RNA 结合蛋白 RBM47 通过调节 AXIN1 mRNA 稳定性和 Wnt/β-catentin 信号通路抑制非小细胞肺癌转移。

The RNA-binding protein RBM47 inhibits non-small cell lung carcinoma metastasis through modulation of AXIN1 mRNA stability and Wnt/β-catentin signaling.

机构信息

Department of Thoracic Surgery, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, No. 1 Banshan East Road, Gongshu District, Hangzhou, 310022, China.

出版信息

Surg Oncol. 2020 Sep;34:31-39. doi: 10.1016/j.suronc.2020.02.011. Epub 2020 Feb 28.

DOI:10.1016/j.suronc.2020.02.011

PMID:32891348

Abstract

BACKGROUND

Non-small-cell lung cancer (NSCLC) remains a highly prevalent and deadly form of cancer, with efforts to better understand the molecular basis of the progression of this disease being essential to its effective treatment. Several recent studies have highlighted the ability of RNA-binding proteins (RBPs) to regulate a wide range of cellular processes in both healthy and pathogenic contexts. Among these RBPs, RNA binding motif protein 47 (RBM47) has recently been identified as a tumor suppressor in both breast and colon cancers, whereas its role in NSCLC is poorly understood.

METHODS

RBM47 expression in NSCLC samples was evaluated by RT-PCR, western blotting and immunohistochemistry analysis. Molecular and cellular techniques including lentiviral vector-mediated knockdown were used to elucidate the functions and mechanisms of RBM47.

RESULTS

This study sought to analyze the expression and role of RBM47 in NSCLC. In the present study, we observed reduced levels of RBM47 expression in NSCLC, with these reductions corresponding to a poorer prognosis and more advanced disease including a higher TNM stage (p = 0.022), a higher likelihood of tumor thrombus (p = 0.001), and pleural invasion (p = 0.033). Through functional analyses in vitro and in vivo, we further demonstrated that these RBP was able to disrupt the proliferation, migration, and invasion of NSCLC cells. At a molecular level, we determined that RBM47 was able to bind the AXIN1 mRNA, stabilizing it and thereby enhancing the consequent suppression of Wnt/β-catentin signaling.

CONCLUSION

Together our findings reveal that RBM47 targets AXIN1 in order to disrupt Wnt/β-catenin signaling in NSCLC and thereby disrupting tumor progression. These results thus offer new insights into the molecular biology of NSCLC, and suggest that RBM47 may also have value as a prognostic biomarker and/or therapeutic target in NSCLC patients.

摘要

背景

非小细胞肺癌（NSCLC）仍然是一种高度流行和致命的癌症，努力更好地了解这种疾病进展的分子基础对于其有效治疗至关重要。最近的几项研究强调了 RNA 结合蛋白（RBPs）在健康和致病环境中调节广泛的细胞过程的能力。在这些 RBPs 中，RNA 结合基序蛋白 47（RBM47）最近被确定为乳腺癌和结肠癌中的肿瘤抑制因子，而其在 NSCLC 中的作用知之甚少。

方法

通过 RT-PCR、western blot 和免疫组织化学分析评估 NSCLC 样本中的 RBM47 表达。包括慢病毒载体介导的敲低在内的分子和细胞技术用于阐明 RBM47 的功能和机制。

结果

本研究旨在分析 RBM47 在 NSCLC 中的表达和作用。在本研究中，我们观察到 NSCLC 中 RBM47 表达水平降低，这些降低与预后较差和更晚期疾病相关，包括更高的 TNM 分期（p=0.022）、更有可能发生肿瘤血栓形成（p=0.001）和胸膜侵犯（p=0.033）。通过体外和体内的功能分析，我们进一步证明了这些 RBP 能够破坏 NSCLC 细胞的增殖、迁移和侵袭。在分子水平上，我们确定 RBM47 能够结合 AXIN1 mRNA，稳定它，从而增强对 Wnt/β-catentin 信号的抑制。