肿瘤干细胞与肿瘤治疗抵抗密切相关。研究发现放疗抵抗的非小细胞肺癌中癌干细胞比例明显升高，但机制不清。我们前期发现：放疗诱导非小细胞肺癌分化细胞表达癌干细胞标志和特性，mTOR/HIF-1α通路激活；抑制mTOR/HIF-1α，放疗后癌干细胞标志表达明显抑制；并发现HIF-1α作为转录因子可能调控SOX2。由此我们推测mTOR/HIF-1α/SOX2正向调控非小细胞肺癌分化细胞去分化致放疗抵抗。本课题拟在前期基础上：通过液体活检技术研究临床放疗活化mTOR/HIF-1α/SOX2通路与非小细胞肺癌去分化的关系；以癌分化细胞为研究对象明确放疗诱导肺癌分化细胞去分化导致放疗抵抗，阐明放疗通过mTOR/HIF-1α/SOX2通路调控癌分化细胞去分化的分子机制；最后干预mTOR/HIF-1α/SOX2逆转放疗抵抗。本研究将揭示癌干细胞治疗性富集的重要细胞来源及调控机制，为发现新的药物靶点提供依据。

The studies have shown that the tumor stem cells are closely related with the tumor treatment resistance. The resent studies have found that the cancer stem cells in the radioresistance of non-small cell lung cancer (NSCLC) are increased, but the mechanism is not very clear. Our preliminary data have demonstrated that the radiotherapy induced the differentiated cells of NSCLC expressed the surface markers of cancer stem cells, and activated the mTOR/HIF-1α pathway. Inhibition of mTOR/HIF-1α pathway, the expression of cancer stem cells markers was significantly inhibited after radiotherapy. As a transcription factor, HIF-1α regulated SOX2. Thus, we hypothesized that mTOR/HIF-1α/SOX2 pathway may be involved in the regulation of NSCLC dedifferentiation induced by radiotherapy. Based on our preliminary data, through the detection of clinical samples by Next Generation Sequencing and the circulating tumor cells, liquid biopsy, we will verify the relationship between the activation of mTOR/HIF-1α/SOX2 pathway by radiotherapy and the dedifferentiation of NSCLC. As the object of the NSCLC cells differentiated cells (ALDH-CD133-), we will verify that the radiotherapy induce the differentiation cells of NSCLC to become the dedifferentiation cells. We will elucidate the molecular mechanism that the radiotherapy activates the mTOR/HIF-1α/SOX2 pathway to control the dedifferentiation of cells. At last, we will inhibit the mTOR/HIF-1α/SOX2 pathway to reverse the radioresistance of NSCLC in vitro. Our research will elucidate the sources and the molecular mechanisms of the treatment enrichment of the cancer stem cells, and discover the new drug targets.