Chromatin Remodeling Factors Correlate with Epithelial-Mesenchymal Transition of Lung adenocarcinoma

BRG 1和BRM是SWI/SNF染色质重塑复合物中的两个核心催化亚基，被认为是肿瘤抑制因子，但它们在肿瘤发生中的作用尚不清楚。在这里，我们提出的证据表明，BRG 1和BRM的损失参与肺腺癌的进展。对15个肺癌细胞系的分析表明，BRG 1突变与BRG 1表达的丧失相关，并且BRG 1和BRM表达的丧失在E-钙粘蛋白低和波形蛋白高的细胞系中是常见的。93例原发性肺腺癌的免疫组化分析显示BRG 1和BRM分别在11例（12%）和16例（17%）中丢失。BRG 1和BRM的表达缺失在实体为主的腺癌和甲状腺转录因子-1（TTF-1，肺的主要调节因子）低、细胞角蛋白7和E-钙粘蛋白（两种支气管上皮分化的标志物）低的肿瘤中常见。BRG 1缺失与无鳞屑生长模式相关，与表皮生长因子受体（EGFR）突变相互排斥。与此相反，BRM的损失被发现伴随着鳞屑生长模式和EGFR突变。最后，我们分析了442例病例的公开数据集，发现BRG 1和BRM的丢失在E-钙粘蛋白低、TTF-1低和波形蛋白高的病例中很常见，并且与预后不良相关。我们的结论是，BRG 1和BRM的一个或两个的损失是参与肺腺癌的进展为实体为主的肿瘤与上皮间质转化和支气管上皮表型的损失的功能。BRG 1缺失特异性参与EGFR野生型肿瘤的进展，而不是EGFR突变型肿瘤。

BRG1 and BRM, two core catalytic subunits in SWI/SNF chromatin remodeling complexes, have been suggested as tumor suppressors, yet their roles in carcinogenesis are unclear. Here, we present evidence that loss of BRG1 and BRM is involved in the progression of lung adenocarcinomas. Analysis of 15 lung cancer cell lines indicated that BRG1 mutations correlated with loss of BRG1 expression and that loss of BRG1 and BRM expression was frequent in E-cadherin-low and vimentin-high cell lines. Immunohistochemical analysis of 93 primary lung adenocarcinomas showed loss of BRG1 and BRM in 11 (12%) and16 (17%) cases, respectively. Loss of expression of BRG1 and BRM was frequent in solid predominant adenocarcinomas and tumors with low thyroid transcription factor-1 (TTF-1,master regulator of lung) and low cytokeratin7 and E-cadherin (two markers for bronchial epithelial differentiation). Loss of BRG1 was correlated with the absence of lepidic growth patterns and was mutually exclusive of epidermal growth factor receptor (EGFR) mutations. In contrast, loss of BRM was found concomitant with lepidic growth patterns and EGFR mutations. Finally, we analyzed the publicly available dataset of 442 cases and found that loss of BRG1 and BRM was frequent in E-cadherin-low, TTF-1-low, and vimentin-high cases and correlated with poor prognosis. We conclude that loss of either or both BRG1 and BRM is involved in the progression of lung adenocarcinoma into solid predominant tumors with features of epithelial mesenchymal transition and loss of the bronchial epithelial phenotype. BRG1 loss wasspecifically involved in the progression of EGFR wild-type, but not EGFR-mutant tumors.