The effect of HMGB1 on the clinicopathological and prognostic features of non-small cell lung cancer.

Anlin Feng,Bingjiao Yin,Zhenbo Tu

doi:10.18632/oncotarget.7050

Abstract

Several studies have assessed the diagnostic and prognostic values of high mobility group protein box 1 (HMGB1) expression in non-small cell lung cancer (NSCLC), but these results remain controversial. The purpose of this study was to perform a meta-analysis of the gene microarray analyses of datasets from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to evaluate the association of HMGB1 expression with the clinicopathological and prognostic features of patients with NSCLC. Furthermore, we investigated the underlying molecular mechanisms by bioinformatics analysis. Twenty relevant articles involving 2651 patients were included in this meta-analysis; the HMGB1 expression in NSCLC tissues was significantly higher than that in the healthy non-cancer control tissues. We also found an indication by microarray analysis and meta-analysis that HMGB1 expression was associated with the cancer TNM Staging System. In terms of prognostic features, a survival analysis from KM-Plotter tool revealed that the high HMGB1 expression group exhibited poorer survival in lung adenocarcinoma (ADC) and overall NSCLC patients. The survival and disease-free analyses from TCGA datasets also showed that HMGB1 mainly affected the development of patients with ADC. Therefore, we focused on how HMGB1 affected the prognosis and development of ADC using bioinformatics analyses and detected that the mitogen-activated protein kinases (MAPK), apoptosis and cell cycle signaling pathways were the key pathways that varied during HMGB1 up-regulation in ADC. Moreover, various genes such as PLCG2, the phosphatidylinositol-4, 5-bisphosphate 3-kinase superfamily (PI3Ks), protein kinase C (PKC) and DGKZ were selected as hub genes in the gene regulatory network. Our results indicated that HMGB1 is a potential biomarker to predict progression and survival of NSCLC, especially of ADC types.

Highlights

high mobility group protein box 1 (HMGB1) is a highly conserved structural transcription factor with a molecular weight of approximately 30 KD
The pooled model showed a significantly higher protein level of HMGB1 in non-small cell lung cancer (NSCLC) tissues than in para-tumor tissues using IHC methods (6 articles, pooled mean difference 3.87, 95% CI 2.665.62, Z=7.1, P=0.000, see Figure 2B)
Certain factors remain unclear that are related to the overexpression and prognosis of HMGB1 in NSCLC

Summary

Introduction

HMGB1 is a highly conserved structural transcription factor with a molecular weight of approximately 30 KD. The HMGB1 protein contains three domains: two positively charged DNA-binding motifs (box A and B) and a C-terminal acidic tail. HMGB1 plays an important role as a DNA-binding protein to sustain nucleosome structure [2] and as an architectural transcription factor regulating gene expression [3, 4]. HMGB1 can be released into the extracellular matrix, where it exerts crucial functions in inflammation and carcinogenesis through its receptors including receptor for advanced glycation end-products (RAGE), the tolllike receptor (TLR) 2, and TLR 4 [5,6,7]. Extracellular HMGB1 has multiple pro-tumor roles in tumorigenesis, such as promotion of angiogenesis, evasion of apoptosis, inhibition of antitumor immunity, inflammation, promotion of tissue invasion and metastasis [12,13,14,15,16]

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