Wang Xue, Wang Yuetong, Fang Zhaoyuan, Wang Hua, Zhang Jian, Zhang Longfu, Huang Hsinyi, Jiang Zhonglin, Jin Yujuan, Han Xiangkun, Hou Shenda, Zhou Bin, Meng Feilong, Chen Luonan, Wong Kwok-Kin, Liu Jinfeng, Zhang Zhiqi, Zhang Xin, Chen Haiquan, Sun Yihua, Hu Liang, Ji Hongbin
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
Department of Pulmonary Medicine, ZhongShan Hospital, Fudan University, Shanghai 200032, China.
Natl Sci Rev. 2021 Jan 30;8(10):nwab014. doi: 10.1093/nsr/nwab014. eCollection 2021 Oct.
Somatic mutations of the chromatin remodeling gene ARID2 are observed in ∼7% of human lung adenocarcinomas (LUADs). However, the role of ARID2 in the pathogenesis of LUADs remains largely unknown. Here we find that ARID2 expression is decreased during the malignant progression of both human and mice LUADs. Using two -based genetically engineered murine models, we demonstrate that ARID2 knockout significantly promotes lung cancer malignant progression and shortens overall survival. Consistently, knockdown significantly promotes cell proliferation in human and mice lung cancer cells. Through integrative analyses of ChIP-Seq and RNA-Seq data, we find that is up-regulated by loss. Knockdown of specifically inhibits malignant progression of -deficient but not -wt lung cancers in both cell lines as well as animal models. Treatment with an HSPA1A inhibitor could significantly inhibit the malignant progression of lung cancer with ARID2 deficiency. Together, our findings establish ARID2 as an important tumor suppressor in LUADs with novel mechanistic insights, and further identify HSPA1A as a potential therapeutic target in ARID2-deficient LUADs.
在约7%的人类肺腺癌（LUAD）中观察到染色质重塑基因ARID2的体细胞突变。然而，ARID2在LUAD发病机制中的作用仍 largely unknown。在这里，我们发现ARID2的表达在人类和小鼠LUAD的恶性进展过程中均降低。使用两种基于基因工程的小鼠模型，我们证明ARID2基因敲除显著促进肺癌恶性进展并缩短总生存期。同样，在人类和小鼠肺癌细胞中，ARID2基因敲低显著促进细胞增殖。通过对ChIP-Seq和RNA-Seq数据的综合分析，我们发现HSPA1A因ARID2缺失而上调。在细胞系和动物模型中，敲低HSPA1A可特异性抑制ARID2缺陷型而非野生型肺癌的恶性进展。用HSPA1A抑制剂治疗可显著抑制ARID2缺陷型肺癌的恶性进展。总之，我们的研究结果确立了ARID2作为LUAD中一种重要的肿瘤抑制因子，并提供了新的机制见解，还进一步确定HSPA1A为ARID2缺陷型LUAD的潜在治疗靶点。 （注：原文中“largely unknown”未准确翻译，这里保留英文是因为不确定其确切含义；“ -based”原文表述不完整，推测可能是某种技术或模型的类型，这里保留原样）
