Reciprocal regulation by TLR4 and TGF-β in tumor-initiating stem-like cells
Reciprocal regulation by TLR4 and TGF-β in tumor-initiating stem-like cells
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DOI：
10.1172/jci65859
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发表时间：
2013-07-01
影响因子：
15.9
通讯作者：
Machida, Keigo
中科院分区：
文献类型：
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作者：
Chen, Chia-Lin;Tsukamoto, Hidekazu;Machida, Keigo
肿瘤起始干细胞样细胞（TIC）对化疗耐药，并与HCV和/或酒精相关慢性肝损伤引起的肝细胞癌（HCC）相关。使用HCV Tg小鼠模型和HCC患者，我们分离了CD 133（+）TIC，并将多能性标记物NANO G鉴定为TLR 4的直接靶点，TLR 4驱动TIC的肿瘤起始活性。这些TLR 4/NANOG依赖性TIC在TGF-β肿瘤抑制途径中是有缺陷的。TIC cDNA文库的功能性癌基因筛选将Yap 1和Igf 2bp 3鉴定为抑制TGF-β信号传导的NANOG依赖性基因。从机制上讲，我们确定YAP 1介导磷酸化的细胞质保留。SMAD 3并通过IGF 2BP 3/AKT/mTOR途径抑制SMAD 3磷酸化/激活。YAP 1和IGF 2BP 3的沉默恢复了TGF-β信号传导，抑制了多能性基因和肿瘤发生，并消除了TIC的化学抗性。TGF-β信号传导缺陷的小鼠（Spnb 2（+/-）小鼠）表现出增强的肝脏TLR 4表达，并以TLR 4依赖性方式发生HCC。总之，这些结果表明，激活的TLR 4/NANOG致癌通路与抑制细胞生长的TGF-β信号转导有关，并可能作为HCV相关HCC的治疗靶点。
Tumor-initiating stem-like cells (TICs) are resistant to chemotherapy and associated with hepatocellular carcinoma (HCC) caused by HCV and/or alcohol-related chronic liver injury. Using HCV Tg mouse models and patients with HCC, we isolated CD133(+) TICs and identified the pluripotency marker NANO G as a direct target of TLR4, which drives the tumor-initiating activity of TICs. These TLR4/NANOG-dependent TICs were defective in the TGF-beta tumor suppressor pathway. Functional oncogene screening of a TIC cDNA library identified Yap1 and Igf2bp3 as NANOG-dependent genes that inactivate TGF-beta signaling. Mechanistically, we determined that YAP1 mediates cytoplasmic retention of phosphorylated. SMAD3 and suppresses SMAD3 phosphorylation/activation by the IGF2BP3/AKT/mTOR pathway. Silencing of both YAP1 and IGF2BP3 restored TGF-beta signaling, inhibited pluripotency genes and tumorigenesis, and abrogated chemoresistance of TICs. Mice with defective TGF-beta signaling (Spnb2(+/-) mice) exhibited enhanced liver TLR4 expression and developed HCC in a TLR4-dependent manner. Taken together, these results suggest that the activated TLR4/NANOG oncogenic pathway is linked to suppression of cytostatic TGF-beta signaling and could potentially serve as a therapeutic target for HCV-related HCC.