PTEN/PI3K信号通路经HIF1a/ABCG2蛋白介导胶质瘤高压氧化疗增敏分子机制研究

The resistance of glioma on chemotherapy contributed to gliomoa stem cells. In our preliminary experiments, glioma stem cells markers CD133/ABCG2 were highly expressed under hypoxia conditions for differentiated glioma cells and promoted cell proliferation. Glioma stem cells highly expressed GFAP and inhibited cell proliferation after hyperbaric oxygenation. HIF1a and ABCG2 presented highly expression for differentiated cells under hypoxia, but its expression became lower while we over-expressed PTEN or inhibited PI3K. The question is that whether PTEN/PI3K and HIF1a/ABCG2 make an influence on the dedifferentiation process. Based on above, we speculate reciprocal inhibition of PTEN/PI3K-HIF1a/ABCG2 ignaling pathway leads to the resistance of glioma to chemotherapy via inducing dedifferentiated under hypoxia for differentiated glioma cells, and hyperbaric oxygenation promote the differentiation of glioma stem cells and leads to inversion effect. This study firstly elucidates besides glioma stem cells, differentiated glioma cells can also express similar biological changes to chemotherapy resistance of glioma stem cells in hypoxia and higher sensibility with hyperbaric oxygenation via PTEN/PI3K-HIF1a/ABCG2 signaling pathway, which provides a new thinking for glioma treatment.

胶质瘤干细胞对化疗药物的不敏感是胶质瘤化疗耐受的关键因素。我们前期发现缺氧可以诱导已分化胶质瘤细胞高表达肿瘤干细胞标记蛋白CD133/ABCG2，并促进细胞增殖。高压氧则诱导胶质瘤干细胞高表达分化标记蛋白GFAP，进而抑制细胞增殖。HIF1a及ABCG2蛋白缺氧环境下均高表达，进一步过表达PTEN或敲低PI3K后，可降低HIF1a/ABCG2表达并促进细胞凋亡，但PTEN/PI3K、HIF1a/ABCG2如何调控上述实验现象，目前未见报道。我们推测：PTEN/PI3K信号通路可能经HIF1a/ABCG2蛋白调控已分化胶质瘤细胞缺氧逆分化而化疗抵抗，或诱导胶质瘤干细胞高压氧促分化而化疗增敏。本项目拟在前期研究基础上，以细胞间分化与去分化理论为依据，探讨PTEN/PI3K-HIF1a/ABCG2通路调控胶质瘤缺氧耐药及高压氧化疗增敏分子机制，从而为胶质瘤治疗提供新的思考方向及治疗靶点。

胶质瘤干细胞对化疗药物的不敏感是胶质瘤化疗耐受的关键因素。我们研究发现缺氧可以诱导已分化胶质瘤细胞高表达CD133/CD15/NESTIN/ABCG2/SOX2/KLF4等肿瘤干细胞标记蛋白，细胞分化降低，成球/增殖加快，细胞耐药性增加；而HIF1α作为缺氧诱导因子在缺氧条件下表达增加，干扰其表达后CD133/CD15/NESTIN/ABCG2/SOX2/KLF4等肿瘤干细胞标记蛋白表达显著降低，细胞凋亡增加，耐药性降低；高氧可降低HIF1α及CD133/CD15/NESTIN/ABCG2/SOX2/KLF4等肿瘤干细胞标记蛋白表达，细胞凋亡增加，耐药降低。因此我们得出结论：缺氧条件下HIF1α可诱导普通分化胶质瘤细胞逆分化为肿瘤干样细胞而化疗抵抗，而高氧可通过HIF1α阻断缺氧逆分化过程，使得肿瘤干样细胞减少进而促进了化疗增敏。该结论的证明为胶质瘤的治疗提供了新的思考方向，同时也为临床上高压氧治疗胶质瘤并改善患者预后提供了新的理论依据。