IL-1β promotes stemness and invasiveness of colon cancer cells through Zeb1 activation.
IL-1β promotes stemness and invasiveness of colon cancer cells through Zeb1 activation.
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DOI：
10.1186/1476-4598-11-87
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发表时间：
2012-11-23
期刊：
影响因子：
37.3
通讯作者：
Shi J
中科院分区：
文献类型：
--
作者：
Li Y;Wang L;Pappan L;Galliher-Beckley A;Shi J
IL-1β是一种多效性促炎细胞因子，其上调与包括胃肠道肿瘤在内的多种癌症密切相关。然而，目前尚不清楚IL-1β如何促进这些炎症相关癌症的发生和发展。在此，我们研究了IL-1β在结肠癌干细胞（CSC）发育中的作用。采用自我更新法、软琼脂法、侵袭法、实时荧光定量PCR法、免疫印迹法和shRNA敲除法，研究了IL-1β对人原发性结肠癌细胞和结肠癌细胞系HCT-116肿瘤干细胞发育和上皮间充质转化（EMT）的影响。我们发现IL-1β可以提高结肠癌细胞在无血清培养基中的成球能力。il -1β诱导的微球显示出干细胞的特征——干细胞因子基因（Bmi1和Nestin）的上调和耐药性的增加。重要的是，在il -1β诱导的微球中，EMT激活因子Zeb1的表达增加，表明EMT与il -1β诱导的CSC自我更新之间可能存在密切关联。事实上，IL-1β治疗导致结肠癌细胞EMT， E-cadherin缺失，Zeb1上调，间充质表型增加。此外，shrna介导的HCT-116细胞中Zeb1的敲低逆转了il -1β诱导的EMT和干细胞形成。我们的研究结果表明，IL-1β可能通过激活CSC自我更新和EMT来促进结肠肿瘤的生长和侵袭，而Zeb1在这两个过程中起着关键作用。因此，IL-1β和Zeb1可能是结肠癌干细胞治疗的新靶点。
IL-1β is a pleiotropic pro-inflammatory cytokine and its up-regulation is closely associated with various cancers including gastrointestinal tumors. However, it remains unclear how IL-1β may contribute to the initiation and development of these inflammation-associated cancers. Here we investigated the role of IL-1β in colon cancer stem cell (CSC) development. Using self-renewal assay, soft-agar assay, invasion assay, real-time PCR analysis, immunoblot assay and shRNA knockdown, we determined the effects of IL-1β on cancer stem cell development and epithelial-mesenchymal transition (EMT) in human primary colon cancer cells and colon cancer cell line HCT-116. We found that IL-1β can increase sphere-forming capability of colon cancer cells in serum-free medium. IL-1β-induced spheres displayed an up-regulation of stemness factor genes (Bmi1 and Nestin) and increased drug resistance, hallmarks of CSCs. Importantly, expression of EMT activator Zeb1 was increased in IL-1β-induced spheres, indicating that there might be a close association between EMT and IL-1β-induced CSC self-renewal. Indeed, IL-1β treatment led to EMT of colon cancer cells with loss of E-cadherin, up-regulation of Zeb1, and gain of the mesenchymal phenotype. Furthermore, shRNA-mediated knockdown of Zeb1 in HCT-116 cells reversed IL-1β-induced EMT and stem cell formation. Our findings indicate that IL-1β may promote colon tumor growth and invasion through activation of CSC self-renewal and EMT, and Zeb1 plays a critical role in these two processes. Thus, IL-1β and Zeb1 might be new therapeutic targets against colon cancer stem cells.
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影响因子：
8
作者：
Kaler, P.;Augenlicht, L.;Klampfer, L.
通讯作者：
Klampfer, L.
影响因子：
64.8
作者：
O'Brien, Catherine A.;Pollett, Aaron;Dick, John E.
通讯作者：
Dick, John E.
DOI：
10.1073/pnas.0703478104
发表时间：
2007-06-12
影响因子：
11.1
作者：
Dalerba, Piero;Dylla, Scott J.;Clarke, Michael F.
通讯作者：
Clarke, Michael F.
影响因子：
--
作者：
Kaler, Pawan;Godasi, Bramara N;Augenlicht, Leonard;Klampfer, Lidija
通讯作者：
Klampfer, Lidija
影响因子：
3.4
作者：
Dohadwala, Mariam;Wang, Guanyu;John, Maie A. St.
通讯作者：
John, Maie A. St.