二甲双胍通过抑制 NFE2L1 通路的激活来抑制非小细胞肺癌中间隙连接β蛋白的表达。

Metformin suppresses NFE2L1 pathway activation to inhibit gap junction beta protein expression in NSCLC.

机构信息

Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.

Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.

出版信息

Cancer Med. 2024 Apr;13(7):e7021. doi: 10.1002/cam4.7021.

DOI:10.1002/cam4.7021

PMID:38562019

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10985411/

Abstract

OBJECTIVE

Non-small-cell lung cancer (NSCLC) is a deadly form of cancer that exhibits extensive intercellular communication which contributed to chemoradiotherapy resistance. Recent evidence suggests that arrange of key proteins are involved in lung cancer progression, including gap junction proteins (GJPs).

METHODS AND RESULTS

In this study, we examined the expression patterns of GJPs in NSCLC, uncovering that both gap junction protein, beta 2 (GJB2) and gap junction protein, beta 2 (GJB3) are increased in LUAD and LUSC. We observed a correlation between the upregulation of GJB2, GJB3 in clinical samples and a worse prognosis in patients with NSCLC. By examining the mechanics, we additionally discovered that nuclear factor erythroid-2-related factor 1 (NFE2L1) had the capability to enhance the expression of connexin26 and connexin 31 in the NSCLC cell line A549. In addition, the use of metformin was discovered to cause significant downregulation of gap junction protein, betas (GJBs) by limiting the presence of NFE2L1 in the cytoplasm.

CONCLUSION

This emphasizes the potential of targeting GJBs as a viable treatment approach for NSCLC patients receiving metformin.

摘要

目的

非小细胞肺癌（NSCLC）是一种致命的癌症形式，其表现出广泛的细胞间通讯，这导致了化学放射疗法的耐药性。最近的证据表明，一系列关键蛋白参与了肺癌的进展，包括缝隙连接蛋白（GJPs）。

方法和结果

在这项研究中，我们研究了 NSCLC 中 GJPs 的表达模式，发现连接蛋白β2（GJB2）和连接蛋白β3（GJB3）在 LUAD 和 LUSC 中均增加。我们观察到 GJB2 和 GJB3 在临床样本中的上调与 NSCLC 患者预后较差之间存在相关性。通过研究机制，我们还发现核因子红细胞 2 相关因子 1（NFE2L1）能够增强 NSCLC 细胞系 A549 中连接蛋白 26 和连接蛋白 31 的表达。此外，发现二甲双胍的使用通过限制 NFE2L1 在细胞质中的存在，导致 GJBs（GJBs）的显著下调。