Abstract
Glioblastoma (GBM) is characterized by rapid and lethal infiltration of brain tissue, which is the primary cause of treatment failure and deaths for GBM. Therefore, understanding the molecular mechanisms of tumor cell invasion is crucial for the treatment of GBM. In this study, we dissected the single-cell RNA-seq data of 3345 cells from four patients and identified dysregulated genes including long non-coding RNAs (lncRNAs), which were involved in the development and progression of GBM. Based on co-expression network analysis, we identified a module (M1) that significantly overlapped with the largest number of dysregulated genes and was confirmed to be associated with GBM invasion by integrating EMT signature, experiment-validated invasive marker and pseudotime trajectory analysis. Further, we denoted invasion-associated lncRNAs which showed significant correlations with M1 and revealed their gradually increased expression levels along the tumor cell invasion trajectory, such as VIM-AS1, WWTR1-AS1, and NEAT1. We also observed the contribution of higher expression of these lncRNAs to poorer survival of GBM patients. These results were mostly recaptured in another validation data of 7930 single cells from 28 GBM patients. Our findings identified lncRNAs that played critical roles in regulating or controlling cell invasion and migration of GBM and provided new insights into the molecular mechanisms underlying GBM invasion as well as potential targets for the treatment of GBM.
Highlights
Glioblastoma (GBM) is the most common primary malignant brain tumor, comprising 16% of all primary brain and central nervous system neoplasms (Thakkar et al, 2014), with the average ageadjusted incidence rate of 3.2 per 100,000 population (Ostrom et al, 2015)
Previous studies have reported the close relationships of protein-coding genes (PCGs) and long non-coding RNAs (lncRNAs) with cancers using bulk RNA sequencing data (Chen Q. et al, 2018; Tao et al, 2020), few have focused on the roles of lncRNAs in tumorigenesis and progression of GBM at single-cell level
We observed a small part of lncRNAs had comparably high expression levels with PCGs
Summary
Glioblastoma (GBM) is the most common primary malignant brain tumor, comprising 16% of all primary brain and central nervous system neoplasms (Thakkar et al, 2014), with the average ageadjusted incidence rate of 3.2 per 100,000 population (Ostrom et al, 2015). Apart from protein-coding genes (PCGs), long non-coding RNAs (lncRNAs), as one kind of important regulators in biological development and disease progression (Batista and Chang, 2013), were frequently reported to control the invasion and metastasis of diverse cancer types, including glioblastoma. The gain-of-function or loss-of-function experiments validated the association of lncRNAs SChLAP1 and Zbtb7a with invasive prostate cancer (Prensner et al, 2013; Wang et al, 2013). These studies contributed to the understanding of tumor invasion, they mostly focused on few lncRNAs. Besides, utilizing traditional experiment techniques including bulk RNA sequencing has limitations in revealing the molecular mechanisms underlying GBM invasion
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