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High Positive Correlations between ANRIL and p16-CDKN2A/p15-CDKN2B/p14-ARF Gene Cluster Overexpression in Multi-Tumor Types Suggest Deregulated Activation of an ANRIL–ARF Bidirectional Promoter

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Platform of Experimental Pathology, Institut Curie, 75248 Paris, France
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Unit of Pharmacogenomics, Department of Genetics, Institut Curie, 75248 Paris, France
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Department of Diagnostic and Theranostic Medicine, Institut Curie, 75248 Paris, France
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Department of Pathology, Beaujon Hospital, APHP Nord, 92110 Clichy, France
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Department of Pathology, Foch Hospital, 92150 Suresnes, France
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Department of Genetics, Cochin Hospital, APHP, 75014 Paris, France
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Cochin Institute, Inserm U1016, Paris Descartes University, 75014 Paris, France
*
Author to whom correspondence should be addressed.
Non-Coding RNA 2019, 5(3), 44; https://doi.org/10.3390/ncrna5030044
Received: 12 June 2019 / Revised: 8 August 2019 / Accepted: 15 August 2019 / Published: 21 August 2019
The CDKN2B-AS1 gene, also called ANRIL, is located at the human CDKN2A/B locus at 9p21.3 and transcribed by RNA polymerase II into a long non-coding RNA of 3834 bp. The CDKN2B-AS1 gene overlaps a critical region of 125 kb covering the CDKN2B gene. The CDKN2A/B locus encompasses three major tumor suppressors juxtaposed and joined into a p16-CDKN2A/p15-CDKN2B/p14-ARF gene cluster. CDKN2A encodes splice variants p16-CDKN2A and p14-ARF, and CDKN2B encodes p15-CDKN2B. ANRIL shares a bidirectional promoter with the p14-ARF gene and is transcribed from the opposite strand to the cluster. We performed an analysis of the expression level of ANRIL and tumor suppressor p16-CDKN2A, p15-CDKN2B, and p14-ARF genes using quantitative RT-PCR in a multitumor panel. We observed the overexpression of the four genes ANRIL, p16-CDKN2A, p15-CDKN2B, and p14-ARF in the great majority of the 17 different cancer types. ANRIL was upregulated in 13/17 tumors compared to normal tissues, ranging from 5% (prostate cancer) to 91% (cervix cancer), with variable expression of p16-CDKN2A, p15-CDKN2B, and p14-ARF genes. A high positive correlation was identified between levels of expression of ANRIL and the three tumor suppressors. The strongest positive association was observed with p14-ARF (p < 0.001) in all but one (lung squamous cell carcinoma) of the examined tumor types. This correlation suggests coordinated deregulated mechanisms in all cancer types through aberrant activation of a bidirectional p14-ARF/ANRIL promoter. Furthermore, significant positive correlation was unexpectedly established in prostatic carcinomas, in contradiction with previous data. View Full-Text
Keywords: lncRNA; ANRIL overexpression; p16-CDKN2A/p15-CDKN2B/p14-ARF cluster lncRNA; ANRIL overexpression; p16-CDKN2A/p15-CDKN2B/p14-ARF cluster
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Drak Alsibai, K.; Vacher, S.; Meseure, D.; Nicolas, A.; Lae, M.; Schnitzler, A.; Chemlali, W.; Cros, J.; Longchampt, E.; Cacheux, W.; Pignot, G.; Callens, C.; Pasmant, E.; Allory, Y.; Bieche, I. High Positive Correlations between ANRIL and p16-CDKN2A/p15-CDKN2B/p14-ARF Gene Cluster Overexpression in Multi-Tumor Types Suggest Deregulated Activation of an ANRIL–ARF Bidirectional Promoter. Non-Coding RNA 2019, 5, 44.

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