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Upregulation of miR-362-3p Modulates Proliferation and Anchorage-Independent Growth by Directly Targeting Tob2 in
Hongxing Shen1, Wenjuan Li1, Yuan Tian1
1College of Life Sciences, Wuhan University, Wuhan 430072, China.
Abstract:
The dysregulation of microRNAs (miRNAs) contributes to the pathogenesis of human malignancies, and miRNA expression can be affected by genetic and epigenetic changes, such as methylation of the CpG islands of their promoters. To identify miRNAs regulated by DNA methylation, the global miRNA expression profile was analyzed in two hepatocellular carcinoma (HCC) cell lines and two normal immortalized cell lines treated with 5-Aza-2'-deoxycytidine (DAC, an inhibitor of DNA methylation) plus TSA (Trichostatin A, histone deacetylase inhibitor). Results revealed that these epigenetic drugs differentially affect miRNA expression that is dependent or independent of cell type, especially miR-362-3p. miR-362-3p expression increased while methylation of its promoter significantly decreased in human HCC cells and tissues compared with normal cells and adjacent noncancerous tissues. Ectopic expression of miR-362-3p increased proliferation and anchorage-independent soft agar growth and its expression inhibition had opposing effects that were associated with regulation of its direct target-Tob2 in HCC cells. Inhibition of Tob2 recapitulated the effects of miR-362-3p overexpression, whereas enforced Tob2 expression reversed the promoting effects of miR-362-3p. Tob2 expression was reduced in human primary HCCs compared to adjacent noncancerous tissues. Our findings suggest that dysregulation of miR-362-3p and Tob2 may contribute to HCC malignancy.
Insights
Dysregulation of microRNA-362-3p (miR-362-3p) and Tob2 contributes to hepatocellular carcinoma (HCC) development. Epigenetic changes affect miR-362-3p, impacting HCC cell growth and malignancy.
Area of Science:
- Molecular Biology
- Oncology
- Epigenetics
Background:
- MicroRNA (miRNA) dysregulation is implicated in human cancer pathogenesis.
- Epigenetic modifications, including DNA methylation, can alter miRNA expression.
- Hepatocellular carcinoma (HCC) is a major malignancy where miRNA roles are increasingly recognized.
Purpose of the Study:
- To identify microRNAs regulated by DNA methylation in hepatocellular carcinoma.
- To investigate the role of miR-362-3p and its target Tob2 in HCC development.
Main Methods:
- Global miRNA expression profiling of HCC and normal cell lines treated with DNA methylation and histone deacetylase inhibitors (5-Aza-2'-deoxycytidine and Trichostatin A).
- Analysis of miR-362-3p promoter methylation and expression in HCC cells and tissues.
- Functional studies involving ectopic expression and inhibition of miR-362-3p and Tob2 in HCC cells.
Main Results:
- Epigenetic drugs differentially modulated miRNA expression in HCC cells.
- miR-362-3p expression increased, while its promoter methylation decreased in HCC cells and tissues.
- miR-362-3p overexpression promoted HCC cell proliferation and anchorage-independent growth by targeting Tob2.
- Tob2 expression was reduced in HCC tissues, and its regulation by miR-362-3p was confirmed.
Conclusions:
- Dysregulation of miR-362-3p and its target Tob2 is associated with hepatocellular carcinoma malignancy.
- Epigenetic mechanisms, particularly DNA methylation, play a role in regulating miR-362-3p in HCC.
- miR-362-3p and Tob2 represent potential therapeutic targets for HCC.
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