Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan, Taiwan.
Cell Death Dis. 2024 Mar 18;15(3):225. doi: 10.1038/s41419-024-06610-z.
Lung cancer is the major cause of death worldwide. Activation of oncogenes or inhibition of tumor suppressors causes cancer formation. Previous studies have indicated that PTEN, as a tumor suppressor, inhibits cancer formation. In this study, we studied the role of PTEN in EGFR-induced lung cancer in vivo. Interestingly, loss of PTEN increased bronchial cell hyperplasia but decreased alveolar cell hyperplasia in EGFRPTEN-induced lung cancer. Systematic analysis of gene expression by RNA-seq showed that several genes related to ciliogenesis were upregulated in EGFRPTEN-induced lung cancer and subsequently showed that bronchial ciliated cells were hyperplastic. Several critical ciliogenesis-related genes, such as Mucin5A, DNAI2, and DNAI3, were found to be regulated by NR2F1. Next, NR2F1 was found to be inhibited by overexpression of PTEN, indicating that PTEN negatively regulates NR2F1, thereby inhibiting the expression of ciliogenesis-related genes and leading to the inhibition of bronchial cell hyperplasia during EGFR-induced lung cancer progression. In addition, we also found that PTEN decreased AKT phosphorylation in A549, KRAS mutant, and H1299 cells but increased AKT phosphorylation in PC9, EGFR, and H1299 cells, suggesting that PTEN may function as a tumor suppressor and an oncogene in lung cancers with KRAS mutation and EGFR mutation, respectively. PTEN acts as a double-edged sword that differentially regulates EGFR-induced lung cancer progression in different genomic backgrounds. Understanding the PTEN in lung cancer with different genetic backgrounds will be beneficial for therapy in the future.
肺癌是全球主要的死亡原因。癌基因的激活或肿瘤抑制因子的抑制导致癌症的形成。先前的研究表明，PTEN 作为一种肿瘤抑制因子，抑制癌症的形成。在这项研究中，我们研究了 PTEN 在 EGFR 诱导的肺癌中的体内作用。有趣的是，PTEN 的缺失增加了支气管细胞的增生，但减少了 EGFRPTEN 诱导的肺癌中的肺泡细胞增生。通过 RNA-seq 进行的系统基因表达分析表明，几个与纤毛发生相关的基因在 EGFRPTEN 诱导的肺癌中上调，随后显示支气管纤毛细胞增生。几个关键的纤毛发生相关基因，如 Mucin5A、DNAI2 和 DNAI3，被发现受 NR2F1 调节。接下来，发现 NR2F1 受 PTEN 过表达的抑制，表明 PTEN 负调控 NR2F1，从而抑制纤毛发生相关基因的表达，并导致 EGFR 诱导的肺癌进展过程中支气管细胞增生的抑制。此外，我们还发现 PTEN 降低了 A549、KRAS 突变和 H1299 细胞中的 AKT 磷酸化，但增加了 PC9、EGFR 和 H1299 细胞中的 AKT 磷酸化，这表明 PTEN 可能分别作为 KRAS 突变和 EGFR 突变肺癌中的肿瘤抑制因子和癌基因发挥作用。PTEN 作为一把双刃剑，在不同的基因组背景下差异调节 EGFR 诱导的肺癌进展。了解不同遗传背景下的 PTEN 将有助于未来的治疗。
