文章:

SLC34A2通过上调LRRK2/TTF-1/SELENBP1轴抑制肺腺癌的发生和进展

SLC34A2 inhibits tumorigenesis and progression via upregulating LRRK2/TTF-1/SELENBP1 axis in lung adenocarcinoma 

原文发布日期：2025-07-02 

英文摘要：

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. 

摘要翻译：

肺泡II型上皮细胞（AT2细胞）具有干细胞特性，异常的AT2细胞是肺腺癌（LUAD）的起源细胞之一。然而，AT2细胞在恶性转化为LUAD细胞过程中基因表达的异常变化尚不明确。值得注意的是，SLC34A2是肺AT2细胞的特异性基因。我们前期研究发现SLC34A2过表达能显著抑制LUAD细胞的增殖、迁移和侵袭能力，但其在LUAD中的作用机制至今仍未阐明。本研究发现在癌旁非肿瘤组织中，Napi2b（SLC34A2）、SELENBP1、TTF-1和LRRK2蛋白均表达于人AT2细胞。但在LUAD组织中，SLC34A2、SELENBP1、TTF-1和LRRK2的表达水平均显著降低，且SLC34A2表达分别与SELENBP1、TTF-1和LRRK2表达呈明显正相关。机制研究表明，SLC34A2过表达可通过上调LRRK2表达抑制MEK/ERK信号通路激活，进而抑制p-TTF-1(Ser327)的表达——后者通过增强TTF-1转录活性上调SELENBP1表达。最终，SLC34A2过表达通过上调SELENBP1抑制PI3K/AKT/mTOR信号通路激活，显著抑制LUAD的恶性表型。本研究首次揭示了SLC34A2/LRRK2/TTF-1/SELENBP1信号轴及其抑制LUAD细胞恶性表型的作用机制，为推进SLC34A2的临床应用研究提供了理论依据，也为未来探索AT2细胞恶性转化为LUAD细胞的机制提供了新思路。

原文链接：

SLC34A2 inhibits tumorigenesis and progression via upregulating LRRK2