肿瘤干细胞是肿瘤耐药和复发的根源，侧群（SP）细胞在生物学行为上被认为等同于肿瘤干细胞。我们的前期研究发现胆囊癌SP细胞内ROS水平较非SP细胞更低，耐药性更强；通过基因芯片筛查，我们发现在胆囊癌SP细胞内存在核转录因子Nrf2及其下游抗氧化基因HO-1、NQO1、MnSOD、GPX和药泵蛋白ABCG2的高表达。Nrf2是细胞氧化还原的中枢调节者,能够调控下游抗氧化基因以及药泵蛋白ABCG2的表达。本研究将从细胞、动物和临床标本三个层面首次揭示：① SP细胞内Nrf2过表达和/或过度激活→Nrf2转录活性↑→SP细胞内抗氧化基因HO-1、NQO1、MnSOD、GPX表达上调→细胞内ROS↓→SP细胞更加耐药；② Nrf2上调SP细胞ABCG2的表达，导致SP细胞耐药进一步加强。这将有助于阐明胆囊癌的耐药机制，证实Nrf2是胆囊癌SP细胞的特征性分子，并可作为判断胆囊癌患者化疗敏感性的指标。

Cancer stem cells are the source of drug resistance and relapse and side population (SP) cells are considered equivalent to cancer stem cells in biological behaviors. We previously found that gallbladder cancer SP cells harbored lower ROS levels and showed stronger drug resistance than non-SP cells. Through screening gene chip, we found that the expression levels of nuclear transcription factor Nrf2 and its downstream antioxidant genes HO-1, NQO1, MnSOD, GPX and drug pump protein ABCG2 in gallbladder cancer SP cells were all higher.It was reported that Nrf2, a cellular central regulation of redox, can induct expressions of antioxidant proteins genes and drug pump protein ABGC2. In this study, via the cell, animal and clinical experiments, we will for the first time reveal that Nrf2 overexpression and / or excessive activation in SP cells will strengthen transcriptional activities of Nrf2, which causes higher expressions of downstream antioxidant genes, such as HO-1、NQO1、MnSOD and GPX, resulting in lower ROS level and stronger drug resistance at last. Meanwhile Nrf2 can regulate expressions of drug pump ABCG2 in SP cells, leading to stronger drug resistance. It is very helpful to clarify the drug-resistant mechanisms of gallbladder cancer and to confirm that Nrf2 is a characteristic molecular of SP cells of gallbladder cancer and Nrf2 can be regarded as an index judging chemotherapy sensitivity to patients with gallbladder cancer.