The aberrant expression of MEG3 regulated by UHRF1 predicts the prognosis of hepatocellular carcinoma

Abstract

MEG3 as a tumor suppressor has been reported to be linked with pathogenesis of malignancies including hepatocellular carcinoma (HCC). However, the mechanism of MEG3 in HCC still remains unclear. In our study, the aberrant decreased level of MEG3 in 72 tumor tissues obtained from HCC patients and cell lines was examined by using real-time PCR. The inhibition affection in proliferation and inducing affection in apoptosis was further confirmed in vivo and vitro, we also demonstrated that MEG3 regulates HCC cell proliferation and apoptosis partially via the accumulation of p53. Besides, the hypermethylation of MEG3 in promoter region was identified by bisulfite sequencing while MEG3 increased with the inhibition of methylation. Subsequently, UHRF1, a new identified oncogene which is required for DNA methylation and recruits, was investigated. A negative correlation of MEG3 and UHRF1 expression was verified in primary HCC tissues. Down-regulation of UHRF1 induced MEG3 expression in HCC cell lines, which could be reversed by the up-regulation of UHRF1. In addition, up-regulation of MEG3 in HCC cells partially diminished the promotion of proliferation induced by UHRF1. Moreover, Kaplan-Meier analysis demonstrated that the patients with low expression of MEG3 indicated worse overall and relapse-free survivals compared with high expression of MEG3. Cox proportional hazards analyses showed that MEG3 expression was an independent prognostic factor for HCC patients. In conclusion, we demonstrated MEG3, acting as a potential biomarker in predicting the prognosis of HCC, was regulated by UHRF1 via recruiting DNMT1 and regulated p53 expression.

UHRF1 promotes human osteosarcoma cell invasion by downregulating the expression of E-cadherin in an Rb1-dependent manner

“…UHRF1 is overexpressed and associated with tumor stages, and predicts poor prognosis in various types of cancer (15,21). UHRF1 has previously been identified as an oncogene in hepatocellular carcinoma (19,20). Furthermore, the overexpression of UHRF1 destabilizes and delocalizes DNMT1, and causes DNA hypomethylation in cancer cells (19).…”

“…Furthermore, the overexpression of UHRF1 destabilizes and delocalizes DNMT1, and causes DNA hypomethylation in cancer cells (19). Although several studies have demonstrated the function of UHRF1 in tumorigenesis and tumor progression (14,17,20), little is known regarding the function of UHRF1 in human osteosarcoma cells. In the present study, the expression of UHRF1 was detected in all of the human osteosarcoma cell lines examined.…”

“…The overexpression of UHRF1 has also been reported to reduce the radiosensitivity of human breast cancer cells and HeLa cells to γ-irradiation (18). Previous studies have demonstrated that UHRF1 is an oncogene in hepatocellular carcinoma (19,20 Furthermore, the overexpression of UHRF1 destabilizes and delocalizes DNA (cytosine-5-)-methyltransferase 1 (DNMT1) and causes DNA hypomethylation in cancer cells (19). Despite these findings, little is known regarding the function of UHRF1 in human osteosarcoma cells.…”

Non-coding RNAs: New therapeutic targets and opportunities for hepatocellular carcinoma

“…MEG3 is the first lncRNA found to be expressed in a variety of normal tissues. As a tumor suppressor, MEG3 is reportedly linked to the pathogenesis of malignancies (including HCCs) [72] . Zhuo et al have shown that MEG3 plays a crucial role in regulating gene expression by recruiting DNMT1, and promoting the cell growth of HCC cells [72] .…”

Long noncoding RNAs in hepatocellular carcinoma: Novel insights into their mechanism

“…UHRF1, as a new identified oncogene, contributes to the upregulation of MEG3 in HCC by regulating DNMT1, while upregulation of MEG3 in HCC cells can partially diminish the promotion of proliferation produced by UHRF1. In addition, UHRF1/ DNMT1/MEG3/p53 axis signaling pathway is involved in HCC progression [99] . Furthermore, loss of MEG3 gene expression is related to hypermethylation of the promoter region in HCC [82] .…”