低氧相关lncRNA UTGF调控TGF-β信号传导及转移的作用及机制

肝癌在我国高发且预后极差，易早期转移是导致患者死亡率高的主要原因。由HIF1α和TGFβ介导的上皮间质转换（EMT），是促进转移的重要机制。然而，肝癌中HIF1α/TGFβ通路间的调控关系尚不清楚。lncRNA是一类不编码蛋白的新分子。前期我们发现lncUTGF可能介导HIF1α/TGFβ通路的交流：低氧促进lncUTGF的表达，沉默HIF1α则削弱该作用；低氧也可促进TGFβ/SMADs信号传导，敲低lncUTGF则可阻断此传导，并抑制TGFβ介导的EMT激活及肿瘤转移。以此为基础，本项目拟开展以下工作：1）阐明低氧诱导lncUTGF表达的分子机制；2）揭示lncUTGF在HIF1α/TGFβ通路互作网络中的作用及机制；3）探究lncUTGF在TGFβ介导的肝癌转移中的作用。研究结果将揭示一条新的HIF1α/lncUTGF/TGFβ通路调控轴及其在转移中的作用，可为肿瘤治疗提供新靶点。

Hepatocellular carcinoma (HCC) is a worldwide common malignancy with frequent early recurrence and high mortality, which are mainly resulted from the early metastasis. The epithelial-mesenchymal transition (EMT) mediated by HIF1α and TGFβ/SMADs pathway is an important mechanism to promote tumor metastasis. However, the regulatory relationship between HIF1α and TGFβ signaling in HCC remains obscure. Long non-coding RNAs belong to a class of novel non-protein coding transcripts. In this study, we found that lncUTGF may mediate the crosstalk of HIF1α and TGFβ/SMADs signaling: hypoxia induced HIF1α expression, while silencing HIF1α attenuated this promotive effect; hypoxia also promoted TGFβ/SMADs signaling, while knockdown of lncUTGF blocked this stimulative effect, and inhibited TGFβ-induced EMT and tumor metastasis. Based on these data, the following research areas will be involved in the project: 1) to clarify the mechanism of how hypoxia regulate lncUTGF expression; 2) to disclose the role and the mechanism of lncUTGF in HIF1α/TGFβ signaling crosstalk; 3) to explore the regulatory role of lncUTGF in TGFβ-induced metastasis. The results will identify a novel HIF1α/lncUTGF/TGFβ signaling regulatory axis and disclose the significance of its deregulation in metastasis, which may provide a new therapeutic target for anti-tumor metastasis.