Identification of Cerebrospinal Fluid MicroRNAs Associated With Leptomeningeal Metastasis From Lung Adenocarcinoma.

Zhenyu Pan,Yong Chen,Hua He,Guozi Yang,Tongchao Jiang,Pengxiang Gao,Gang Zhao

doi:10.3389/fonc.2020.00387

Abstract

Background: Leptomeningeal metastasis (LM) has frequently been observed in patients with lung adenocarcinoma. So far, its diagnosis and disease course monitoring are still extremely difficult. Moreover, there is no effective treatment regimen for LM due to a lack knowledge on the molecular mechanism of LM. This study aimed to identify LM-related cerebrospinal fluid (CSF) miRNAs, which have potential value for diagnosing and monitoring LM and exploring the molecular mechanism.Methods: CSF miRNAs were screened and verified by microarray analysis and quantitative real-time PCR (qRT-PCR) in LM patients with lung adenocarcinoma and non-LM controls, and the diagnostic performance of candidate miRNAs was evaluated. Then, candidate miRNAs in matched CSF samples from LM patients at diagnosis, after initial therapy, at relapse, and after salvage therapy, were analyzed to assess the relationship between CSF miRNAs and LM disease course. The effect of candidate miRNAs on proliferation, invasion, and migration of lung adenocarcinoma cell lines was assessed. The targeted genes of the candidate miRNA were predicted by TargetScan, miRDB, and miRTarbase online analysis tools. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to analyze the functional categories of predicted target genes.Results: CSF miR-7975, miR-7977, and miR-7641 were screened and verified to be statistically significantly up-regulated in LM patients compared to non-LM controls. The three miRNAs, when combined, exhibited optimal diagnostic performance. Longitudinal data of CSF miR-7975 and miR-7977 correlated well with clinical courses of LM. Overexpression of miR-7977 promoted proliferation, migration, and invasion of lung adenocarcinoma cells. Moreover, 385 targeted genes of miR-7977 were predicted and were involved in various pathways related to cancer metastasis.Conclusions: This study offers insights for future research of CSF miRNAs as robust tools for diagnosing and monitoring LM. It also reveals a novel pathway for exploration of underlying mechanisms of LM.

Highlights

Leptomeningeal metastasis (LM) is known as a devastating cancer complication that occurs when malignant cells disseminate to leptomeninges and cerebrospinal fluid (CSF) compartments [1,2,3]
To evaluate whether specific miRNA signatures were detectable in CSF samples from LM patients with lung adenocarcinoma, a microarray analysis of 2,549 human miRNAs was performed
In order to screen specific miRNAs correlated with the development of LM, we performed miRNA microarray in CSF samples of six LM patients at diagnosis and their matched CSF samples after efficacious LM-directed therapy

Summary

Introduction

Leptomeningeal metastasis (LM) is known as a devastating cancer complication that occurs when malignant cells disseminate to leptomeninges and cerebrospinal fluid (CSF) compartments [1,2,3]. About 10% of patients with metastatic cancer suffer from LM during their course of the disease [4]. The diagnosis and disease course monitoring for LM are still challenging. There is no effective treatment regimen for LM from lung adenocarcinoma due to lacking understanding of the molecular mechanism of LM. Its diagnosis and disease course monitoring are still extremely difficult. There is no effective treatment regimen for LM due to a lack knowledge on the molecular mechanism of LM. This study aimed to identify LM-related cerebrospinal fluid (CSF) miRNAs, which have potential value for diagnosing and monitoring LM and exploring the molecular mechanism

Objectives

Methods

Results

Discussion

Conclusion