Loss of the SWI/SNF ATPase subunits BRM and BRG1 drives lung cancer development.
Loss of the SWI/SNF ATPase subunits BRM and BRG1 drives lung cancer development.
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DOI：
10.18632/oncoscience.323
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Reisman DN
中科院分区：
文献类型：
--
作者：
Marquez-Vilendrer SB;Rai SK;Gramling SJ;Lu L;Reisman DN
BRG1和BRM的失活加速了肺癌的发展，缩短了肿瘤潜伏期，并导致了分化的丧失。具有BRG1和/或BRM缺失的肿瘤通过局部肿瘤侵袭和远端肿瘤转移的发展来观察人类肺癌的演变，从而使该模型在肺癌研究中有用。BRG1缺失在一定程度上通过驱动E-钙粘蛋白缺失和Vimentin上调导致肿瘤转移。由于BRG1/BRM的双重缺失导致肿瘤抑制基因、DNA修复、分化和细胞黏附基因的下调，以及伴随而来的癌基因、血管生成、转移和抗凋亡基因的上调，从而改变了超过6%的小鼠基因组，进一步加速了肿瘤的发展。此外，BRG1/BRM基因表达的这种变化导致BRG1/BRM基因敲除小鼠的致瘤性几乎是野生型小鼠的两倍。最重要的是，BRG1/BRM驱动的肺癌发展在组织学和临床上反映了人类肺癌的发展，从而使该GEMM模型具有潜在的实用价值。
Inactivation of Brg1 and Brm accelerated lung tumor development, shortened tumor latency, and caused a loss of differentiation. Tumors with Brg1 and/or Brm loss recapitulated the evolution of human lung cancer as observed by the development of local tumor invasion as well as distal tumor metastasis, thereby making this model useful in lung cancer studies. Brg1 loss contributed to metastasis in part by driving E-cadherin loss and Vimentin up-regulation. By changing more than 6% of the murine genome with the down-regulation of tumor suppressors, DNA repair, differentiation and cell adhesion genes, and the concomitant up-regulation of oncogenes, angiogenesis, metastasis and antiapoptosis genes, caused by the dual loss of Brg1/Brm further accelerated tumor development. Additionally, this Brg1/Brm-driven change in gene expression resulted in a nearly two-fold increase in tumorigenicity in Brg1/Brm knockout mice compared with wild type mice. Most importantly, Brg1/Brm-driven lung cancer development histologically and clinically reflects human lung cancer development thereby making this GEMM model potentially useful.