The biphasic role of NF-kappaB in progression and chemoresistance of ovarian cancer.
The biphasic role of NF-kappaB in progression and chemoresistance of ovarian cancer.
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DOI：
10.1158/1078-0432.ccr-10-3265
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发表时间：
2011-04-15
期刊：
影响因子：
--
通讯作者：
Liu J
中科院分区：
文献类型：
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作者：
Yang G;Xiao X;Rosen DG;Cheng X;Wu X;Chang B;Liu G;Xue F;Mercado-Uribe I;Chiao P;Du X;Liu J
NF-κB是已知促进肿瘤发生的转录因子。然而，NF-κB也被认为是促凋亡的，并可能作为一种肿瘤抑制因子发挥作用，尽管这种功能性作用在人类癌症中尚未得到广泛研究。用IκBα的S32 A和S36 A突变的显性失活突变体抑制卵巢癌细胞系中NF-κB的功能。与亲本细胞相比，在衍生细胞系中检查转录能力、肿瘤发生、凋亡和药物敏感性。我们还分析了卵巢癌组织芯片中NF-κB p65核表达与患者生存率的关系。我们发现NF-κB在四种卵巢癌细胞系中作为肿瘤抑制因子发挥作用，但在其侵袭性化疗耐药的同基因变异体中作为癌基因发挥作用。NF-κB可通过激活或抑制丝裂原活化蛋白激酶（MAPK）磷酸化在亲本或侵袭性化疗耐药变异细胞系中发挥其促凋亡或抗凋亡作用。我们还表明，上皮癌组织中p65的核积累与化疗的良好反应相关，并可预测卵巢癌患者的总生存期较长。我们的数据提供了强有力的证据，NF-κB可以作为一个双相调节器，通过调节MAPK和细胞凋亡抑制或促进卵巢癌的生长。
NF-κB is a transcription factor known to promote tumorigenesis. However, NF-κB is also known to be proapoptotic and may potentially function as a tumor suppressor, although such a functional role has not been extensively investigated in human cancer. A dominant-negative mutant of IκBα with mutations at S32A and S36A was used to inhibit the function of NF-κB in ovarian cancer cell lines. The transcription ability, tumorigenesis, apoptosis, and drug sensitivity were examined in derivative cell lines in comparison with parental cells. We also analyzed the association of nuclear expression of NF-κB p65 with patient survival in an ovarian cancer tissue array. We show that NF-κB functions as a tumor suppressor in four ovarian cancer cell lines, but it functions as an oncogene in their aggressive chemoresistant isogenic variants. NF-κB can exert its proapoptotic or antiapoptotic effect by activating or repressing mitogen-activated protein kinase (MAPK) phosphorylation in parental or aggressive chemoresistant variant cell lines. We also show that the nuclear accumulation of p65 in epithelial cancer tissue is associated with a good response to chemotherapy and can predict longer overall survival for patients with ovarian cancer. Our data provide strong evidence that NF-κB can function as a biphasic regulator, either suppressing or enhancing ovarian cancer growth through the regulation of MAPK and cellular apoptosis.