NFκB Promotes Ovarian Tumorigenesis via Classical Pathways That Support Proliferative Cancer Cells and Alternative Pathways That Support ALDH(+) Cancer Stem-like Cells.
NFκB Promotes Ovarian Tumorigenesis via Classical Pathways That Support Proliferative Cancer Cells and Alternative Pathways That Support ALDH(+) Cancer Stem-like Cells.
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DOI：
10.1158/0008-5472.can-17-0366
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发表时间：
2017-12-15
期刊：
影响因子：
11.2
通讯作者：
Annunziata CM
中科院分区：
文献类型：
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作者：
House CD;Jordan E;Hernandez L;Ozaki M;James JM;Kim M;Kruhlak MJ;Batchelor E;Elloumi F;Cam MC;Annunziata CM
了解支持肿瘤起始细胞(TIC)的机制对于抗击晚期复发癌症至关重要。在这里，我们表明，在晚期卵巢癌中，通过RelB转录因子的NF-kB信号通过直接调节癌症干细胞样相关酶乙醛脱氢酶(ALDH)来支持TIC群体。在皮下和法氏囊内移植的人卵巢癌小鼠模型中，丢失RelB显著抑制类球体的形成、ALDH的表达和活性、化疗耐药性和肿瘤形成。RelB还影响ALDH基因ALDH1A2的表达。有趣的是，经典的通过RELA转录因子的核因子-kB信号在法氏囊内模型的肿瘤发生中同样重要，但对ALDH没有影响。在这种情况下，通过RELA的经典信号对细胞增殖是必不可少的，而另一种信号通路不是。我们的结果表明，核因子-kB如何通过不同的经典和替代信号通路维持不同的癌症表型，这对于改善对疾病复发和治疗反应的理解具有重要意义。
Understanding the mechanisms supporting tumor-initiating cells (TIC) is vital to combat advanced stage recurrent cancers. Here we show that in advanced ovarian cancers NF-kB signaling via the RelB transcription factor supports TIC populations by directly regulating the cancer stem-like associated enzyme aldehyde dehydrogenase (ALDH). Loss of RelB significantly inhibited spheroid formation, ALDH expression and activity, chemoresistance, and tumorigenesis in subcutaneous and intrabursal mouse xenograft models of human ovarian cancer. RelB also affected expression of the ALDH gene ALDH1A2. Interestingly, classical NF-kB signaling through the RelA transcription factor was equally important for tumorigenesis in the intrabursal model, but had no effect on ALDH. In this case, classical signaling via RelA was essential for proliferating cells, whereas the alternative signaling pathway was not. Our results show how NF-kB sustains diverse cancer phenotypes via distinct classical and alternative signaling pathways, with implications for improved understanding of disease recurrence and therapeutic response.