Progenitor/stem cells give rise to liver cancer due to aberrant TGF-β and IL-6 signaling
Progenitor/stem cells give rise to liver cancer due to aberrant TGF-β and IL-6 signaling
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DOI：
10.1073/pnas.0705395105
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发表时间：
2008-02-19
影响因子：
11.1
通讯作者：
Mishra, Lopa
中科院分区：
文献类型：
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作者：
Tang, Yi;Kitisin, Krit;Mishra, Lopa
癌症干细胞（CSC）对于多种癌症的起始、繁殖和治疗抗性至关重要。然而，在实体器官“癌症干细胞”（如肝脏干细胞）中，特定信号通路之间的功能相互作用仍然难以捉摸。我们报告说，在再生人类肝脏中，每30，000 - 50，000个细胞中有2 - 4个细胞表达干细胞蛋白Stat 3、Oct 4和Nanog，沿着有促分化蛋白TGF-β受体11型（TBRII）和胚胎肝胞衬蛋白（ELF）。对人肝细胞癌（HCC）的检查揭示了用干细胞标记物标记的细胞意外地失去了TBRII和ELF。elf（+/-）小鼠自发地发展HCC;这些肿瘤的表达分析突出了参与IL-6信号传导途径的基因的显著活化，包括IL-6和Stat 3，表明HCC可能产生于具有失活的TGF-β信号传导的IL-6驱动的转化干细胞。类似地，通过产生涉及IL-6的正调节因子间-α-胰蛋白酶转运蛋白-重链-4（ITIH 4）的小鼠敲除来抑制IL-6信号传导，导致elf（+/-）小鼠中HCC的减少。这项研究揭示了IL-6（一种主要的干细胞信号传导途径）和TGF-β信号传导途径在哺乳动物HCC（一种前肠致死性癌症）调节中的意外功能联系。这些实验表明靶向IL-6在缺乏功能性TGF-β途径的HCC中具有重要的治疗作用。
Cancer stem cells (CSCs) are critical for the initiation, propagation, and treatment resistance of multiple cancers. Yet functional interactions between specific signaling pathways in solid organ "cancer stem cells," such as those of the liver, remain elusive. We report that in regenerating human liver, two to four cells per 30,000-50,000 cells express stem cell proteins Stat3, Oct4, and Nanog, along with the prodifferentiation proteins TGF-beta-receptor type 11 (TBRII) and embryonic liver fodrin (ELF). Examination of human hepatocellular cancer (HCC) reveals cells that label with stem cell markers that have unexpectedly lost TBRII and ELF. elf(+/-) mice spontaneously develop HCC; expression analysis of these tumors highlighted the marked activation of the genes involved in the IL-6 signaling pathway, including IL-6 and Stat3, suggesting that HCC could arise from an IL-6-driven transformed stem cell with inactivated TGF-beta signaling. Similarly, suppression of IL-6 signaling, through the generation of mouse knockouts involving a positive regulator of IL-6, Inter-alpha-trypsin inhibitor-heavy chain-4 (ITIH4), resulted in reduction in HCC in elf(+/-) mice. This study reveals an unexpected functional link between IL-6, a major stem cell signaling pathway, and the TGF-beta signaling pathway in the modulation of mammalian HCC, a lethal cancer of the foregut. These experiments suggest an important therapeutic role for targeting IL-6 in HCCs lacking a functional TGF-beta pathway.