Requirement of evading apoptosis for HIF-1α-induced malignant progression in mouse cells
Requirement of evading apoptosis for HIF-1α-induced malignant progression in mouse cells
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DOI：
10.4161/cc.10.14.16313
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发表时间：
2011-07-15
期刊：
影响因子：
4.3
通讯作者：
Huang, L. Eric
中科院分区：
文献类型：
--
作者：
Hayashi, Masami;Yoo, Yoo Young-Gun;Huang, L. Eric
肿瘤缺氧与基因改变和恶性进展有关。我们以前的研究表明，低氧诱导的转录因子HIF-1α通过需要HIF-1αPAS-B亚域的非规范作用模式来抑制肿瘤细胞的DNA修复。HIF-1α参与基因改变提出了一个有趣的问题，即正常细胞是否会以不同的方式对低氧应激做出反应，以避免基因改变。在这项研究中，我们选择了几种类型的小鼠细胞，从良性到恶性，从凋亡熟练到凋亡缺陷，并确定了它们对HIF-1α表达的反应。与我们之前的发现一致的是，在所有被检测的细胞中，短暂的低氧和HIF-1α的表达抑制了DNA修复并诱导了DNA损伤；然而，累积的DNA损伤只发生在凋亡缺陷的恶性细胞中，这些细胞被持续表达HIF-1α或HIF-1αPAS-B本身。根据细胞凋亡作为癌症屏障的理论，只有这些凋亡缺陷的细胞获得了锚定无关的生长和上皮-间充质转化。此外，这些细胞通过抑制自噬而表现出增强的Akt活性和对依托泊苷的耐药性。总之，我们的结果明确了细胞凋亡在防止HIF-1α诱导的基因改变从而防止恶性进展中的重要作用。
Tumor hypoxia is correlated with genetic alteration and malignant progression. Our previous studies indicated that the hypoxia-inducible transcription factor, HIF-1 alpha, is responsible for hypoxic suppression of DNA repair in tumor cells by a non-canonical mode of action that requires the HIF-1 alpha PAS-B subdomain. The involvement of HIF-1 alpha in genetic alteration has raised an intriguing question as to whether normal cells would respond to hypoxic stress differently to avert genetic alteration. In this study, we chose several mouse cell types ranging from benign to malignant, apoptosis-proficient to apoptosis-deficient and determined their responses to HIF-1 alpha expression. In agreement with our previous findings, transient hypoxia and HIF-1 alpha expression inhibited DNA repair and induced DNA damage in all cell types examined; however, cumulative DNA damage only occurred in apoptosis-deficient, malignant cells transduced for sustained expression of HIF-1 alpha or HIF-1 alpha PAS-B itself. In keeping with the theory of apoptosis as a cancer barrier, only these apoptosis-deficient cells acquired anchorage-independent growth and epithelial-mesenchymal transition. Furthermore, these cells exhibited increased Akt activity and resistance to etoposide by inhibiting autophagy. Altogether, our results define an essential role for apoptosis to prevent HIF-1 alpha-induced genetic alteration and thereby malignant progression.