Choi Yiseul, Park Jinju, Ko Young San, Kim Younghoon, Pyo Jung-Soo, Jang Bo Gun, Kim Min A, Lee Jae-Seon, Chang Mee Soo, Lee Byung Lan
Department of Tumor Biology (Cancer Research Institute), Seoul National University College of Medicine, Seoul 03080, South Korea.
Department of Forensic Medicine, National Forensic Service Busan Institute, Yangsan 50612, South Korea.
Biochem Biophys Res Commun. 2017 Nov 25;493(3):1349-1355. doi: 10.1016/j.bbrc.2017.09.163. Epub 2017 Sep 29.
Gastric cancer (GC) is a major of cause of cancer-related death and is characterized by its heterogeneity and molecular complexity. FOXO1 is a transcription factor that plays a key role in GC growth and metastasis. However, the implication of FOXO1 in GC cell stemness has been elusive. This study, for the first time, demonstrates that FOXO1 regulates GC cell stemness in association with LGR5. FOXO1 expression was significantly lower in GC tumorsphere cells than in adherent GC cells. FOXO1 silencing and overexpression promoted and inhibited the tumorsphere formation capacity of GC cells, respectively. Additionally, there was an inverse correlation between FOXO1 and GC stem cell marker LGR5 in human GC specimens. Further in vitro and in vivo experiments showed that negative crosstalk between these two molecules exists and that LGR5 silencing reversed the FOXO1 shRNA-induced tumorsphere formation even without FOXO1 restoration. Taken together, our results suggest that FOXO1 inhibits the self-renewal capacity of GC cells through interaction with LGR5. Thus, FOXO1/LGR5 signaling pathway may provide a novel targeted therapy for GC.
胃癌（GC）是癌症相关死亡的主要原因之一，其特点是具有异质性和分子复杂性。FOXO1是一种转录因子，在胃癌的生长和转移中起关键作用。然而，FOXO1在胃癌细胞干性中的作用尚不清楚。本研究首次证明FOXO1与LGR5共同调节胃癌细胞干性。FOXO1在胃癌肿瘤球细胞中的表达明显低于贴壁生长的胃癌细胞。FOXO1沉默和过表达分别促进和抑制了胃癌细胞的肿瘤球形成能力。此外，在人类胃癌标本中，FOXO1与胃癌干细胞标志物LGR5之间存在负相关。进一步的体外和体内实验表明，这两种分子之间存在负向相互作用，并且即使在没有FOXO1恢复的情况下，LGR5沉默也能逆转FOXO1 shRNA诱导的肿瘤球形成。综上所述，我们的结果表明FOXO1通过与LGR5相互作用抑制胃癌细胞的自我更新能力。因此，FOXO1/LGR5信号通路可能为胃癌提供一种新的靶向治疗方法。
