Hypoxic tumor microenvironment activates GLI2 via HIF-1α and TGF-β2 to promote chemoresistance in colorectal cancer
Hypoxic tumor microenvironment activates GLI2 via HIF-1α and TGF-β2 to promote chemoresistance in colorectal cancer
复制标题
DOI：
10.1073/pnas.1801348115
复制
发表时间：
2018-06-26
影响因子：
11.1
通讯作者：
Yu, Qiang
中科院分区：
文献类型：
--
作者：
Tang, Yen-An;Chen, Yu-feng;Yu, Qiang
结直肠癌患者经常在化疗后复发，因为干细胞或祖细胞被称为癌症干细胞（CSCs）存活。虽然已知肿瘤基质因子有助于化疗耐药，但尚不完全清楚缺氧肿瘤微环境中的CSCs如何逃避化疗。在这里，我们报道了缺氧诱导因子（HIF-1 α）和癌症相关成纤维细胞（CAFs）分泌的tgf - β 2聚集在一起，激活CSCs中hedgehog转录因子GLI2的表达，导致干细胞/去分化增加和对化疗的内在抗性。遗传或小分子抑制剂消融HIF-1 α / tgf - β 2介导的GLI2信号有效逆转肿瘤微环境引起的化疗耐药。重要的是，HIF1 α / tgf - β 2/GLI2的高表达水平与化疗后患者复发密切相关，突出了结直肠癌化疗耐药的潜在生物标志物和治疗靶点。因此，我们的研究揭示了低氧结直肠癌肿瘤微环境促进癌细胞严重度和化疗耐药的分子机制，并提出了一种潜在的靶向治疗方法来减轻化疗耐药。
Colorectal cancer patients often relapse after chemotherapy, owing to the survival of stem or progenitor cells referred to as cancer stem cells (CSCs). Although tumor stromal factors are known to contribute to chemoresistance, it remains not fully understood how CSCs in the hypoxic tumor microenvironment escape the chemotherapy. Here, we report that hypoxia-inducible factor (HIF-1 alpha) and cancer-associated fibroblasts (CAFs)-secreted TGF-beta 2 converge to activate the expression of hedgehog transcription factor GLI2 in CSCs, resulting in increased stemness/dedifferentiation and intrinsic resistance to chemotherapy. Genetic or small-molecule inhibitor-based ablation of HIF-1 alpha/TGF-beta 2-mediated GLI2 signaling effectively reversed the chemoresistance caused by the tumor microenvironment. Importantly, high expression levels of HIF1 alpha/TGF-beta 2/GLI2 correlated robustly with the patient relapse following chemotherapy, highlighting a potential biomarker and therapeutic target for chemoresistance in colorectal cancer. Our study thus uncovers a molecular mechanism by which hypoxic colorectal tumor microenvironment promotes cancer cell sternness and resistance to chemotherapy and suggests a potentially targeted treatment approach to mitigating chemoresistance.