BICC1 as a novel prognostic biomarker in gastric cancer correlating with immune infiltrates

https://doi.org/10.1016/j.intimp.2020.106828Get rights and content

Highlights

  • •

    BICC1 was overexpressed in gastric cancer.

  • •

    High expression of BICC1 was correlated with poor prognosis in gastric cancer.

  • •

    BICC1 was positively associated with tumor-infiltrating immune cells.

  • •

    BICC1 was correlated with multiple tumor/immune signaling pathways.

Abstract

Aim

BicC family RNA-binding protein 1 (BICC1) codes an RNA-binding protein that regulates gene expression and modulates cell proliferation and apoptosis. We aim at investigating the role of BICC1 in gastric carcinogenesis.

Methods

BICC1 mRNA expression in gastric cancer (GC) was examined using the Tumor Immune Estimation Resource (TIMER), The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Correlations between BICC1 expression and clinicopathological parameters were analyzed. The Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan–Meier plotter databases were used to examine the clinical prognostic significance of BICC1 in GC. Signaling pathways related to BICC1 expression were identified by gene set enrichment analysis (GSEA).

TIMER and CIBERSORT were used to analyze the correlations among BICC1, BICC1-coexpressed genes and tumor-infiltrating immune cells.

Results

BICC1 was highly expressed in GC and significantly correlated with grade (P = 0.002), TNM stage (P = 0.033), invasion depth (P = 0.001) and vital status (P = 0.009) of GC patients. High BICC1 expression correlated with poor overall survival. The GSEA results showed that cell adhesion-, tumor- and immune- related pathways were significantly enriched in samples with high BICC1 expression. BICC1 and its coexpressed genes were positively related to tumor-infiltrating immune cells and were strongly correlated with tumor-infiltrating macrophages (all r ≥ 0.582, P < 0.0001). The CIBERSORT database revealed that BICC1 correlated with M2 macrophages (P < 0.0001), regulatory T cells (P < 0.0001), resting mast cells (P < 0.0001), activated memory CD4+ T cells (P = 0.002), resting NK cells (P = 0.002), activated dendritic cells (P = 0.002), and follicular helper T cells (P = 0.016). The results from TIMER database confirmed that BICC1 is closely associated with the markers of M2 macrophages and tumor-associated macrophages (all r ≥ 0.5, P < 0.0001).

Conclusion

BICC1 may be a potential prognostic biomarker in GC and correlates with immune infiltrates.

Introduction

Gastric cancer (GC) is the fifth most frequently diagnosed cancer and is responsible for 8.2% of all deaths from cancer, which makes it the third leading cause of cancer death worldwide [1]. Despite the substantial improvements in diagnosis and treatment, the prognosis of GC patients remains poor [2]. Abnormal gene expression is closely associated with tumorigenesis and the prognosis of GC patients [3], [4]. However, the molecular mechanisms underlying the gastric carcinogenesis remain unclear.

BicC family RNA-binding protein 1 (BICC1) encodes an RNA-binding protein, which can regulate gene expression via modulating protein translation [5], [6]. BICC1 is ubiquitously expressed and plays an important role in regulating vertebrate embryogenesis, especially in the kidney [7], [8]. Many studies have revealed that BICC1 can modulate biological processes such as proliferation and apoptosis [9], [10]. In addition, BICC1 has been found to be related to immune cell infiltration in pancreas development [9]. Recently, the correlation between BICC1 expression and tumors and its prognostic value have been revealed. BICC1 is overexpressed in oral cancer and can significantly increase cell viability and suppress apoptosis [11]. Overexpression of BICC1 is closely correlated with poor prognosis of patients with oral cancer [11]. Moreover, BICC1 can form a fusion gene with epidermal growth factor receptor, which might have an important impact on cancer transformation [12]. However, there is limited evidence regarding the association between BICC1 and tumors, and the role of BICC1 in GC remains unclear.

In this study, BICC1 expression in GC and the correlations between BICC1 expression and clinicopathological features, as well as prognosis were analyzed using sequencing data sets. The possible molecular function of BICC1 was revealed through GSEA with TCGA data. In addition, the association between BICC1 and tumor-infiltrating immune cells was investigated. This study revealed the potential role of BICC1 in tumor immunology and its prognostic value, which will help understand a possible mechanism for gastric carcinogenesis.

Section snippets

BICC1 gene expression analysis

The mRNA levels of BICC1 in several cancers, including GC were analyzed using the Tumor Immune Estimation Resource (TIMER) database with The Cancer Genome Atlas (TCGA) data (https://cistrome.shinyapps.io/timer/) [13]. Level 3 RNA-sequencing data of GC patients were downloaded from the UCSC Xena browser (https://xenabrowser.net/) [14], which analyze data from The Cancer Genome Atlas (TCGA). We selected three datasets (GSE54129, GSE26942 [15] and GSE118916 [16]) containing GC tissue and normal

Elevated expression of BICC1 in GC

We initially evaluated BICC1 transcription levels in different human tumors by analyzing TCGA RNA-seq data using the TIMER database (Fig. 1A). BICC1 mRNA expression was remarkably higher in GC tissue compared with normal gastric tissue. In addition, BICC1 was also found to be highly expressed in the tissues of bile duct cancer (CHOL) and head and neck cancer (HNSC) tissues and significantly lower in bladder cancer (BLCA), kidney clear cell carcinoma (KIRC), breast cancer (BRCA), kidney

Discussion

GC is a common malignant neoplasm of the human digestive system. Despite significant improvements in diagnostic and therapeutic strategies for GC over the past decades, the prognosis of GC patients remains poor. Abnormal gene expression may be involved in tumorigenesis and associated with the prognosis of patients [20], [21]. However, the molecular mechanism of gastric carcinogenesis is still unclear. In the present study, we first demonstrated that BICC1 expression was remarkably increased in

Funding

This work was supported by National Key Research and Development Program of China (No. 2016YFC1302201), National Natural Science Foundation of China (No. 81970502, No. 81860107, No. 81260076), and Leading Talent Training Plan of the Gan-Po Outstanding Talents 555 Project of Jiangxi Province (2010-3-61).

CRediT authorship contribution statement

Rulin Zhao: Conceptualization, Methodology, Validation, Software, Visualization, Writing - original draft. Chao Peng: Software, Visualization, Writing - review & editing. Conghua Song: Validation, Writing - review & editing. Qiaoyun Zhao: Software, Validation. Jianfang Rong: Validation. Huan Wang: Software. Wenjie Ding: Software. Fangfei Wang: Visualization. Yong Xie: Conceptualization, Methodology, Supervision.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

We acknowledge the TIMER, TCGA, GEPIA, GEO and Kaplan-Meier plotter databases for free use.

References (37)

  • L.A. Lemaire et al.

    Bicaudal C1 promotes pancreatic NEUROG3+ endocrine progenitor differentiation and ductal morphogenesis

    Development

    (2015)
  • Y. Arai et al.

    Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma

    Hepatology

    (2014)
  • T. Li et al.

    TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells

    Cancer Res.

    (2017)
  • M.S. Cline et al.

    Exploring TCGA pan-cancer data at the UCSC cancer genomics browser

    Sci. Rep.

    (2013)
  • S.C. Oh et al.

    Clinical and genomic landscape of gastric cancer with a mesenchymal phenotype

    Nat. Commun.

    (2018)
  • L. Li et al.

    FN1, SPARC, and SERPINE1 are highly expressed and significantly related to a poor prognosis of gastric adenocarcinoma revealed by microarray and bioinformatics

    Sci. Rep.

    (2019)
  • R. Edgar et al.

    Gene expression omnibus: NCBI gene expression and hybridization array data repository

    Nucleic Acids Res.

    (2002)
  • Z. Tang et al.

    GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses

    Nucleic Acids Res.

    (2017)
    • View full text
    © 2020 Elsevier B.V. All rights reserved.