Brg1 is required to maintain colorectal cancer stem cells
Brg1 is required to maintain colorectal cancer stem cells
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DOI：
10.1002/path.5759
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发表时间：
2021-08-20
影响因子：
7.3
通讯作者：
Seno, Hiroshi
中科院分区：
文献类型：
--
作者：
Yoshikawa, Takaaki;Fukuda, Akihisa;Seno, Hiroshi
能够自我更新并持续产生子代细胞的肿瘤细胞被称为肿瘤干细胞(TSCs)，被认为是潜在的治疗靶点。然而，TSCs的生存和功能的潜在机制还不完全清楚。我们之前曾报道染色质重塑调节因子BRG1是小鼠肠道干细胞所必需的，而Dclk1是肠道TSC的标志物。在本研究中，我们研究了Dclk1(+)肠道肿瘤细胞中BRG1在维持小鼠肠道肿瘤中的作用。Dclk1(+)肠道肿瘤细胞中BRG1的特异性消融可减少APC(Min)小鼠的肠道肿瘤，而BRG1的持续消融可维持肠道肿瘤的减少。对Dclk1(+)肠道肿瘤细胞进行BRG1去除的谱系追踪表明，BRG1缺失的Dclk1(+)肠道肿瘤细胞不产生其后代肿瘤细胞，表明BRG1对Dclk1(+)肠道肿瘤细胞的自我更新是必不可少的。BRG1消融5天后，我们观察到Dclk1(+)肿瘤细胞凋亡率增加。此外，在球形培养系统中，BRG1对肠道肿瘤细胞的干性至关重要。BRG1基因敲除也损害了人结直肠癌(CRC)细胞的增殖和增加了细胞的凋亡。基因芯片分析显示，BRG1抑制使人结直肠癌细胞凋亡相关基因表达上调，干细胞相关基因表达下调。在人类结直肠癌患者中，BRG1的高表达一直与疾病特异性生存不良相关。这些数据表明，BRG1通过抑制凋亡在小鼠肠道TSCs中发挥关键作用，并且对人CRC细胞的细胞存活和干细胞特性至关重要。因此，BRG1代表了人类结直肠癌治疗的新靶点。(C)2021年大不列颠及爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
Tumor cells capable of self-renewal and continuous production of progeny cells are called tumor stem cells (TSCs) and are considered to be potential therapeutic targets. However, the mechanisms underlying the survival and function of TSCs are not fully understood. We previously reported that chromatin remodeling regulator Brg1 is essential for intestinal stem cells in mice and Dclk1 is an intestinal TSC marker. In this study, we investigated the role of Brg1 in Dclk1(+) intestinal tumor cells for the maintenance of intestinal tumors in mice. Specific ablation of Brg1 in Dclk1(+) intestinal tumor cells reduced intestinal tumors in Apc(Min) mice, and continuous ablation of Brg1 maintained the reduction of intestinal tumors. Lineage tracing in the context of Brg1 ablation in Dclk1(+) intestinal tumor cells revealed that Brg1-null Dclk1(+) intestinal tumor cells did not give rise to their descendent tumor cells, indicating that Brg1 is essential for the self-renewal of Dclk1(+) intestinal tumor cells. Five days after Brg1 ablation, we observed increased apoptosis in Dclk1(+) tumor cells. Furthermore, Brg1 was crucial for the stemness of intestinal tumor cells in a spheroid culture system. BRG1 knockdown also impaired cell proliferation and increased apoptosis in human colorectal cancer (CRC) cells. Microarray analysis revealed that apoptosis-related genes were upregulated and stem cell-related genes were downregulated in human CRC cells by BRG1 suppression. Consistently, high BRG1 expression correlated with poor disease-specific survival in human CRC patients. These data indicate that Brg1 plays a crucial role in intestinal TSCs in mice by inhibiting apoptosis and is critical for cell survival and stem cell features in human CRC cells. Thus, BRG1 represents a new therapeutic target for human CRC. (c) 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.