重塑蛋白通过 EMT 通路抑制 NAT10 从而延缓非小细胞肺癌进展。

Remodelin delays non-small cell lung cancer progression by inhibiting NAT10 via the EMT pathway.

机构信息

The First School of Clinical Medicine, Southern Medical University, Guangzhou, China.

Department of Thoracic Surgery, Shenzhen Hospital, Southern Medical University, Shenzhen, China.

出版信息

Cancer Med. 2024 Jun;13(11):e7283. doi: 10.1002/cam4.7283.

DOI:10.1002/cam4.7283

PMID:38826095

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11145023/

Abstract

BACKGROUND

Lung cancer remains the foremost reason of cancer-related mortality, with invasion and metastasis profoundly influencing patient prognosis. N-acetyltransferase 10 (NAT10) catalyzes the exclusive N (4)-acetylcytidine (ac4C) modification in eukaryotic RNA. NAT10 dysregulation is linked to various diseases, yet its role in non-small cell lung cancer (NSCLC) invasion and metastasis remains unclear. Our study delves into the clinical significance and functional aspects of NAT10 in NSCLC.

METHODS

We investigated NAT10's clinical relevance using The Cancer Genome Atlas (TCGA) and a group of 98 NSCLC patients. Employing WB, qRT-PCR, and IHC analyses, we assessed NAT10 expression in NSCLC tissues, bronchial epithelial cells (BECs), NSCLC cell lines, and mouse xenografts. Further, knockdown and overexpression techniques (siRNA, shRNA, and plasmid) were employed to evaluate NAT10's effects. A series of assays were carried out, including CCK-8, colony formation, wound healing, and transwell assays, to elucidate NAT10's role in proliferation, invasion, and metastasis. Additionally, we utilized lung cancer patient-derived 3D organoids, mouse xenograft models, and Remodelin (NAT10 inhibitor) to corroborate these findings.

RESULTS

Our investigations revealed high NAT10 expression in NSCLC tissues, cell lines and mouse xenograft models. High NAT10 level correlated with advanced T stage, lymph node metastasis and poor overall survive. NAT10 knockdown curtailed proliferation, invasion, and migration, whereas NAT10 overexpression yielded contrary effects. Furthermore, diminished NAT10 levels correlated with increased E-cadherin level whereas decreased N-cadherin and vimentin expressions, while heightened NAT10 expression displayed contrasting results. Notably, Remodelin efficiently attenuated NSCLC proliferation, invasion, and migration by inhibiting NAT10 through the epithelial-mesenchymal transition (EMT) pathway.

CONCLUSIONS

Our data underscore NAT10 as a potential therapeutic target for NSCLC, presenting avenues for targeted intervention against lung cancer through NAT10 inhibition.

摘要

背景

肺癌仍是癌症相关死亡的首要原因，其侵袭和转移严重影响患者预后。N-乙酰基转移酶 10（NAT10）催化真核 RNA 中独特的 N（4）-乙酰胞嘧啶（ac4C）修饰。NAT10 失调与多种疾病有关，但它在非小细胞肺癌（NSCLC）侵袭和转移中的作用尚不清楚。我们的研究探讨了 NAT10 在 NSCLC 中的临床意义和功能方面。

方法

我们使用 The Cancer Genome Atlas（TCGA）和一组 98 名 NSCLC 患者研究了 NAT10 的临床相关性。我们使用 WB、qRT-PCR 和 IHC 分析评估了 NSCLC 组织、支气管上皮细胞（BEC）、NSCLC 细胞系和小鼠异种移植中的 NAT10 表达。进一步，使用 siRNA、shRNA 和质粒等方法进行了 NAT10 的敲低和过表达实验。进行了一系列实验，包括 CCK-8、集落形成、划痕愈合和 Transwell 分析，以阐明 NAT10 在增殖、侵袭和转移中的作用。此外，我们还利用肺癌患者来源的 3D 类器官、小鼠异种移植模型和 Remodelin（NAT10 抑制剂）来验证这些发现。

结果

我们的研究表明，NAT10 在 NSCLC 组织、细胞系和小鼠异种移植模型中高表达。高水平的 NAT10 与晚期 T 分期、淋巴结转移和总体生存不良相关。NAT10 敲低抑制了增殖、侵袭和迁移，而过表达则产生了相反的效果。此外，NAT10 水平降低与 E-钙黏蛋白水平升高相关，而 N-钙黏蛋白和波形蛋白表达降低，而 NAT10 表达升高则显示出相反的结果。值得注意的是，Remodelin 通过抑制 NAT10 抑制上皮-间充质转化（EMT）通路，有效抑制 NSCLC 的增殖、侵袭和迁移。