Gene Summary

Gene:CDKN2B-AS1; CDKN2B antisense RNA 1
Aliases: ANRIL, p15AS, PCAT12, CDKN2BAS, CDKN2B-AS, NCRNA00089
Summary:This gene is located within the CDKN2B-CDKN2A gene cluster at chromosome 9p21. The gene product is a functional RNA molecule that interacts with polycomb repressive complex-1 (PRC1) and -2 (PRC2), leading to epigenetic silencing of other genes in this cluster. This region is a significant genetic susceptibility locus for cardiovascular disease, and has also been linked to a number of other pathologies, including several cancers, intracranial aneurysm, type-2 diabetes, periodontitis, Alzheimer's disease, endometriosis, frailty in the elderly, and glaucoma. Multiple alternatively processed transcript variants have been detected, some of which may take the form of circular RNA molecules (PMID:21151960). [provided by RefSeq, May 2014]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 31 August, 2019

Cancer Overview

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Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: CDKN2B-AS1 (cancer-related)

Matsunaga N, Wakasaki T, Yasumatsu R, Kotake Y
Long Noncoding RNA,
Anticancer Res. 2019; 39(8):4073-4077 [PubMed] Related Publications
BACKGROUND/AIM: ANRIL is a long noncoding RNA located on INK4 locus, which encodes p15 and p16 that cause G
MATERIALS AND METHODS: Cells were transfected with siRNA oligonucleotides targeting ANRIL. Transfected cells were subjected to cell-cycle and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis.
RESULTS: Depletion of ANRIL increased p15 mRNA in FaDu cells, and p15 and p16 mRNA in CAL27 cells and inhibited proliferation of these cells. Cell cycle analysis showed that depletion of ANRIL caused arrest at the G

Hong CH, Lin SH, Lee CH
CCL21 Induces mTOR-dependent MALAT1 Expression, Leading to Cell Migration in Cutaneous T-Cell Lymphoma.
In Vivo. 2019 May-Jun; 33(3):793-800 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mycosis fungoides (MF) is indolent, but may disseminate to leukemia. We reported that C-C motif chemokine ligand 21 (CCL21) is associated with MF invasion and progression. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long noncoding RNA, is associated with several cancer types, however, how it interacts with CCL21 to regulate MF progression, remains unclear.
MATERIALS AND METHODS: Expression of long noncoding RNAs MALAT1, antisense noncoding RNA in the INK4 locus (ANRIL), Hox antisense intergenic RNA (HOTAIR), highly up-regulated in liver cancer RNA (HULC), and leukemia-associated non-coding insulin-like growth factor 1 receptor activator RNA 1 (LUNAR1) in tissues from MF was studied using polymerase chain reaction and RNA interference in MF cell line MyLa were used to address this question.
RESULTS: Expression of MALAT1 was selectively increased in MF tissues. C-C Chemokine receptor type 7 (CCR7) expression was found to be increased in MyLa cells. CCL21 was found not only to mediate migration, but also to enhance MALAT1 and mammalian target of rapamycin (mTOR) activation in MyLa cells. Knockdown of MALAT1 abrogated CCL21-mediated migration, but not mTOR activation. In contrast, mTOR inhibition reduced CCL21-mediated migration and MALAT1 expression.
CONCLUSION: CCL21 induced mTOR activation in MyLa cells, followed by expression of MALAT1, causing cell migration. MALAT1 and mTOR are potential therapeutic targets for MF.

Li G, Zhu Y
Effect of lncRNA ANRIL knockdown on proliferation and cisplatin chemoresistance of osteosarcoma cells in vitro.
Pathol Res Pract. 2019; 215(5):931-938 [PubMed] Related Publications
Chemoresistance is a major obstacle in treating cancer, including osteosarcoma. LncRNA ANRIL (ANRIL) is involved in the growth and metastasis of osteosarcoma cells, however, its role in chemoresistance remains unclear. In this study, ANRIL shRNA was used to knock down its endogenous expression in U2-OS and Saos-2 osteosarcoma cell lines. Our data showed that ANRIL-silenced cells were more sensitive to cisplatin: apoptotic ratio was increased and cleaved caspase-3 level was upregulated. Furthermore, the expression level of miR-125a-5p, a microRNA that can bind to ANRIL, was elevated in ANRIL-silenced cells. MiR-125a-5p inhibitor attenuated ANRIL knockdown-induced chemosensitivity to cisplatin. In addition, ANRIL knockdown resulted in a reduction in STAT3, a target of miR-125a-5p, in osteosarcoma cells. Forced overexpression of STAT3 weakened the chemosensitivity of ANRIL-silenced cells to cisplatin. In conclusion, our study demonstrates that ANRIL knockdown sensitizes osteosarcoma cells to cisplatin-induced cytotoxicity, suggesting ANRIL as a therapeutic target for osteosarcoma chemotherapy.

Yu F, Pang G, Zhao G
ANRIL acts as onco-lncRNA by regulation of microRNA-24/c-Myc, MEK/ERK and Wnt/β-catenin pathway in retinoblastoma.
Int J Biol Macromol. 2019; 128:583-592 [PubMed] Related Publications
Retinoblastoma is the most common intraocular malignant tumor in infants and children with metastatic potential. This study aimed to investigate the effects of antisense non-coding RNA in the INK4 locus (ANRIL) on retinoblastoma cell viability, migration and invasion, as well as the potential downstream molecules and possible signaling pathways. We found that ANRIL was highly expressed in retinoblastoma tissues and cells. Overexpression of ANRIL promoted the viability, migration and invasion of retinoblastoma Y79 cells and retinal pigment epithelial ARPE-19 cells, as well as activated MEK/ERK and Wnt/β-catenin pathways. Suppression of ANRIL had opposite effects. Moreover, ANRIL negatively regulated the expression of miR-24, which played tumor suppressive roles in retinoblastoma cells. Furthermore, ANRIL positively regulated the expression of c-Myc, which was a target gene of miR-24 in retinoblastoma cells. In Conclusion, Our research verified the oncogenic roles of ANRIL in retinoblastoma. Overexpression of ANRIL promoted viability, migration and invasion of retinoblastoma cells by activating MEK/ERK and Wnt/β-catenin pathways, as well as down-regulating miR-24 and then up-regulating c-Myc.

Cao T, Shen J, Pan W, et al.
Upregulation of long noncoding RNA ANRIL correlates with tumor progression and poor prognosis in esophageal squamous cell carcinoma.
J BUON. 2018 Nov-Dec; 23(6):1862-1866 [PubMed] Related Publications
PURPOSE: Esophageal cancer (EC) is the 9th most common carcinoma worldwide with poor prognosis. Specific biomarkers can help predicting the development of esophageal squamous cell carcinoma (ESCC), which can improve the assessment of prognosis. This study aimed to explore long noncoding RNA (lncRNA) ANRIL expression and its potential value in ESCC prognosis.
METHODS: Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was utilized to detect lncRNA ANRIL expression in 50 pairs of ESCC and matched normal samples in order to explore the role of lncRNA ANRIL in ESCC. Moreover, the association was investigated between clinical characteristics of ESCC and the expression level of ANRIL.
RESULTS: Disease-free survival (DFS) and overall survival (OS) were significantly shorter in ESCC patients with higher expression level of lncRNA ANRIL. ESCC tissues examined showed an obvious increment in ANRIL expression when compared to normal tissues. Furthermore, ANRIL was positively related to lymph nodes metastasis, TNM stage and tumor clinical stage. Moreover, upregulated ANRIL expression was remarkably associated with shorter survival in ESCC patients,which was also an independent prognostic factor for both OS and DFS.
CONCLUSIONS: This study suggested that lncRNA ANRIL could be a potential oncogene of ESCC. ANRIL expression might be served as another potential therapeutic target and prognostic biomarker for ESCC.

Zhu B, Zhu Y, Tian J, et al.
A functional variant rs1537373 in 9p21.3 region is associated with pancreatic cancer risk.
Mol Carcinog. 2019; 58(5):760-766 [PubMed] Related Publications
9p21.3 has been identified as an unexpected hot point in multiple diseases GWAS including cancers, and we performed a two-stage case-control studies integrating functional assay strategy to find the potential functional variants modified susceptibility to pancreatic cancer (PC). An expanded Illumina HumanExome Beadchip of PC including 943 cases and 3908 controls was used to examine 39 tagSNPs in 9p21.3 and the promising single nucleotide polymorphism (SNP) was validated in stage 2 comprising 624 cases and 1048 controls. The strongest signal was rs6475609 (Odds ratio, OR = 0.81, 95% confidence interval, CI = 0.72-0.91) maps to the long non-coding RNA ANRIL. Bioinformatics analysis revealed rs1537373 lies in the linkage disequilibrium (LD) block which the rs6475609 tagged might have potential function and was also associated with a decreased risk of PC in both stages (OR = 0.82, 95% CI = 0.75-0.90 in combined analysis). Dual luciferase reporter assay and the electrophoretic mobility shift assay (EMSA) verified rs1537373 as the best candidate causative variant for influencing the activity of enhancer through differential binding to certain transcription factor. The expression quantitative trait loci (e-QTL) analysis indicated the genotypes of rs1537373 were associated with expression of CDKN2B gene (P dominant = 6.00 × 10

Aalijahan H, Ghorbian S
Long non-coding RNAs and cervical cancer.
Exp Mol Pathol. 2019; 106:7-16 [PubMed] Related Publications
Cervical cancer is determined as the second highest number of deaths factor in female cancers. Here is a need to find new biomarkers for detection and preliminary prognosis, metastasis. To find new treatment to enhance the survival of cervical cancer patients, pivotal actions are necessitated to be implemented. Long non-coding RNAs (lncRNAs) appear to be the crucial modulators in various processes and critically influence the oncogenesis. The commencement and general review actions of the following lncRNAs HOTAIR, H19, XIST, CCHE1, EBIC, MALAT1, ANRIL, LET, NEAT1, BLACAT1, UFC1, SNHG16 and SNHG20 are focused in this review article. Roles of the lncRNAs in cervical cancer in terms of prognosis and tumor progression, invasion and metastasis, apoptosis, and radio-resistance are pointed out. In this review the utilization of lncRNAs as biomarkers in cervical cancer prognosis for metastasis is discussed. An overview of this review will be useful for selection of biomarkers in diagnosis, prognosis, and targeted therapy of cervical cancer in the future.

Wang JB, Jin Y, Wu P, et al.
Tumor suppressor PLZF regulated by lncRNA ANRIL suppresses proliferation and epithelial mesenchymal transformation of gastric cancer cells.
Oncol Rep. 2019; 41(2):1007-1018 [PubMed] Related Publications
Promyelocytic leukemia zinc finger (PLZF) plays important roles in tumorigenic and developmental processes of various types of cancers. However, the expression of PLZF in gastric cancer (GC) has not been reported. The aim of the present study was to investigate the expression level and potential status of PLZF in GC as well as its possible mechanism. In the present study, we found that PLZF was downregulated in the majority of GC cell lines and tumor tissues and that alteration of PLZF expression was closely correlated with a malignant phenotype, epithelial‑mesenchymal transformation and overall survival. Evaluation of in vitro proliferation, colony information, migration and invasion indicated that PLZF gene transduction induced a less malignant phenotype, which was also confirmed through in vivo studies performed in athymic nude mice. Furthermore, we assessed the expression levels of the lncRNA ANRIL in GC and found that it was negatively associated with the level of PLZF and that ANRIL indirectly methylated PLZF to suppress its expression via binding with polycomb repressive complex 2. When GC cells were treated with the methylation inhibitor 5‑Aza‑2'‑deoxycytidine, the expression of PLZF increased, which further confirmed that PLZF was methylated. These results indicated that constitutive ANRIL activation was a possible cause of the lack of PLZF expression in GC cells. Coupled deregulation of PLZF and ANRIL may account for most of the alterations described in GC, and PLZF may become a potential target of GC therapy.

Yang Y, Peng XW
The silencing of long non-coding RNA ANRIL suppresses invasion, and promotes apoptosis of retinoblastoma cells through the ATM-E2F1 signaling pathway.
Biosci Rep. 2018; 38(6) [PubMed] Free Access to Full Article Related Publications
As one of the most common primary intraocular carcinomas, retinoblastoma generally stems from the inactivation of the retinoblastoma

Zhang Z, Feng L, Liu P, Duan W
ANRIL promotes chemoresistance via disturbing expression of ABCC1 by regulating the expression of Let-7a in colorectal cancer.
Biosci Rep. 2018; 38(6) [PubMed] Free Access to Full Article Related Publications
Increasing evidence indicates that long non-coding RNAs (lncRNAs) antisense non-coding RNA in the INK4 locus (ANRIL) has been involved in various diseases and promotes tumorigenesis and cancer progression as an oncogenic gene. However, the effect of ANRIL on chemoresistance remains still unknown in colorectal cancer (CRC). Here, we investigated ANRIL expression in 63 cases of colorectal cancer specimens and matched normal tissues. Results revealed that ANRIL was up-regulated in tumor tissues samples from patients with CRC and CRC cell lines. Increased ANRIL expression in CRC was associated with poor clinical prognosis. Kaplan-Meier analysis showed that ANRIL was associated with overall survival of patients with colorectal cancer, and patients with high ANRIL expression tended to have unfavorable outcome.

Song Z, Wu W, Chen M, et al.
Long Noncoding RNA ANRIL Supports Proliferation of Adult T-Cell Leukemia Cells through Cooperation with EZH2.
J Virol. 2018; 92(24) [PubMed] Free Access to Full Article Related Publications
Adult T-cell leukemia (ATL) is a highly aggressive T-cell malignancy induced by human T-cell leukemia virus type 1 (HTLV-1) infection. Long noncoding RNA (lncRNA) plays a critical role in the development and progression of multiple human cancers. However, the function of lncRNA in HTLV-1-induced oncogenesis has not been elucidated. In the present study, we show that the expression level of the lncRNA ANRIL was elevated in HTLV-1-infected cell lines and clinical ATL samples. E2F1 induced ANRIL transcription by enhancing its promoter activity. Knockdown of ANRIL in ATL cells repressed cellular proliferation and increased apoptosis

Huang D, Bi C, Zhao Q, et al.
Knockdown long non-coding RNA ANRIL inhibits proliferation, migration and invasion of HepG2 cells by down-regulation of miR-191.
BMC Cancer. 2018; 18(1):919 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignant tumor with high fatality rate. Recent studies reported that up-regulation of long non-coding RNA antisense non-coding RNA in the INK4 locus (lncRNA ANRIL) was found in HCC tissues, and which could affect HCC cells biological processes. However, the potential molecular mechanism of ANRIL in HCC is still unclear. The study aimed to uncover the effect of ANRIL on HepG2 cells growth, migration and invasion.
METHODS: The knockdown expression vectors of ANRIL were transfected into HepG2 cells, and qRT-PCR, CCK-8, flow cytometry, Transwell and western blot assays were performed to analyze the effect of ANRIL on cell proliferation, apoptosis, migration and invasion. The relative expression of miR-191 was then examined in ANRIL knockdown vector transfected cells. These experiments were repeated again for exploring the effect of miR-191 on HepG2 cells. NF-κB and Wnt/β-catenin signaling pathways were examined by using western blot assay.
RESULTS: Knockdown of ANRIL inhibited proliferation, induced apoptosis, meanwhile suppressed migration and invasion of HepG2 cells. Additionally, the results showed that the expression level of miR-191 was down-regulated by ANRIL knockdown in HepG2 cells. Importantly, overexpression of miR-191 reversed the anti-tumor effect of ANRIL on cell proliferation, apoptosis, migration and invasion in HepG2 cells. Besides, we found that ANRIL knockdown inactivated NF-κB and Wnt/β-catenin pathways by regulating miR-191.
CONCLUSIONS: These data demonstrated that ANRIL knockdown suppressed proliferation, migration, invasion, and promoted apoptosis in HepG2 cells by down-regulating miR-191 and inactivating NF-κB and Wnt/β-catenin signaling pathways.

Thiele JA, Hosek P, Kralovcova E, et al.
lncRNAs in Non-Malignant Tissue Have Prognostic Value in Colorectal Cancer.
Int J Mol Sci. 2018; 19(9) [PubMed] Free Access to Full Article Related Publications
Although colorectal cancer (CRC) is the third most frequent cause of cancer related death in Europe, clinically relevant biomarkers for therapy guidance and prognosis are insufficiently reliable. Long non-coding RNAs (lncRNAs) are RNAs over 200 nucleotides long that are not translated into proteins but can influence biological processes. There is emerging evidence for their involvement in solid cancer as oncogenes, tumour suppressors or regulators of cell proliferation and metastasis development. The goal of this study was to evaluate the prognostic effect of selected lncRNAs in a retrospective study on CRC patients from the Czech Republic. We used a quantitative PCR approach to measure the expression in paired non-malignant and tumour tissue samples of CRC patients of nine lncRNAs previously shown to be involved in cancer progression-

Zhang WY, Liu YJ, He Y, Chen P
Down-regulation of long non-coding RNA ANRIL inhibits the proliferation, migration and invasion of cervical cancer cells.
Cancer Biomark. 2018; 23(2):243-253 [PubMed] Related Publications
OBJECTIVES: Cervical cancer (CC) is a common malignant tumor in the female reproductive system that is characterized by a high metastatic potential. LncRNA ANRIL has been found to be a cancer oncogene in multiple tumors. In our study, we altered the expression of ANRIL in CC cells and evaluated its ability on influencing proliferation, migration and invasion of CC cells and associated mechanism.
METHODS: Differentially expressed lncRNAs in CC were identified by microarray and TCGA analyses. CC tissues and adjacent tissues were collected in order to extract CC cells. The expression of ANRIL was determined by RT-qPCR. The CC cells were transfected with siRNA or si-NC against ANRIL to find out whether ANRIL can influence the expression of Cyclin D1, CDK4, CDK6, E-cadherin, vimentin and N-cadherin, as well as affect cell proliferation, cell apoptosis, cell migration and cell invasion of CC cells.
RESULTS: Based on TCGA and microarray analyses, ANRIL was predicted to be highly expressed in CC and CC with migration. Then further verification was obtained by means of RT-qPCR that ANRIL was highly expressed in CC tissues. In addition, high expression of ANRIL was related to increased E-cadherin expression, high migration of CC as well as decreased cell apoptosis rate. On the other hand, inhibition of ANRIL expression led to decreased expressions of Cyclin D1, CDK4, CDK6, N-cadherin and Vimentin, along with attenuated cell proliferation, migration and invasion of CC cells.
CONCLUSION: The key findings of our study demonstrated that the inhibition of lncRNA ANRIL reduces the proliferation, migration and invasion capabilities of CC cells. Down-regulation of ANRIL may serve as a potential therapeutic target in the treatment of CC.

Liu P, Zhang M, Niu Q, et al.
Knockdown of long non-coding RNA ANRIL inhibits tumorigenesis in human gastric cancer cells via microRNA-99a-mediated down-regulation of BMI1.
Braz J Med Biol Res. 2018; 51(10):e6839 [PubMed] Free Access to Full Article Related Publications
Long non-coding RNA antisense non-coding RNA in the INK4 locus (ANRIL) has been reported to promote tumorigenesis via regulating microRNA (miR)-99a in gastric cancer cells. However, the role of each component involved in it is still not well understood. This study aimed to verify the role of ANRIL in gastric cancer as well as the underlying mechanisms. ANRIL levels in clinical gastric cancer tissues and cell lines were tested by qPCR. Effects of ANRIL silence on cell viability, migration and invasion, apoptosis, and miR-99a expression in MKN-45 and SGC-7901 cells were measured using CCK-8, Transwell assay, flow cytometry, and qPCR assays, respectively. Then, effects of miR-99a inhibition on ANRIL-silenced cells were evaluated. B-lymphoma Mo-MLV insertion region 1 (BMI1) expression, after abnormal expression of ANRIL and miR-99a, was determined. Finally, expression of key proteins in the apoptotic, Notch, and mTOR pathways was assessed. ANRIL level was elevated in gastric cancer tissues and cell lines. Knockdown of ANRIL suppressed cell viability, migration, and invasion, and increased apoptosis through up-regulating miR-99a. Furthermore, ANRIL silence down-regulated BMI1 via up-regulating miR-99a. BMI1 silence down-regulated Bcl-2 and key kinases in the Notch and mTOR pathways and up-regulated p16 and cleaved caspases. We verified the tumor suppressive effects of ANRIL knockdown in gastric cancer cells via crosstalk with miR-99a. Together, we provided a novel regulatory mechanism for ANRIL in gastric cancer, in which ANRIL silence down-regulated BMI1 via miR-99a, along with activation of the apoptotic pathway and inhibition of the Notch and mTOR pathways.

Sun LY, Li XJ, Sun YM, et al.
LncRNA ANRIL regulates AML development through modulating the glucose metabolism pathway of AdipoR1/AMPK/SIRT1.
Mol Cancer. 2018; 17(1):127 [PubMed] Free Access to Full Article Related Publications
The long noncoding RNA ANRIL has been found to be abnormally expressed and play important roles in different cancers. However, the expression and function of ANRIL in acute myeloid leukemia (AML) remain to be declared. In this study, we found that ANRIL is up-regulated in AML patients at diagnosis and down-regulated in patients after complete remission (CR). Functional studies showed that knockdown of ANRIL expression resulted in a decline in glucose uptake and inhibition of AML cell maintenance in vitro and in vivo. Mechanically, ANRIL was found to repress the expression of Adiponectin receptor (AdipoR1), a key regulator of glucose metabolism. Both ANRIL and AdipoR1 knockdown reduced the expression levels of phosphorylation of AMPK and SIRT1, implying a previously unappreciated ANRIL-AdipoR1-AMPK/SIRT1 signaling pathway in regulating cell glucose metabolism and survival in AML. The study is the first to demonstrate that ANRIL promotes malignant cell survival and cell glucose metabolism to accelerate AML progression and is a potential prognostic marker and therapeutic target in AML treatment.

Huang X, Zhang W, Shao Z
Association between long non-coding RNA polymorphisms and cancer risk: a meta-analysis.
Biosci Rep. 2018; 38(4) [PubMed] Free Access to Full Article Related Publications
Several studies have suggested that long non-coding RNA (lncRNA) gene polymorphisms are associated with cancer risk. In the present study, we conducted a meta-analysis related to studies on the association between lncRNA single-nucleotide polymorphisms (SNPs) and the overall risk of cancer. A total of 12 SNPs in five common lncRNA genes were finally included in the meta-analysis. In the lncRNA antisense non-coding RNA (ncRNA) in the INK4 locus (ANRIL), the rs1333048 A/C, rs4977574 A/G, and rs10757278 A/G polymorphisms, but not rs1333045 C/T, were correlated with overall cancer risk. Our study also demonstrated that other SNPs were correlated with overall cancer risk, namely, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1, rs619586 A/G), HOXA distal transcript antisense RNA (HOTTIP, rs1859168 A/C), and highly up-regulated in liver cancer (HULC, rs7763881 A/C). Moreover, four prostate cancer-associated ncRNA 1 (PRNCR1, rs16901946 G/A, rs13252298 G/A, rs1016343 T/C, and rs1456315 G/A) SNPs were in association with cancer risk. No association was found between the PRNCR1 (rs7007694 C/T) SNP and the risk of cancer. In conclusion, our results suggest that several studied lncRNA SNPs are associated with overall cancer risk. Therefore, they might be potential predictive biomarkers for the risk of cancer. More studies based on larger sample sizes and more lncRNA SNPs are warranted to confirm these findings.

Achour C, Aguilo F
Long non-coding RNA and Polycomb: an intricate partnership in cancer biology.
Front Biosci (Landmark Ed). 2018; 23:2106-2132 [PubMed] Related Publications
High-throughput analyses have revealed that the vast majority of the transcriptome does not code for proteins. These non-translated transcripts, when larger than 200 nucleotides, are termed long non-coding RNAs (lncRNAs), and play fundamental roles in diverse cellular processes. LncRNAs are subject to dynamic chemical modification, adding another layer of complexity to our understanding of the potential roles that lncRNAs play in health and disease. Many lncRNAs regulate transcriptional programs by influencing the epigenetic state through direct interactions with chromatin-modifying proteins. Among these proteins, Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) have been shown to be recruited by lncRNAs to silence target genes. Aberrant expression, deficiency or mutation of both lncRNA and Polycomb have been associated with numerous human diseases, including cancer. In this review, we have highlighted recent findings regarding the concerted mechanism of action of Polycomb group proteins (PcG), acting together with some classically defined lncRNAs including

Chai L, Yuan Y, Chen C, et al.
The role of long non-coding RNA ANRIL in the carcinogenesis of oral cancer by targeting miR-125a.
Biomed Pharmacother. 2018; 103:38-45 [PubMed] Related Publications
Recently, increasing evidence has indicated that lncRNAs may play a critical role in the progression of oral cancer (OC). However, whether lncRNA-ANRIL is involved in the tumorigenesis of OC remains undetermined. In the present study, ANRIL showed significantly higher, while miR-125a showed lower, expression in OC tissues and sera than in normal controls. MTT, colony formation, flow cytometry analysis, wound-healing, transwell and mice xenograft model assays were used to detect the proliferation, migration, and invasion of ARNIL-overexpressing HB56 cells and ARNIL-knockdown CAL27 cells. The results showed that cell proliferation, migration, and invasion were significantly increased by ARNIL overexpression and decreased by ARNIL silencing in oral cancer cells. Furthermore, we found a negative correlation between ARNIL and miR-125a, and ARNIL acts as a miRNA-sponge by directly interacting with miR-125a.

Bahrami A, Hassanian SM, Khazaei M, et al.
The 9p21 locus as a potential therapeutic target and prognostic marker in colorectal cancer.
Pharmacogenomics. 2018; 19(5):463-474 [PubMed] Related Publications
Colorectal cancer (CRC) is a major cause of cancer-related-death worldwide. Despite extensive efforts to identify valid biomarkers for the risk stratification of CRC patients, there are few of proven clinical utility. It is recognized that genetic factors play a major role in determining susceptibility to CRC. Recent genome-wide association studies have demonstrated common genetic variants in a region on chromosome 9p21 associated with an increased risk of CRC. Several genetic polymorphisms have been identified in this region that are associated with CRC. Three genes are located at this locus; CDKN2B(encoding-p15

Yu X, Zheng H, Tse G, et al.
Long non-coding RNAs in melanoma.
Cell Prolif. 2018; 51(4):e12457 [PubMed] Related Publications
Melanoma is the most lethal cutaneous cancer with a highly aggressive and metastatic phenotype. While recent genetic and epigenetic studies have shed new insights into the mechanism of melanoma development, the involvement of regulatory non-coding RNAs remain unclear. Long non-coding RNAs (lncRNAs) are a group of endogenous non-protein-coding RNAs with the capacity to regulate gene expression at multiple levels. Recent evidences have shown that lncRNAs can regulate many cellular processes, such as cell proliferation, differentiation, migration and invasion. In the melanoma, deregulation of a number of lncRNAs, such as HOTAIR, MALAT1, BANCR, ANRIL, SPRY-IT1 and SAMMSON, have been reported. Our review summarizes the functional role of lncRNAs in melanoma and their potential clinical application for diagnosis, prognostication and treatment.

Xie Y, Zhang Y, Du L, et al.
Circulating long noncoding RNA act as potential novel biomarkers for diagnosis and prognosis of non-small cell lung cancer.
Mol Oncol. 2018; 12(5):648-658 [PubMed] Free Access to Full Article Related Publications
Lung cancer is the first leading cause of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Increasing evidence shows that long noncoding RNA (lncRNA) are capable of modulating tumor initiation, proliferation and metastasis. In the present study, we aimed to evaluate whether circulating lncRNA could be used as biomarkers for diagnosis and prognosis of NSCLC. Expression profiles of 14 lncRNA selected from other studies were validated in 20 pairs of tissues by quantitative real-time PCR, and the dysregulated lncRNA thus identified were further validated in serum samples from two independent cohorts along with three tumor makers (CEA, CYFRA21-1, and SCCA). Receiver-operating characteristic analysis was utilized to estimate the diagnostic efficiency of the candidate lncRNA and tumor markers. Importantly, we observed an association between lncRNA expression and overall survival (OS) rate of NSCLC. The expressions of SOX2 overlapping transcript (SOX2OT) and ANRIL were obviously upregulated in NSCLC tissues and serum samples compared with normal controls (P < 0.01). Based on the data from the training set, we next used a logistic regression model to construct an NSCLC diagnostic panel consisting of two lncRNA and three tumor markers. The area under the curve of this panel was 0.853 (95% confidence interval = 0.804-0.894, sensitivity = 77.1%, specificity = 79.2%), and this was distinctly superior to any biomarker alone (all at P < 0.05). Similar results were observed in the validation set. Intriguingly, Kaplan-Meier analysis demonstrated that low expressions of SOX2OT and ANRIL were both associated with higher OS rate (P = 0.008 and 0.017, respectively), and SOX2OT could be used as an independent prognostic factor (P = 0.036). Taken together, our study demonstrated that the newly developed diagnostic panel consisting of SOX2OT, ANRIL, CEA, CYFRA21-1, and SCCA could be valuable in NSCLC diagnosis. LncRNA SOX2OT and ANRIL might be ideal biomarkers for NSCLC prognosis.

Chen YD, Zhang N, Qiu XG, et al.
LncRNA CDKN2BAS rs2157719 genetic variant contributes to medulloblastoma predisposition.
J Gene Med. 2018; 20(1) [PubMed] Related Publications
BACKGROUND: How germline single nucleotide polymorphisms are involved in the etiology of medulloblastoma remans poorly understood. We hypothesized that CCDKN2A/B rs1063192 and rs4977756 and also the long noncoding RNA (lncRNA) CDKN2BAS rs2157719 glioma susceptibility polymorphisms identified by genome-wide association studies may contribute to medulloblastoma predisposition.
METHODS: To test this hypothesis, we genotyped these genetic variants among 160 medulloblastoma patients and 443 health controls in a Chinese population. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression.
RESULTS: We found that only the lncRNA CDKN2BAS rs2157719 T>C genetic polymorphism was significantly associated with an increased medulloblastoma risk (C allele: OR = 1.85, 95% CI = 1.32-2.58; p = 2.7 × 10
CONCLUSIONS: The findings of the present study provide important insights into the genetic complexities and predisposition of medulloblastoma in Chinese, especially at the lncRNA germline variation level.

Zhao B, Lu YL, Yang Y, et al.
Overexpression of lncRNA ANRIL promoted the proliferation and migration of prostate cancer cells via regulating let-7a/TGF-β1/ Smad signaling pathway.
Cancer Biomark. 2018; 21(3):613-620 [PubMed] Free Access to Full Article Related Publications
Long non-coding RNAs (lncRNAs) were playing critical roles in tumorigenesis. However, in prostate cancer, the roles and mechanisms of lncRNAs especially ANRIL were largely unknown. We investigated the effects of ANRIL on the proliferation and migration of prostate cancer cells using CCK-8 assay and Transwell migration assay. Real-time PCR and western blotting assays were used to analyze the levels of ANRIL, let-7a, TGF-β1, p-Smad2 and p-Smad7. Our results showed that ANRIL was significantly overexpressed in prostate cancer tissues compared with corresponding normal tissues. Knockdown of ANRIL significantly inhibited the proliferation and migration of prostate cancer LNCap, PC3 and DU145 cells. Knockdown of ANRIL significantly decreased the levels of TGF-β1 and p-Smad2, and increased the level of p-Smad7 in prostate cancer LNCap cells. We further found that knockdown of ANRIL significantly enhanced the expression of let-7a, and rescue experiment found that let-7a inhibitor recovered the suppressive effects of ANRIL silencing on the proliferation and migration of prostate cancer LNCap, PC3 and DU145 cells. And let-7a inhibitor recovered the suppressive effects of ANRIL silencing on the activity of TGF-β1/Smad signaling pathway in prostate cancer LNCap cells. Taken together, our findings indicated that overexpression of lncRNA ANRIL promoted the proliferation and migration of prostate cancer cells via regulating let-7a/TGF-β1/Smad signaling pathway.

Gutschner T, Richtig G, Haemmerle M, Pichler M
From biomarkers to therapeutic targets-the promises and perils of long non-coding RNAs in cancer.
Cancer Metastasis Rev. 2018; 37(1):83-105 [PubMed] Related Publications
Biomarker-driven personalized cancer therapy is a field of growing interest, and several molecular tests have been developed to detect biomarkers that predict, e.g., response of cancers to particular therapies. Identification of these molecules and understanding their molecular mechanisms is important for cancer prognosis and the development of therapeutics for late stage diseases. In the past, significant efforts have been placed on the discovery of protein or DNA-based biomarkers while only recently the class of long non-coding RNA (lncRNA) has emerged as a new category of biomarker. The mammalian genome is pervasively transcribed yielding a vast amount of non-protein-coding RNAs including lncRNAs. Hence, these transcripts represent a rich source of information that has the potential to significantly contribute to precision medicine in the future. Importantly, many lncRNAs are differentially expressed in carcinomas and they are emerging as potent regulators of tumor progression and metastasis. Here, we will highlight prime examples of lncRNAs that serve as marker for cancer progression or therapy response and which might represent promising therapeutic targets. Furthermore, we will introduce lncRNA targeting tools and strategies, and we will discuss potential pitfalls in translating these into clinical trials.

Rivandi M, Khorrami MS, Fiuji H, et al.
The 9p21 locus: A potential therapeutic target and prognostic marker in breast cancer.
J Cell Physiol. 2018; 233(7):5170-5179 [PubMed] Related Publications
Breast cancer is an important cause of cancer related mortality in women. Despite extensive efforts to identify valid biomarkers for risk stratification, there are relatively few with proven clinical utility. It is recognized that genetic factors play a major role in determining susceptibility to breast cancer. Recent genome-wide-association-studies and gene expression analysis have demonstrated that a locus on chromosome 9p21, which contains three genes; CDKN2B (encoding p15ink4b), CDKN2A (encoding p16ink4a and p14ARF) and the 3' end of CDKN2BAS (an antisense noncoding RNA in the INK4 locus [ANRIL]) are associated with an increased risk of this malignancy. ANRIL has a post transcriptional modulatory activity, which has been shown to perturb the expression of nearby genes and may play an important role in coordinating tissue remodeling through regulation of cell proliferation, apoptosis, aging, extra-cellular matrix remodeling, and inflammatory response. However, the role of ANRIL is not well understood in breast cancer. Hypermethylation of the p14

Murugan AK, Munirajan AK, Alzahrani AS
Long noncoding RNAs: emerging players in thyroid cancer pathogenesis.
Endocr Relat Cancer. 2018; 25(2):R59-R82 [PubMed] Related Publications
Thyroid cancer continues to be the most common malignancy of endocrine glands. The incidence of thyroid cancer has risen significantly over the past 4 decades and has emerged as a major health issue. In recent years, significant progress has been achieved in our understanding of the molecular mechanisms of thyroid carcinogenesis, resulting in significant diagnostic, prognostic and therapeutic implications; yet, it has not reached a satisfactory level. Identifying novel molecular therapeutic targets and molecules for diagnosis and prognosis is expected to advance the overall management of this common malignancy. Long noncoding RNAs (lncRNAs) are implicated in the regulation of various key cellular genes involved in cell differentiation, proliferation, cell cycle, apoptosis, migration and invasion mainly through modulation of gene expression. Recent studies have established that lncRNAs are deregulated in thyroid cancer. In this review, we discuss extensively the tumor-suppressive (for example, LINC00271, MEG3, NAMA, PTCSC1/2/3, etc.) and oncogenic (for example, ANRIL, FAL1, H19, PVT1, etc.) roles of various lncRNAs and their possible disease associations implicated in thyroid carcinogenesis. We briefly summarize the strategies and mechanisms of lncRNA-targeting agents. We also describe the potential role of lncRNAs as prospective novel therapeutic targets, and diagnostic and prognostic markers in thyroid cancer.

Ma J, Li T, Han X, Yuan H
Knockdown of LncRNA ANRIL suppresses cell proliferation, metastasis, and invasion via regulating miR-122-5p expression in hepatocellular carcinoma.
J Cancer Res Clin Oncol. 2018; 144(2):205-214 [PubMed] Related Publications
OBJECTIVE: Previous studies reported that lncRNA antisense non-coding RNA in the INK4 locus (ANRIL) was upregulated in hepatocellular carcinoma (HCC) tissues and decreased expression of ANRIL could suppress cell proliferation, metastasis, and invasion and induce apoptosis of HCC cells. However, the molecular mechanism of ANRIL involved in HCC tumorigenesis is still unknown.
METHODS: The expressions of ANRIL and miR-122-5p in HCC tissues and cells were quantified by qRT-PCR. MTT assay, colony formation assay, wound healing assay, and transwell invasion assay were performed to evaluate cell growth, metastasis, and invasion, respectively. RNA immunoprecipitation (RIP) assay and luciferase reporter assay were performed to determine whether ANRIL could directly bind to miR-122-5p in HCC cells. Xenograft tumor experiment was conducted to confirm the biological role and underlying mechanism of ANRIL in vivo.
RESULTS: The results showed that ANRIL was upregulated and miR-122-5p was downregulated in HCC tissues and cells. ANRIL was negatively correlated with miR-122-5p expression in HCC tissues. Knockdown of ANRIL or miR-122-5p overexpression suppressed HCC cell viability, colony formation ability, metastasis, and invasion. ANRIL was demonstrated to directly bind to miR-122-5p and inhibit its expression. Forced expression of ANRIL abolished the inhibitory effect of miR-122-5p overexpression on HCC progression. In vivo experiment demonstrated that ANRIL knockdown impeded tumor growth in vivo and increased miR-122-5p expression.
CONCLUSION: Our finding suggested that knockdown of ANRIL suppressed cell proliferation, metastasis and invasion via regulating miR-122-5p expression in HCC, illustrating the underlying mechanism of the oncogenic role of ANRIL in HCC.

Dong X, Jin Z, Chen Y, et al.
Knockdown of long non-coding RNA ANRIL inhibits proliferation, migration, and invasion but promotes apoptosis of human glioma cells by upregulation of miR-34a.
J Cell Biochem. 2018; 119(3):2708-2718 [PubMed] Related Publications
Gliomas are the most common types of primary central nervous system malignancy found in adults. Long non-coding RNA antisense non-coding RNA in the INK4 locus (ANRIL) variants are associated with glioma and miR-34a is markedly downregulated in U251 glioma cells. The 3'-untranslated region (3'UTR) of silent information regulator 1 (Sirt1) contains a conserved site that is targeted directly by miR-34a. Therefore, in this study, we investigated the roles of ANRIL, miR-34a, and Sirt1 in glioma and their potential interactions. Firstly, expression of ANRIL in normal glia cells and five glioma cell lines was measured. Then, effects of ANRIL suppression on cell proliferation, apoptosis, migration and invasion of U251 cells as well as expression of miR-34a were assessed. Meanwhile, effects of miR-34a on U251 cells silencing ANRIL were tested. Whether Sirt1 is a target of miR-34a was verified, followed by estimating the role of Sirt1 overexpression in U251 cells overexpressing miR-34a. Finally, the involved signaling pathways were assessed. ANRIL was upregulated in glioma cells and its suppression inhibited cell proliferation, migration and invasion but promoted cell apoptosis. ANRIL acted as a sponge of miR-34a, and Sirt1 is a target of miR-34a. Then, Sirt1 was proved to function through activation of the PI3K/AKT and mTOR signaling pathways. In conclusion, ANRIL was upregulated in glioma, and its inhibition could repress cell proliferation, migration and invasion but inhibit cell apoptosis through miR-34a-mediated downregulation of Sirt1, involving the inactivation of the PI3K/AKT and mTOR pathways.

Sun W, Yang Y, Xu C, Guo J
Regulatory mechanisms of long noncoding RNAs on gene expression in cancers.
Cancer Genet. 2017; 216-217:105-110 [PubMed] Related Publications
Long non-coding RNAs (lncRNAs) are a heterogeneous class of RNAs that are non-protein coding transcripts longer than 200 nucleotides. In this review, we introduce the mechanisms by which lncRNAs regulate gene expression in four parts, epigenetic regulation (genetic imprinting and chromatin remodeling), transcriptional regulation (molecular decoy), post-transcriptional regulation (splicing and mRNA decay), and translational regulation. H19, Xist, and others are involved in genomic imprinting. HOTAIR and ANRIL function in chromatin remodeling. GAS5 is degraded through an RNA decay pathway. NEAT1 and MALAT1 function not only in the regulation of transcription but also in splicing.

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