Department of Thoracic Surgery, Daping Hospital, Army Medical University, Chongqing, China.
College of Pulmonary and Critical Care Medicine, Chinese PLA General Hospital, Beijing, China.
Thorac Cancer. 2021 May;12(10):1558-1569. doi: 10.1111/1759-7714.13944. Epub 2021 Mar 23.
Recurrence is a major challenge in early-stage lung adenocarcinoma (LUAD) treatment. Here, we investigated the role and mechanism of high-mobility group AT-hook 1 (HMGA1) and glucose-regulated protein 75-kDa (GRP75) in stage I LUAD and evaluated their potential as biomarkers for predicting the recurrence and prognosis of stage I LUAD.
The TCGA dataset was used to investigate the clinical significance of HMGA1 and GRP75 in early-stage LUAD. The biological functions of HMGA1 and GRP75 in LUAD were investigated both in vitro and in vivo through overexpression and knockdown experiments. The interaction and regulation between HMGA1 and GRP75 were evaluated with coimmunoprecipitation and ubiquitination assays. The downstream signaling pathway of the GRP75/HMGA1 axis was investigated by mRNA-sequencing analysis.
Both HMGA1 expression levels and GRP75 expression levels were associated with recurrence in stage I LUAD patients. In particular, HMGA1 had potential as an independent prognostic factor in stage I LUAD patients. Overexpression of GRP75 or HMGA1 significantly stimulated LUAD cell growth and metastasis, while silencing GRP75 or HMGA1 inhibited LUAD cell growth and metastasis in vitro and in vivo. Importantly, GRP75 inhibited ubiquitination-mediated HMGA1 degradation by directly binding to HMGA1, thereby causes HMGA1 upregulation in LUAD. In addition, the GRP75/HMGA1 axis played its role by activating JNK/c-JUN signaling in LUAD.
The activation of GRP75/HMGA1/JNK/c-JUN signaling is an important mechanism that promotes the progression of stage I LUAD, and a high level of HMGA1 is a novel biomarker for predicting recurrence and a poor prognosis in stage I LUAD patients.
复发是早期肺腺癌（LUAD）治疗的主要挑战。在这里，我们研究了高迁移率族 AT 钩蛋白 1（HMGA1）和葡萄糖调节蛋白 75kDa（GRP75）在 I 期 LUAD 中的作用和机制，并评估了它们作为预测 I 期 LUAD 复发和预后的生物标志物的潜力。
使用 TCGA 数据集研究 HMGA1 和 GRP75 在早期 LUAD 中的临床意义。通过过表达和敲低实验，在体外和体内研究了 HMGA1 和 GRP75 在 LUAD 中的生物学功能。通过免疫共沉淀和泛素化测定评估了 HMGA1 和 GRP75 之间的相互作用和调节。通过 mRNA 测序分析研究了 GRP75/HMGA1 轴的下游信号通路。
HMGA1 表达水平和 GRP75 表达水平均与 I 期 LUAD 患者的复发相关。特别是，HMGA1 可能是 I 期 LUAD 患者的独立预后因素。过表达 GRP75 或 HMGA1 显著刺激 LUAD 细胞生长和转移，而沉默 GRP75 或 HMGA1 则抑制 LUAD 细胞在体外和体内的生长和转移。重要的是，GRP75 通过直接与 HMGA1 结合抑制泛素化介导的 HMGA1 降解，从而导致 LUAD 中 HMGA1 的上调。此外，GRP75/HMGA1 轴通过激活 LUAD 中的 JNK/c-JUN 信号发挥作用。
GRP75/HMGA1/JNK/c-JUN 信号的激活是促进 I 期 LUAD 进展的重要机制，高水平的 HMGA1 是预测 I 期 LUAD 患者复发和预后不良的新生物标志物。
