Yu Beiqin, Gu Dongsheng, Zhang Xiaoli, Liu Bingya, Xie Jingwu
Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Departments of Pediatrics, Biochemistry and Molecular Biology, Pharmacology and Toxicology, The Wells Center for Pediatrics Research and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Departments of Pediatrics, Biochemistry and Molecular Biology, Pharmacology and Toxicology, The Wells Center for Pediatrics Research and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
J Genet Genomics. 2017 Aug 20;44(8):375-383. doi: 10.1016/j.jgg.2017.04.008. Epub 2017 Jul 25.
Gastric cancer is a leading cause of cancer-related mortality worldwide, and options to treat gastric cancer are limited. Fluorouracil (5Fu)-based chemotherapy is frequently used as a neoadjuvant or an adjuvant agent for gastric cancer therapy. Most patients with advanced gastric cancer eventually succumb to the disease despite the fact that some patients respond initially to chemotherapy. Thus, identifying molecular mechanisms responsible for chemotherapy resistance will help design novel strategies to treat gastric cancer. In this study, we discovered that residual cancer cells following 5Fu treatment have elevated expression of hedgehog (Hg) target genes GLI1 and GLI2, suggestive of Hh signaling activation. Hh signaling, a pathway essential for embryonic development, is an important regulator for putative cancer stem cells/residual cancer cells. We found that high GLI1/GLI2 expression is associated with some features of putative cancer stem cells, such as increased side population. We demonstrated that GLI2 knockdown sensitized gastric cancer cells to 5Fu treatment, decreased ABCG2 expression, and reduced side population. Elevated GLI2 expression is also associated with an increase in tumor sphere size, another marker for putative cancer stem cells. We believe that GLI2 regulates putative cancer stem cells through direct regulation of ABCG2. ABCG2 can rescue the GLI2 shRNA effects in 5Fu response, tumor sphere formation and side population changes, suggesting that ABCG2 is an important mediator for GLI2-associated 5Fu resistance. The relevance of our studies to gastric cancer patient care is reflected by our discovery that high GLI1/GLI2/ABCG2 expression is associated with a high incidence of cancer relapse in two cohorts of gastric cancer patients who underwent chemotherapy (containing 5Fu). Taken together, we have identified a molecular mechanism by which gastric cancer cells gain 5Fu resistance.
胃癌是全球癌症相关死亡的主要原因之一，且胃癌的治疗选择有限。基于氟尿嘧啶（5Fu）的化疗经常被用作胃癌治疗的新辅助或辅助药物。尽管有些患者最初对化疗有反应，但大多数晚期胃癌患者最终仍死于该疾病。因此，确定化疗耐药的分子机制将有助于设计治疗胃癌的新策略。在本研究中，我们发现5Fu治疗后的残留癌细胞中，刺猬信号通路（Hh）靶基因GLI1和GLI2的表达升高，提示Hh信号通路被激活。Hh信号通路是胚胎发育所必需的途径，是假定的癌症干细胞/残留癌细胞的重要调节因子。我们发现高GLI1/GLI2表达与假定的癌症干细胞的一些特征相关，如侧群细胞增加。我们证明，敲低GLI2可使胃癌细胞对5Fu治疗敏感，降低ABCG2表达，并减少侧群细胞。GLI2表达升高还与肿瘤球大小增加有关，肿瘤球大小是假定的癌症干细胞的另一个标志物。我们认为，GLI2通过直接调控ABCG2来调节假定的癌症干细胞。ABCG2可以挽救GLI2 shRNA在5Fu反应、肿瘤球形成和侧群细胞变化方面的作用，这表明ABCG2是GLI2相关5Fu耐药的重要介导因子。我们的研究与胃癌患者护理的相关性体现在我们的发现中，即高GLI1/GLI2/ABCG2表达与两组接受化疗（含5Fu）的胃癌患者的癌症复发高发生率相关。综上所述，我们确定了一种胃癌细胞获得5Fu耐药性的分子机制。
