ANRIL: A lncRNA at the CDKN2A/B Locus With Roles in Cancer and Metabolic Disease

Abstract

The CDKN2A/B genomic locus is associated with risk of human cancers and metabolic disease. Although the locus contains several important protein-coding genes, studies suggest disease roles for a lesser-known antisense lncRNA encoded at this locus, called ANRIL. ANRIL is a complex gene containing at least 21 exons in simians, with many reported linear and circular isoforms. Like other genes, abundance of ANRIL is regulated by epigenetics, classic transcription regulation, splicing, and post-transcriptional influences such as RNA stability and microRNAs. Known molecular functions of ANRIL include in cis and in trans gene regulation through chromatin modification complexes, and influence over microRNA signaling networks. Polymorphisms at the ANRIL gene are linked to risk for many different cancers, as well as risk of atherosclerotic cardiovascular disease, bone mass, obesity and type 2 diabetes. A broad array of variable reported impacts of polymorphisms on ANRIL abundance, splicing and function suggests that ANRIL has cell-type and context-dependent regulation and actions. In cancer cells, ANRIL gain of function increases proliferation, metastasis, cell survival and epithelial-mesenchymal transformation, whereas ANRIL loss of function decreases tumor size and growth, invasion and metastasis, and increases apoptosis and senescence. In metabolic disease, polymorphisms at the ANRIL gene are linked to risk of type 2 diabetes, coronary artery disease, coronary artery calcium score, myocardial infarction, and stroke. Intriguingly, with the exception of one polymorphism in exon 2 of ANRIL, the single nucleotide polymorphisms (SNPs) associated with atherosclerosis and diabetes are non-overlapping. Evidence suggests that ANRIL gain of function increases atherosclerosis; in diabetes, a risk-SNP reduced the pancreatic beta cell proliferation index. Studies are limited by the uncertain relevance of rodent models to ANRIL studies, since most ANRIL exons do not exist in mouse. Diverse cell-type-dependent results suggest it is necessary to perform studies in the relevant primary human tissue for each disease. Much remains to be learned about the biology of ANRIL in human health and disease; this research area may lead to insight into disease mechanisms and therapeutic approaches.

Impact of four lncRNA polymorphisms (rs2151280, rs7763881, rs1136410, and rs3787016) on glioma risk and prognosis: A case‐control study

“…ANRIL is an antisense lncRNA encoded at the CDKN2A/B locus with roles in cancer risks and metabolic diseases, such as type 2 diabetes, coronary artery disease, myocardial infarction, and stroke. 34 Li et al 35 reviewed that the lncRNA ANRIL is an oncogene of various tumors such as gastric cancer, lung cancer, hepatocellular cancer, and esophageal squamous cell cancer. Another study found that ANRIL was upregulated in glioma, promoting cell proliferation, migration and invasion, and inhibiting apoptosis by downregulating mir-34a.…”

Retracted Article: LncRNA OIP5-AS1 contributes to ox-LDL-induced inflammation and oxidative stress through regulating the miR-128-3p/CDKN2A axis in macrophages

“…Motterle et al indicated that chr9p21 variation affected the level of CDKN2A through regulating lncRNA ANRIL expression, which modulates the proliferation of vascular smooth muscle cells and enhances AS. 18,20 Therefore, CDKN2A is clearly related to the development of AS. However, whether CDKN2A mediates ox-LDL-induced cell progression in AS is unknown.…”

Expression of long non-coding RNA ANRIL predicts a poor prognosis in intrahepatic cholangiocarcinoma

“…Interestingly, this locus is associated with an increased risk of cancer and metabolic disease, including type 2 diabetes, obesity and cardiovascular diseases 37 . ANRIL expression and function have been extensively investigated in several cancers but not in iCCA 38 .…”