Cell-type specific tumorigenesis with Ras oncogenes in human lung epithelial cells
Cell-type specific tumorigenesis with Ras oncogenes in human lung epithelial cells
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DOI：
10.1016/j.bbrc.2020.02.113
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发表时间：
2020-04-30
影响因子：
3.1
通讯作者：
Yamamoto, Yusuke
中科院分区：
文献类型：
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作者：
Kumazaki, Minami;Shimomura, Iwao;Yamamoto, Yusuke
致癌Ras突变是癌症中发病率最高的最常见的基因组异常之一;它有三种亚型：Hras，Kras和Nras。虽然Ras亚型在一级序列中高度相似，但根据组织或细胞类型，每个突变频率明显不同。关于非小细胞肺癌，几乎所有的Kras突变都在肺腺癌中检测到，而肺鳞状细胞癌非常罕见。在这里，我们专注于突变Ras亚型的细胞类型特异性肿瘤发生，并确定肺腺癌和鳞状细胞癌之间的致癌信号输出的机制。在永生化支气管上皮细胞（BEC-E6 E7/myc）和永生化小气道上皮细胞（SAEC-E6 E7/myc）中突变Ras亚型的体外转化模型显示，只有HrasG 12 V突变，而不是KrasG 12 V突变，可以诱导BEC-E6 E7/myc中的肿瘤发生。相反，SAEC-E6 E7/myc对KrasG 12 V突变的敏感性高于HrasG 12 V突变。通过软琼脂试验和迁移试验证实突变型Ras对BEC-E6 E7/myc和SAEC-E6 E7/myc的转化。表达HrasG 12 V的BEC-E6 E7/myc显著增加MAPK/ERK信号传导，而表达KrasG 12 V的SAEC-E6 E7/myc中PI 3 K/AKT信号传导显著升高。这些结果表明，在肺腺癌和鳞状细胞癌之间的肿瘤发生与致癌Ras突变的上下文依赖性。(C)2020爱思唯尔公司All rights reserved.
The oncogenic Ras mutation is one of the most common genomic abnormalities having the highest incidence in cancer; it has three isoforms: Hras, Kras, and Nras. Although the Ras isoforms are highly similar in the primary sequence, each mutational frequency is clearly distinct according to tissue- or cell-type. Regarding non-small-cell lung carcinoma, almost all Kras mutations have been detected in lung adenocarcinoma, whereas lung squamous cell carcinoma is extremely rare. Here, we focus on the cell-type specific tumorigenesis of mutant Ras isoforms and determine the mechanisms of oncogenic signaling outputs between lung adenocarcinoma and squamous cell carcinoma. An in vitro transformation model with mutant Ras isoforms in immortalized bronchial epithelial cells (BEC-E6E7/myc) and immortalized small airway epithelial cells (SAEC-E6E7/myc) revealed that only the HrasG12V mutation, not the KrasG12V mutation, could induce tumorigenesis in BEC-E6E7/myc. In contrast, SAEC-E6E7/myc showed high sensitivity to the KrasG12V mutation compared with the HrasG12V mutation. The transformation of BEC-E6E7/myc and SAEC-E6E7/myc with mutant Ras isoforms was confirmed by soft agar assay and migration assay. HrasG12V-expressing BEC-E6E7/myc significantly increased MAPK/ERK signaling, whereas PI3K/AKT signaling was significantly elevated in KrasG12V-expressing SAEC-E6E7/myc. These results suggest a context dependency with oncogenic Ras mutations in tumorigenesis between lung adenocarcinoma and squamous cell carcinoma. (C) 2020 Elsevier Inc. All rights reserved.