RELL1, a novel oncogene, accelerates tumor progression and regulates immune infiltrates in glioma
Introduction
Glioma is one of the most common malignant tumors affecting the central nervous system (CNS) [1], [2]. Despite advancements in independent and combinatorial treatments involving chemotherapy and radiotherapy, and in standard procedures such as surgical resection and neuro-oncology, the survival rate of malignant glioma patients remains very poor [3], [4]. According to the glioma grading classification criteria of the World Health Organization (WHO), gliomas are traditionally classified as high-grade gliomas (HGGs) (IIIāIV) and low-grade gliomas (LGGs) (IāII) [5]. A range of immune cells, along with various non-cancerous cells including endothelial cells, pericytes, astrocytes, and tumor cells, are present in the glioma microenvironment [6].
The usual line of treatment for glioma involves radiation and chemotherapy combined with surgery [7]. In malignant gliomas, temozolomide (TMZ) has been found to be particularly effective [8]. In cases of high-grade gliomas, post-operative radiotherapy becomes essential. Nonetheless, the most common adverse effects of chemotherapy involve fatigue, anemia, and nausea. At the same time, both chemoradiotherapy and radiotherapy have been known to show systemic toxicities and severe local adverse effects [9]. Hence, there is an urgent need to identify an effective marker for measuring the efficacy of chemotherapy and radiotherapy. Moreover, in view of the 2016 update on CNS tumor classification by the WHO, isocitrate dehydrogenase (IDH) mutations have been accepted as novel indicators in the prediction of glioma patient outcome [10]. Nonetheless, the IDH mechanism in glioma remains unclear [11].
RELL1 is a protein-coding gene that was previously unreported in the cancer field. RELL1 is a member of the tumor necrosis factor (TNF) receptor family and belongs to the receptor expressed in the lymphoid tissues (RELT) family [12]. RELL1 activates the pro-inflammatory pathway by binding to TNF receptor-related factor 1 (TRAF1) [13]. Several other cellular processes, such as the stress response, inflammatory response, migration, and cell proliferation, are induced by members of the TNF receptor family [14], while brain edema, neuronal cell apoptosis, and neutrophil infiltration of the brain tissue are induced by TNF-Ī± [15]. For predicting survival outcomes in gliomas and pertinent chemotherapeutic responses, pre-treatment natural killer (NK) cell count is considered to be a prognostic marker.
In our study, 1,018 samples from the CGGA and 703 samples from TGCA were downloaded to investigate the mechanism of RELL1 function in glioma. We analyzed the correlation between RELL1 expression and clinical characteristics. Then, we investigated the correlation between RELL1 expression and immune cell infiltration in glioma via a widely accepted evaluation algorithm, CIBERSORT. The work presented here provides a detailed analysis of the role of RELL1 in glioma development, which will aid the understanding of the mechanisms underlying glioma. The workflow is shown in the additional materials (Fig. S1).
Section snippets
Survival and expression analysis by GEPIA
The Gene Expression Profiling Interactive Analysis (GEPIA) (http://gepia.cancer-pku.cn/index.html) is an online database that was used in the evaluation of the correlation between RELL1 expression and the survival information of glioma patients [16]. The RNA sequencing expression data of 9,736 tumors and 8,587 normal samples from TCGA and the GTEx projects were analyzed on the GEPIA web server using a standard procession protocol. The evaluation of the correlation between RELL1 expression and
Associations between RELL1 expression and survival outcomes in glioma
RELL1 was found to be drastically overexpressed in GBM (num (T)Ā =Ā 518; num (N)Ā =Ā 207) and to be increased in LGG (num (T)Ā =Ā 518; num (N)Ā =Ā 207; Fig. 1A). Moreover, the lower expression of RELL1 was significantly correlated with favorable OS (num (low)Ā =Ā 338; num (high)Ā =Ā 338, PĀ <Ā 0.001; Fig. 1B).
RELL1 is an independent prognostic marker for glioma patients
Univariate Cox regression analyses were used to evaluate the utility of RELL1 expression (Table 1). Univariate analysis using Cox regression established certain factors that included RELL1 expression (P
Discussion
Glioma is the most common primary tumor type in the human CNS [23], and the lack of effective treatment for patients with glioma malignancies is driving the design of novel therapeutic strategies [24]. These strategies aim to take advantage of the common glioma phenotypes along with the altered metabolism of glioma cells. A logical therapeutic approach is represented by the simultaneous targeting of glioma cells with modulation of the glioma microenvironment [25].
In our study, we demonstrated
Declaration of Competing Interest
None.
Acknowledgments
We thank H. Nikki March, PhD, and Alla Bradley, PhD, from Liwen Bianji, Edanz Editing China (www.liwenbianji.cn/ac), for editing a draft of this manuscript.
Funding
This work was supported by Jiangsu Modern Hospital Management Research (JSY-3-2019-053).
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