HNRNPD/MAD2L2 轴促进肺腺癌的进展，是一个潜在的预后生物标志物。

HNRNPD/MAD2L2 axis facilitates lung adenocarcinoma progression and is a potential prognostic biomarker.

机构信息

Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, China.

The First Clinical Medical College of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, China.

出版信息

Cell Signal. 2024 Dec;124:111443. doi: 10.1016/j.cellsig.2024.111443. Epub 2024 Oct 2.

DOI:10.1016/j.cellsig.2024.111443

PMID:39366534

Abstract

BACKGROUND

Although progress has been made in the treatment of LAUD, the survival rate for patients remains poor. An in-depth grasp of the molecular pathways implicated in LUAD progression is vital for improving diagnosis and treatment strategies. This study aims to explore novel molecular mechanisms driving LUAD progression and identify new potential prognostic biomarkers for LAUD patients.

METHODS

Based on mass spectrometry analysis of human LUAD tissues, HNRNPD and MAD2L2 were identified as potential key proteins involved in LUAD progression. Subsequently, the interplay between HNRNPD and MAD2L2 was examined through dual-luciferase reporter assays, RNA-seq analysis, and various molecular biology techniques. Ultimately, the role of the HNRNPD/MAD2L2 axis in LUAD advancement and its potential as a prognostic indicator were investigated utilizing LUAD specimens, cell lines, and xenograft mouse models.

RESULTS

In human LAUD tissues and cell lines, elevated levels of HNRNPD and MAD2L2 proteins were discovered. It was determined that HNRNPD binds to the MAD2L2 promoter, forming a regulatory axis at the transcriptional level. Subsequently, both in vitro and in vivo data demonstrated that the downregulation of the HNRNPD/MAD2L2 axis inhibited LUAD progression, while this effect could be rescued by MAD2L2 upregulation. Conversely, the upregulation of the HNRNPD/MAD2L2 axis facilitated LUAD progression, and this outcome could be reversed by MAD2L2 knockdown. Mechanistically, the downregulation of HNRNPD suppressed the promoter activity and transcription of MAD2L2, thus inhibiting the PI3K/HIF1α/ANGPTL4 pathway and tumor angiogenesis. Finally, it was confirmed that LUAD patients with high levels of both HNRNPD and MAD2L2 exhibited the poorest prognosis. Therefore, the HNRNPD/MAD2L2 axis has been identified as a potential predictive indicator for LUAD patients.

CONCLUSIONS

The HNRNPD/MAD2L2 axis facilitates LUAD progression and serves as a potential prognostic biomarker.

摘要

背景

尽管在 LAUD 的治疗方面已经取得了进展，但患者的生存率仍然较差。深入了解 LUAD 进展中涉及的分子途径对于改善诊断和治疗策略至关重要。本研究旨在探讨驱动 LUAD 进展的新分子机制，并确定 LAUD 患者新的潜在预后生物标志物。

方法

基于对人 LUAD 组织的质谱分析，确定 HNRNPD 和 MAD2L2 是潜在的 LUAD 进展关键蛋白。随后，通过双荧光素酶报告基因分析、RNA-seq 分析和各种分子生物学技术研究 HNRNPD 和 MAD2L2 之间的相互作用。最终，利用 LUAD 标本、细胞系和异种移植小鼠模型研究了 HNRNPD/MAD2L2 轴在 LUAD 进展中的作用及其作为预后指标的潜力。

结果

在人 LAUD 组织和细胞系中发现 HNRNPD 和 MAD2L2 蛋白水平升高。确定 HNRNPD 与 MAD2L2 启动子结合，在转录水平形成调节轴。随后，体内外数据均表明，下调 HNRNPD/MAD2L2 轴抑制 LUAD 进展，而 MAD2L2 上调可挽救此作用。相反，上调 HNRNPD/MAD2L2 轴促进 LUAD 进展，而 MAD2L2 敲低可逆转此结果。机制上，下调 HNRNPD 抑制 MAD2L2 启动子活性和转录，从而抑制 PI3K/HIF1α/ANGPTL4 通路和肿瘤血管生成。最后，证实 LUAD 患者中 HNRNPD 和 MAD2L2 水平均高的患者预后最差。因此，HNRNPD/MAD2L2 轴被确定为 LUAD 患者的潜在预测指标。