Comprehensive Analysis of a ceRNA Network Identifies lncR-C3orf35 Associated with Poor Prognosis in Osteosarcoma.

Yi Shi,Jinze Li,Ze Zhuang,Kun Wang,Tangzhao Liang,Wenhui Zhang,Jianhua Ren,Yuangao Liu,Ronghan He,Zhe Wang

doi:10.1155/2020/3178037

Abstract

Osteosarcoma is a highly malignant bone cancer which primarily occurs in children and young adults. Increasing evidence indicates that long noncoding RNAs (lncRNAs), which function as competing endogenous RNAs (ceRNAs) that sponge microRNAs (miRNAs) and messenger RNAs (mRNAs), play a pivotal role in the pathogenesis and progression of cancers. The regulatory mechanisms of lncRNA-mediated ceRNAs in osteosarcoma have not been fully elucidated. In this study, we identified differentially expressed lncRNAs, miRNAs, and mRNAs in osteosarcoma based on RNA microarray profiles in the Gene Expression Omnibus (GEO) database. A ceRNA network was constructed utilizing bioinformatic tools. Kaplan-Meier survival analysis showed that lncR-C3orf35 and HMGB1 were associated with poor prognosis of osteosarcoma patients. Furthermore, results of Gene Set Enrichment Analysis (GSEA) suggested that lncR-C3orf35 may be involved in cellular invasion, the Toll-like receptor signaling pathway, and immune cell infiltration in the tumor microenvironment. Further analysis showed that patients with osteosarcoma metastasis expressed higher levels of lncR-C3orf35 and HMGB1 compared to metastasis-free patients. Moreover, the metastasis-free survival rate of the high lncR-C3orf35/HMGB1 expression group was significantly lower than that of the low expression group. The ESTIMATE algorithm was used to calculate the immune score and stromal scores for each sample. High lncR-C3orf35 and HMGB1 levels were correlated with low immune scores. ImmuCellAI analysis revealed that a low proportion of macrophage infiltration was associated with high lncR-C3orf35 and HMGB1 expression. The differential expression of lncR-C3orf35, miR-142-3p, and HMGB1 was further verified by quantitative real-time PCR. This study indicates that lncR-C3orf35 could be considered as a novel potential biomarker and therapeutic target of osteosarcoma, which may contribute to a better understanding of ceRNA regulatory mechanisms.

Highlights

Osteosarcoma, the most common bone malignancy, is a major cause of cancer-associated mortality in children and adolescents [1]
RNA expression profiles of osteosarcoma were collected from Gene Expression Omnibus (GEO). long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) microarray datasets were deposited by Sadikovic et al [15] and Fritsche-Guenther et al [16] with accession numbers GSE12865 and GSE14593, respectively (Table 1)
With the differentially expressed criteria of absolute logFC > 1 and p < 0:05, a total of 824 DE mRNAs (DEmRNAs) and 4 DElncRNAs were identified in the GSE143599 dataset (Figure 1)

Summary

Introduction

Osteosarcoma, the most common bone malignancy, is a major cause of cancer-associated mortality in children and adolescents [1]. Osteosarcoma primarily affects the terminus of long bones, such as proximal tibias and distal femurs. 5 new osteosarcoma cases occur per million people under the age of 20 each year in America [2]. The incidence of osteosarcoma has increased by 0.3% per year over the last decades [3]. For patients exhibiting osteosarcoma metastasis at diagnosis, the 5-year survival rate is less than 30% [4]. The mechanisms underlying osteosarcoma carcinogenesis and progression have not been fully elucidated, and novel biomarkers such as therapeutic targets and predictors of prognosis are needed to be investigated

Methods

Results

Conclusion