Long non-coding RNA ANRIL is upregulated in hepatocellular carcinoma and regulates cell proliferation by epigenetic silencing of KLF2

Abstract

BackgroundHepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death, especially in China. And the mechanism of its progression remains poorly understood. Growing evidence indicates that long non-coding RNAs (lncRNAs) are found to be dysregulated in many cancers, including HCC. CDKN2B antisense RNA1 (ANRIL), a lncRNA, coclustered mainly with p14/ARF has been reported to be dysregulated in gastric cancer, esophageal squamous cell carcinoma, and lung cancer. However, its clinical significance and potential role in HCC is still not documented.Methods and resultsIn this study, expression of ANRIL was analyzed in 77 HCC tissues and matched normal tissues by using quantitative real-time polymerase chain reaction (qRT-PCR). ANRIL expression was up-regulated in HCC tissues, and the higher expression of ANRIL was significantly correlated with tumor size and Barcelona Clinic Liver Cancer (BCLC) stage. Moreover, taking advantage of loss of function experiments in HCC cells, we found that knockdown of ANRIL expression could impair cell proliferation and invasion and induce cell apoptosis both in vitro and in vivo. We also found that ANRIL could epigenetically repress KLF2 transcription in HCC cells by binding with PRC2 and recruiting it to KLF2 promoter region. We also found that Sp1 could regulate the expression of ANRIL.ConclusionOur results suggest that lncRNA ANRIL, as a growth regulator, may serve as a new biomarker and target for therapy in HCC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-015-0153-1) contains supplementary material, which is available to authorized users.

TET2 regulates LncRNA‐ANRIL expression and inhibits the growth of human gastric cancer cells

“…In a previous work, the authors found that lncRNA‐ANRIL promoted gastric cancer cell growth partly through epigenetically repressing the expression 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. Although the oncogenic role of ANRIL was also found in some other cancer types, inducing lung cancer , hepatocellular carcinoma , esophageal squamous cell carcinoma , and gastric cancer , the underlying mechanism behind lncRNA‐ANRIL regulation remains elusive. Here, we found that TET2 binds to the promoter of lncRNA‐ANRIL and regulates the expression of lncRNA‐ANRIL and its downstream genes (INK4a, INK4b, and ARF).…”

Krüppel‐like factor 2 inhibits hepatocarcinogenesis through negative regulation of the Hedgehog pathway

“…Multiple long‐chain non‐coding RNA (TUG1, ANRIL, XIST and ZFAS1) and miRNA (miR‐9) can regulate KLF2 expression. Although the function of KLF2 in liver cancer has not been directly investigated and reported, relevant studies have indicated that long‐chain non‐coding RNA such as TUG1 and ANRIL can promote the occurrence of liver cancer and development by apparent silencing of KLF2 expression . Such studies all indicate that KLF2 can negatively regulate liver cancer occurrence and development.…”

“…KLF2 is downregulated in gastric cancer, liver cancer, non-small-cell lung cancer and pancreatic ductal adenocarcinoma. [23][24][25] Multiple long-chain noncoding RNA (TUG1, ANRIL, XIST and ZFAS1) and miRNA (miR-9) can regulate KLF2 expression [23][24][25][26][27][28] . Although the function of KLF2 in liver cancer has not been directly investigated and reported, relevant studies have indicated that long-chain non-coding RNA such as TUG1 and ANRIL can promote the occurrence of liver cancer and development by apparent silencing of KLF2 expression.…”

Long noncoding RNA expression profiles in sub-lethal heat-treated hepatoma carcinoma cells

“…Recently, research suggests that lncRNAs are important in complicated diseases such as cancer [22]. Several lncRNA have been identified as being involved in the development and progression of HCC, such as lncRNA-HEIH [23], HOTAIR [24, 25], lncRNA MVIH [26], lncRNA-Dreh [27], HOTTIP/HOXA13 [28, 29], URHC [30], PCNA-AS1 [31], UFC1 [32], HULC [33], CCAT1 [34], PVT1 [35], ANRIL [36, 37], ZEB1-AS1 [38], PANDAR [39], DANCR [40]. Some of these lncRNA were also identified in our microarray data.…”