c-Myc is regulated by HIF-2α in chronic hypoxia and influences sensitivity to 5-FU in colon cancer.
c-Myc is regulated by HIF-2α in chronic hypoxia and influences sensitivity to 5-FU in colon cancer.
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DOI：
10.18632/oncotarget.12911
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发表时间：
2016-11-29
期刊：
影响因子：
--
通讯作者：
Chung DC
中科院分区：
文献类型：
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作者：
Wang L;Xue M;Chung DC
结直肠癌（crc）在扩大过程中不可避免地变得缺氧，这对肿瘤细胞提出了独特的代谢要求。低氧应激可增强癌细胞的侵袭性，诱导化疗耐药。c-Myc是一种受缺氧诱导因子（hypoxia inducible factors, hfs）调控的癌基因，在细胞增殖和代谢中起关键作用。然而，c-Myc与hfs之间的相互作用及其在crc低氧适应中的临床意义尚不清楚。我们证明，结肠癌细胞中的c-Myc mRNA和蛋白水平在缺氧应激（1% O2） 2小时内被诱导，但当暴露于长时间缺氧时，c-Myc mRNA和蛋白水平显著下调。在慢性缺氧（1% O2超过8小时）中，HIF-2α而非HIF-1α在结肠癌细胞中逐渐积累。HIF-2α的下调增加了慢性缺氧中c-Myc及其下游靶点cyclinD1的水平，表明HIF-2α可能具有下调c-Myc的功能。慢性缺氧抑制cyclinD1、CDK4和CDK6的表达，诱导G1期阻滞和5-氟尿嘧啶（5-FU）耐药。c-Myc的过表达逆转了cyclinD1、CDK4和CDK6的抑制，加速了缺氧下G1/S期转变，增强了对5-FU的敏感性。相反，敲低c-Myc会损害结肠癌细胞的5-FU化学敏感性。综上所述，HIF-2α在慢性缺氧中调节c-Myc的表达，从而控制慢性缺氧环境下结肠癌细胞对5-FU治疗的敏感性。
Colorectal cancers (CRCs) invariably become hypoxic as they enlarge, and this places unique metabolic demands upon the tumor cells. Hypoxic stress can enhance the invasiveness of cancer cells and induce chemoresistance. c-Myc, an oncogene regulated by hypoxia inducible factors (HIFs), plays a critical role in cell proliferation and metabolism. However, the interplay between c-Myc and HIFs and its clinical significance in hypoxic adaptation in CRCs are unknown. We demonstrate that c-Myc mRNA and protein levels in colon cancer cells are induced within 2 h of hypoxic stress (1% O2) but are then significantly downregulated when exposed to prolonged hypoxia. In chronic hypoxia (over 8 h at 1% O2), HIF-2α but not HIF-1α gradually accumulated in colon cancer cells. Knockdown of HIF-2α increased levels of c-Myc and its downstream target cyclinD1 in chronic hypoxia, indicating that HIF-2α may function to downregulate c-Myc. Chronic hypoxia suppressed the expression of cyclinD1, CDK4, and CDK6, inducing G1 phase block and 5-flurouracil (5-FU) chemoresistance. Overexpression of c-Myc reversed the inhibition of cyclinD1, CDK4, and CDK6, which accelerated the G1/S phase transition under hypoxia and enhanced sensitivity to 5-FU. In contrast, knockdown of c-Myc impaired 5-FU chemosensitivity in colon cancer cells. In summary, HIF-2α plays an important role in regulating the expression of c-Myc in chronic hypoxia, and consequently controls the sensitivity of colon cancer cells to 5-FU treatment in this environment.