Hematopoietic transcription factor GFI1 promotes anchorage independence by sustaining ERK activity in cancer cells.
Hematopoietic transcription factor GFI1 promotes anchorage independence by sustaining ERK activity in cancer cells.
复制标题
造血转录因子 GFI1 通过维持癌细胞中的 ERK 活性来促进锚定独立性。
DOI：
10.1172/jci149551
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发表时间：
2022-09-01
影响因子：
15.9
通讯作者：
Liu, Zhe
中科院分区：
文献类型：
--
作者：
Wang, Hao;Lin, Zhenzhen;Nian, Zhe;Zhang, Wei;Liu, Wenxu;Yan, Fei;Xiao, Zengtuan;Wang, Xia;Zhang, Zhenfa;Ma, Zhenyi;Liu, Zhe
从依赖锚定生长到不依赖锚定生长的转变是上皮转移所必需的。然而，其潜在的机制尚不完全清楚。在这项研究中，我们发现生长因子独立-1 （growth factor independence -1, GFI1）是肺癌细胞锚定独立性的关键调节因子，这是一种在造血过程中驱动从贴壁内皮细胞向悬浮造血细胞转变的转录因子。GFI1增加了异种移植模型中循环和肺浸润肿瘤细胞的数量，并预测肺癌患者预后不良。在机制上，GFI1抑制多种粘附分子的表达，促进底物脱离。同时，GFI1重新配置了RASGRP2基因的染色质结构并增加了其表达，导致Rap1激活，随后在脱离后持续激活ERK，这导致肿瘤细胞中ERK信号依赖。我们的研究揭示了癌细胞劫持造血因子获得锚定独立性的机制，并提示干预ERK信号可能抑制转移并改善gfi1阳性肺癌患者的治疗效果。
The switch from anchorage-dependent to anchorage-independent growth is essential for epithelial metastasis. The underlying mechanism, however, is not fully understood. In this study, we identified growth factor independent-1 (GFI1), a transcription factor that drives the transition from adherent endothelial cells to suspended hematopoietic cells during hematopoiesis, as a critical regulator of anchorage independence in lung cancer cells. GFI1 elevated the numbers of circulating and lung-infiltrating tumor cells in xenograft models and predicted poor prognosis of patients with lung cancer. Mechanistically, GFI1 inhibited the expression of multiple adhesion molecules and facilitated substrate detachment. Concomitantly, GFI1 reconfigured the chromatin structure of the RASGRP2 gene and increased its expression, causing Rap1 activation and subsequent sustained ERK activation upon detachment, and this led to ERK signaling dependency in tumor cells. Our studies unveiled a mechanism by which carcinoma cells hijacked a hematopoietic factor to gain anchorage independence and suggested that the intervention of ERK signaling may suppress metastasis and improve the therapeutic outcome of patients with GFI1-positive lung cancer.