Long noncoding RNA ANRIL indicates a poor prognosis of gastric cancer and promotes tumor growth by epigenetically silencing of miR-99a/miR-449a.

Er-Bao Zhang,Rong Kong,Rui Xia,Tong-Peng Xu,Jin-Song Yang,Wei De,Dan-Dan Yin,Liang-Hui You,Jin Fei Chen,Ming Sun,Liang Han

doi:10.18632/oncotarget.1902

Abstract

Long noncoding RNAs are involved in diseases including cancer. Here, we reported that ANRIL (CDKN2B-AS1), a 3.8-kb long noncoding RNA, recruiting and binding to PRC2, was generally upregulated in human gastric cancer (GC) tissues. In a cohort of 120 GC patients, the higher expression of ANRIL was significantly correlated with a higher TNM stage (P=0.041) and tumor size (P=0.001). Multivariate analyses revealed that ANRIL expression served as an independent predictor for overall survival (P=0.036). Further experiments revealed that ANRIL knockdown significantly repressed the proliferation both in vitro and in vivo. We also showed that E2F1 could induce ANRIL and ANRIL-mediated growth promotion is in part due to epigenetic repression of miR-99a/miR-449a in Trans (controlling the targets--mTOR and CDK6/E2F1 pathway) by binding to PRC2, thus forming a positive feedback loop, continuing to promote GC cell proliferation. To our knowledge, this is the first report showed that the role of ANRIL in the progression of GC and ANRIL could crosstalk with microRNAs in epigenetic level. Our results suggest that ANRIL, as a growth regulator, may serve as a candidate prognostic biomarker and target for new therapies in human gastric cancer.

Highlights

Gastric cancer (GC) is the second leading cause of cancer death, and is the most common gastrointestinal malignancy in East Asia, Eastern Europe, and parts of Central and South America[1]
We found that the average level of ANRIL in GC tissues was significantly higher than those in corresponding non-tumor tissues
High ANRIL expression in GC tissues was associated with a poor prognosis and could be an independent prognostic indicator

Summary

Introduction

Gastric cancer (GC) is the second leading cause of cancer death, and is the most common gastrointestinal malignancy in East Asia, Eastern Europe, and parts of Central and South America[1]. Gastric cancer is diagnosed at advanced stage accompanied by malignant proliferation in most patients and the prognosis for advanced stage patients is still very poor[2]. The identifications of the new biomarkers and therapeutic targets for GC and a detailed understanding of the molecular mechanisms underlying gastric carcinogenesis will supply an arm for improving diagnosis and treatment of human GC.With the development of whole-genome sequencing technology, it was determined that less than 2% of the mammalian genome is in protein-encoded regions and the remainder is in noncoding RNAs www.impactjournals.com/oncotarget (ncRNAs)[3]. Among them are long noncoding RNAs (lncRNAs), which are more than 200 nt in length and unable to be translated into proteins. The dysregulation of lncRNAs have been shown in various types of cancer including GC [1013], suggesting that they may display a large regulatory component of the eukaryotic genome

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Conclusion