RNA结合基序蛋白28通过增强STAT3翻译促进肝细胞癌的血管生成

RNA-binding motif protein 28 enhances angiogenesis by improving STAT3 translation in hepatocellular carcinoma

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CANCER LETTERS

影响因子:10.1

分区:医学1区 Top / 肿瘤学2区

发表日期:2024 Nov 01

作者: Hexu Han, Yin Yuan, Caiying Li, Lei Liu, Hong Yu, Gaohua Han, Qiang Wang, Mei Lin, Junxing Huang

DOI: 10.1016/j.canlet.2024.217191

摘要

肝细胞癌（HCC）是一种常见的恶性肿瘤，具有广泛的血管生成特征。然而，其发病机制尚不完全清楚。既往研究表明，RNA结合蛋白（RBPs）在HCC的发病中起重要作用。本研究观察到HCC组织中RBM28表达升高，且与肿瘤微血管密度呈正相关，与患者预后呈负相关。过表达RBM28促进人脐静脉内皮细胞（HUVECs）管腔形成，而抑制RBM28则产生相反效果。进一步利用转基因小鼠模型和化学诱导的HCC模型评估RBM28在HCC中的作用。采用多种分子检测技术和高通量检测方法，分析RBM28在促进HCC血管生成中的作用机制。研究发现，升高的RBM28直接结合STAT3 mRNA，招募翻译起始因子EIF4E，促进STAT3表达，增强血管内皮生长因子A（VEGFA）的分泌和表达，从而促进HCC的血管新生。通过多队列临床样本和动物模型验证RBM28作为HCC潜在诊断和治疗靶点的可能性。总之，本研究揭示了RBM28在HCC发病、临床诊断及治疗中的潜在作用机制。

Abstract

Hepatocellular carcinoma (HCC) is a prevalent malignant tumor characterized by extensive angiogenesis. However, the underlying mechanisms of HCC pathogenesis remain unclear. Previous studies have shown that RNA-binding proteins (RBPs) are implicated in HCC pathogenesis. In this study, we observed that increased RBM28 expression in HCC tissues was positively correlated with tumor microvascular density and negatively correlated with patient prognosis. Overexpression of RBM28 in HCC cells promoted tubule formation in human umbilical vein endothelial cells, whereas inhibition of RBM28 had the opposite effect, furthermore, the role of RBM28 in the progression of HCC was assessed using transgenic mouse models and chemically induced HCC models. We used various molecular assays and high-throughput detection methods to evaluate the role of RBM28 in promoting angiogenesis in HCC. Increased RBM28 expression in HCC directly binds to STAT3 mRNA, recruiting EIF4E to increase STAT3 expression and enhancing the secretion and expression of vascular endothelial growth factor A; consequently, promoting neovascularization in HCC. The potential of RBM28 as a viable diagnostic and therapeutic target for HCC was assessed using multi-cohort clinical samples and animal models. In summary, our results provide insights into the pathogenesis, clinical diagnosis, and treatment of HCC.