Upregulation of long noncoding RNA HOXA-AS3 promotes tumor progression and predicts poor prognosis in glioma.

Fan Wu,Fan Yang,Wen Wang,Chuanbao Zhang,Tao Jiang,Xiaoyan Yan,Jing Chen,Haoyuan Wang,Tingyu Liang,Jinquan Cai

doi:10.18632/oncotarget.18162

Abstract

Long noncoding RNAs (lncRNAs) have recently emerged as new potentially promising therapeutic targets in many cancers. However, their prognostic value and biological functions associated with glioma remain to be elucidated. Here, High-throughput RNAseq was performed to detect the expression profiles of lncRNAs in 325 human glioma tissues. It was shown that a novel lncRNA HOXA-AS3 was one of the most significantly upregulated lncRNAs in glioma tissues. Quantitative PCR further verified the increased expression of HOXA-AS3 in patient samples and glioma cell lines. Uni and Multivariate Cox regression analysis revealed that HOXA-AS3 was an independent prognostic factor in glioma patients. Gene set enrichment analysis indicated that the gene sets correlated with HOXA-AS3 expression were involved in cell cycle progression and E2F targets. Functionally, HOXA-AS3 silencing resulted in proliferation arrest by altering cell cycle progression and promoting cell apoptosis, and impaired cell migration in glioma cells. Furthermore, the growth-inhibiting effect of HOXA-AS3 knockdown was also demonstrated in Xenograft mouse model. Our results highlight the important role of HOXA-AS3 in glioma progression, and indicate that HOXA-AS3 may be served as a valuable prognostic biomarker for glioma.

Highlights

Gliomas are the most common and malignant primary brain tumors, accounting for 70% of adult malignant primary brain tumors, and the yearly incidence is approximately 6 cases per 100000 [1]
Since the low grade gliomas will develop into secondary glioblastoma partially, significance analysis of microarray (SAM) analysis with edgeR package (P value < 0.05, FDR < 0.05) was performed to compare the differentially expressed ncRNAs between grade II gliomas (35 astrocytoma, 27 oligodendroglioma, 33 oligoastrocytoma) and sGBM (34) respectively (Figure 1A). 174 ncRNAs of aberrant expression were observed, and 12 up-regulated ncRNAs of most significance were listed in Figure 1B, including several tumorigenesis-related Long noncoding RNAs (lncRNAs) (H19, HOTAIR)
We found that lncRNA HOXA-AS3 expression was gradually increased along with glioma pathological grade (Supplementary Figure 1A)

Summary

Introduction

Gliomas are the most common and malignant primary brain tumors, accounting for 70% of adult malignant primary brain tumors, and the yearly incidence is approximately 6 cases per 100000 [1]. The progress of treatments for glioma is hampered due to the infiltrative growth and inherent resistance to both chemo and radiotherapy [3]. Increasing evidence have demonstrated that lncRNAs play essential roles in large range of cellular processes, including proliferation, metastasis, differentiation and stem cell pluripotency though epigenetic modification and chromatin remodeling [6]. In the case of glioma, lncRNA XIST exerts tumor-suppressive functions by up-regulating miR-152 in glioblastama stem cells [15]. CRNDE plays an oncogenic role of glioma stem cell through the negative regulation of miR-186 [16]. Our previous study revealed that HOTAIR is a cell cycle-associated lncRNA and servers as a prognostic factor for glioma patient survival [17]. To identify more cancer associated lncRNAs and to investigate their biological functions and underlying mechanisms are critical for better clarifying the molecular biology of glioma

Methods

Results

Conclusion