Genetic variants at the 9p21 locus contribute to atherosclerosis through modulation of ANRIL and CDKN2A/B

Congrains, Ada; Kamide, Kei; Oguro, Ryousuke; Yasuda, Osamu; Miyata, Keishi; Yamamoto, Eiichiro; Kawai, Tatsuo; Kusunoki, Hiroshi; Yamamoto, Hiroko; Takeya, Yasushi; Yamamoto, Kōichi; Onishi, Masanori; Sugimoto, Ken; Katsuya, Tomohiro; Awata, Nobuhisa; Ikebe, Kazunori; Gondo, Yasuyuki; Oike, Yuichi; Ohishi, Mitsuru; Rakugi, Hiromi

doi:10.1016/j.atherosclerosis.2011.11.017

Cited by 291 publications

(247 citation statements)

References 31 publications

(34 reference statements)

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“…Several previous reports have established that ANRIL has a regulatory effect on its neighbours CDKN2A/B (20,21,34); however, there is also evidence that ANRIL acts on certain genes that do not appear to be downstream to CDKN2A/B (35,36), reflecting a very complex regulatory panorama for this lncRNA. To investigate the downstream molecular events involving ANRIL and SOC invasiveness and/or metastasis in the current study, we compared SK-OV-3.…”

Section: Discussionmentioning

confidence: 99%

Long non-coding RNA ANRIL predicts poor prognosis and promotes invasion/metastasis in serous ovarian cancer

Qiu

Lin

Ding

et al. 2015

International Journal of Oncology

120

102

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Abstract. Recent studies have highlighted the role of long non-coding RNAs (lncRNAs) in carcinogenesis and have suggested that genes of this class might be used as biomarkers in cancer. However, whether lncRNAs are involved in serous ovarian cancer (SOC) remains largely unknown. In the present study, we focused on lncRNA antisense non-coding RNA in the INK4 locus (ANRIL) and investigated its expression pattern, clinical significance, and biological function in SOC. We found that ANRIL levels were elevated in SOC tissues compared with normal controls and were highly correlated with advanced FIGO stage, high histological grade, lymph node metastasis, and poor prognosis. Multivariate analysis further revealed that ANRIL is an independent prognostic factor for predicting overall survival of SOC patients. In vitro, we compared differential ANRIL levels between SOC parental cell lines (SK-OV-3, HO8910) and highly metastatic sublines (SK-OV-3.ip1, HO8910-PM). Notably, ANRIL was highly expressed in both SK-OV-3.ip1 cells and HO8910-PM cells. SiRNA-mediated ANRIL silencing in these cells impaired cell migration and invasion. Based on the metastasis-related mRNA microarray analysis and subsequent western blotting confirmation, we found that MET and MMP3 are key downstream genes of ANRIL involved in SOC cell migration/ invasion. Together, our data suggest that lncRNA ANRIL plays an important role in SOC invasion/metastasis and could represent a novel biomarker for predicting poor survival as well a promising therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Long non-coding RNA ANRIL predicts poor prognosis and promotes invasion/metastasis in serous ovarian cancer

Qiu

Lin

Ding

et al. 2015

International Journal of Oncology

120

102

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“…92 In a recent study, ANRIL was found to be upregulated in gastric cancer relative to non-tumor tissue, and could therefore serve as an independent predictor for overall survival in gastric cancer (GC). 93 Regulation of the CDKN2A/B locus by ANRIL indicates that it has a major role in controlling cell proliferation 94 and also facilitates cell proliferation after DNA damage repair (DDR). 95 ANRIL is induced by the E2F1 transcription factor in an ATM-dependent manner after DNA damage.…”

Section: Llme23mentioning

confidence: 99%

Epigenetic regulation in human melanoma: past and future

Sarkar

Leung

Baguley³

et al. 2015

Epigenetics

236

169

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“…These authors also found that common carotid artery atherosclerosis is associated with a significantly lower expression of ANRIL 21) . In contrast, the present study showed that the ANRIL NR_003529 and CDKN2A expression levels are negatively correlated.…”

Section: Ink4amentioning

confidence: 79%

“…CDKN2BAS transcripts have been shown to regulate cell senescence and proliferation in various cell lines. Additionally, CDKN2BAS has been demonstrated to exert regulatory effects upon its neighbors, including CDKN2A/B via histone modification [19][20][21] . CDKN2BAS has been suggested to regulate senescence at the CDKN2A locus, with an associated senescence-dependent role in proliferation.…”

Section: Ink4bmentioning

confidence: 99%

The Severity of Internal Carotid Artery Stenosis is Associated with the Cyclin-Dependent Kinase Inhibitor 2A Gene Expression

Bayoğlu

Arslan

Göde

et al. 2014

JAT

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Aim: The INK4b-ARF-INK4a locus in the chromosome 9p21 region is known to play an important role in the development of atherosclerosis. The INK4/ARF transcript p16INK4a inhibits the activity of the cyclin-dependent kinases CDK4/CDK6 and arrests cell-cycle progression. CDK inhibitors also regulate G1/S phase progression in vascular smooth muscle cells (VSMCs) and may modulate the early stages of atherosclerosis. Therefore, we aimed to study the expression of the INK4/ARF locus genes CDKN2A and CDKN2BAS in order to examine the p16 INK4a protein expression and the level of cell proliferation in carotid plaques and saphenous tissue samples. Methods: A total of 50 patients (33 symptomatic subjects and 17 asymptomatic subjects) with carotid atherosclerosis (CA) were studied. The CDKN2A and CDKN2BAS gene expression levels were determined using quantitative real-time polymerase chain reaction (qRT-PCR). All tissue sections were also analyzed for the p16INK4a and proliferating cell nuclear antigen (PCNA) protein expression using immunohistochemistry (IHC). Results: The CDKN2A gene expression was significantly higher in the carotid plaques than in the saphenous tissues (p= 0.009), whereas no such differences were observed in the CDKN2BAS transcripts (p = 0.157). The carotid plaque CDKN2A mRNA levels were higher in the symptomatic patients than in the asymptomatic patients (p = 0.050); this finding was also associated with the severity of internal carotid artery (ICA) stenosis (p=0.034). The p16INK4a immune (＋) cell counts in the carotid plaques were higher in the symptomatic patients than in the asymptomatic patients (p = 0.056), as was the cell proliferation index (p=0.001). Conclusions: An increased CDKN2A gene expression in carotid plaques may increase the severity of ICA stenosis, thus raising the risk of atherosclerosis and contributing to the development of symptoms. In addition, the p16INK4a expression is associated with carotid atherosclerosis in various patient subgroups.J Atheroscler Thromb, 2014; 21:659-671.

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Genetic variants at the 9p21 locus contribute to atherosclerosis through modulation of ANRIL and CDKN2A/B

Abstract: Disease-associated SNPs at the 9p21 locus predominantly affect the expression of ANRIL. Overall, our results suggest that several CVD-associated SNPs in the 9p21 locus affect the expression of ANRIL, which, in turn modulate cell growth, possibly via CDKN2A/B regulation.

Cited by 291 publications

References 31 publications

Long non-coding RNA ANRIL predicts poor prognosis and promotes invasion/metastasis in serous ovarian cancer

Long non-coding RNA ANRIL predicts poor prognosis and promotes invasion/metastasis in serous ovarian cancer

Epigenetic regulation in human melanoma: past and future

The Severity of Internal Carotid Artery Stenosis is Associated with the Cyclin-Dependent Kinase Inhibitor 2A Gene Expression

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