Zhu Ying, An Ning, Zhang Qiongyin, Liu Yang, Gu Peiling, Zhao Jinzhu, Pan Wuliang, Pu Qiang, Wen Zhu
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Cancer Center, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
Cancer Gene Ther. 2025 Jul 2. doi: 10.1038/s41417-025-00928-2.
Alveolar type II epithelial (AT2) cells have the properties of stem cells, abnormal AT2 cells serve as one of the original cells in lung adenocarcinoma (LUAD). However, the abnormal genes expression of AT2 cells during their malignant transformation into LUAD cells remain poorly understood. Importantly, SLC34A2 is a specific gene in AT2 cells of the lung. Our previous researches have reported that overexpression of SLC34A2 significantly inhibited proliferation, migration and invasion of LUAD cells. But, the underlying mechanisms of SLC34A2 in LUAD are largely unknown until now. Here, the present study discovered that the protein expression of Napi2b (SLC34A2), SELENBP1, TTF-1 and LRRK2 were all located in human AT2 cells of adjacent non-tumor tissues. However, the expression level of SLC34A2, SELENBP1, TTF-1 and LRRK2 were significantly decreased in LUAD tissues, and the expression of SLC34A2 was obviously positive correlation with the expression of SELENBP1, TTF-1 and LRRK2, respectively. Mechanistically, our study elucidated that overexpression of SLC34A2 could inhibit the activation of MEK/ERK signaling pathway through up-regulating the expression of LRRK2, and subsequently suppressed the expression of p-TTF-1(Ser327), which upregulated the expression of SELENBP1 by enhancing TTF-1 transcriptional activity. Ultimately, overexpression of SLC34A2 depressed the activation of PI3K/AKT/mTOR signaling pathway via up-regulating the expression of SELENBP1, which significantly inhibited the malignant characteristics of LUAD. In summary, our current research revealed a novel SLC34A2/LRRK2/TTF-1/SELENBP1 axis and its involvement in inhibiting the malignant characteristics of LUAD cells for the first time, which made contribution to further exploring the clinical application of SLC34A2. Furthermore, it also might offer novel insights into understanding how AT2 cells undergo malignant transformation into LUAD cells in the future.
肺泡Ⅱ型上皮（AT2）细胞具有干细胞特性，异常的AT2细胞是肺腺癌（LUAD）的原始细胞之一。然而，AT2细胞在恶性转化为LUAD细胞过程中的异常基因表达仍知之甚少。重要的是，SLC34A2是肺AT2细胞中的一个特异性基因。我们之前的研究报道，SLC34A2的过表达显著抑制LUAD细胞的增殖、迁移和侵袭。但是，迄今为止，SLC34A2在LUAD中的潜在机制在很大程度上仍不清楚。在此，本研究发现Napi2b（SLC34A2）、SELENBP1、TTF-1和LRRK2的蛋白表达均位于相邻非肿瘤组织的人AT2细胞中。然而，SLC34A2、SELENBP1、TTF-1和LRRK2的表达水平在LUAD组织中显著降低，且SLC34A2的表达分别与SELENBP1、TTF-1和LRRK2的表达呈明显正相关。机制上，我们的研究阐明，SLC34A2的过表达可通过上调LRRK2的表达抑制MEK/ERK信号通路的激活，随后抑制p-TTF-1（Ser327）的表达，而p-TTF-1（Ser327）通过增强TTF-1转录活性上调SELENBP1的表达。最终，SLC34A2的过表达通过上调SELENBP1的表达抑制PI3K/AKT/mTOR信号通路的激活，这显著抑制了LUAD的恶性特征。总之，我们目前的研究首次揭示了一个新的SLC34A2/LRRK2/TTF-1/SELENBP1轴及其在抑制LUAD细胞恶性特征中的作用，这为进一步探索SLC34A2的临床应用做出了贡献。此外，它也可能为未来理解AT2细胞如何恶性转化为LUAD细胞提供新的见解。
Zotero 插件