can interact with hypoxia to activate multiple signaling pathways. Many hypoxic responses are mediated by hypoxia inducible factor-1α (HIF-1α) and HIF-2α, and we sought to define the roles of mutant KRAS and BRAF in the induction of HIF-1α and HIF-2α in colon cancer cells. Ectopic expression of mutant K-ras in Caco2 cells enhanced the hypoxic induction of only HIF-1α, whereas mutant BRAF enhanced both HIF-1α and HIF-2α. Knockout or knockdown of mutant KRAS in DLD1 and HCT116 cells impaired the hypoxic induction of only HIF-1α. HIF-1α mRNA levels were comparable in cells with and without a KRAS mutation. However, the rate of HIF-1α protein synthesis was higher in cells with a KRAS mutation, and this was suppressed by the PI3K inhibitor LY294002. In contrast, knockdown of mutant BRAF in HT29 cells suppressed both HIF-1α and HIF-2α. Although BRAF regulated mRNA levels of both HIF-1α and HIF-2α, knockdown of BRAF or treatment with the MEK inhibitor PD98059 impaired the translation of only HIF-2α. Our data reveal that oncogenic KRAS and BRAF mutations differentially regulate the hypoxic induction of HIF-1α and HIF-2α in colon cancer, and this may potentially contribute to the phenotypic differences of KRAS and BRAF mutations in colon tumors.