Abstract
BackgroundCyclinD1 is crucial for cell cycling and can regulate the expression of Dicer, a crucial regulator of microRNA maturation. However, little is known on how CyclinD1 regulates Dicer and miRNA expression, and the progression of intrahepatic cholangiocarcinoma (ICC).MethodsThe expression of CyclinD1 and Dicer in non-tumor cholangiocytes, ICC cells and tissues as well as their association with clinicopathological characteristics and survival were examined. The potential mechanisms by which CyclinD1 regulates Dicer and relative miRNA expression were determined by immunoprecipitation, ChIP sequence, BSP and luciferase reporter assays following induction of CyclinD1 over-expression or silencing and Dicer silencing. The impact of CyclinD1 and/or Dicer silencing on the growth of ICC was tested in vivo.ResultsUp-regulated CyclinD1 was associated with down-regulated Dicer expression in ICC tissues and poorer overall survival in patients with ICC. CyclinD1 interacted with the nuclear H3K9me3 and SUV39H1 and bound to the Dicer promoter to increase its CpG island methylation in ICC cells. Functionally, CyclinD1 silencing inhibited the malignancy of ICC cells, which were mitigated partially by Dicer silencing in ICC cells. Dicer silencing down-regulated miR-1914-5p and miR-541-5p expression, which targeted and promoted CyclinD1 and CDK6 expression in ICC cells.ConclusionsOur findings uncover that CyclinD1 inhibits Dicer expression by chromatin modification to reduce miR-1914-5p/miR-541-5p expression, which positively-feedback enhances CyclinD1 and CDK6 expression and progression of ICC.
Highlights
CyclinD1 is crucial for cell cycling and can regulate the expression of Dicer, a crucial regulator of microRNA maturation
We identified a new mechanism by which CyclinD1 inhibited Dicer expression by hyper-methylation of the Dicer promoter, which reduced miR-1914-5p and miR-541-5p expression that targeted CyclinD1 and CDK6 expression to promote the progression of intrahepatic cholangiocarcinoma (ICC)
Up-regulated CyclinD1 is associated with down-regulated dicer expression in ICC tissues and related to poor prognosis in patients with ICC To understand the potential relationship between CyclinD1 and Dicer during the development and progression of ICC, the levels of CyclinD1 and Dicer expression in 27 primary ICC and 9 adjacent non-tumor tissues were examined by immunohistochemitry (IHC)
Summary
CyclinD1 is crucial for cell cycling and can regulate the expression of Dicer, a crucial regulator of microRNA maturation. Little is known on how CyclinD1 regulates Dicer and miRNA expression, and the progression of intrahepatic cholangiocarcinoma (ICC). Previous studies have shown that epigenetic modifications, such as the promoter hyper-methylation and dysregulated microRNA expression, have been associated with the development and progression of ICC [5, 6]. 76% of patients have the hyper-methylation in the INK4A (p16) [7], 88% in the SOCS-3 [8], 69% in the RASSF1A [9], and 100% in the SEMA3B [10], leading to their down-regulated expression. The expression of a cluster of 38 miRNAs is dysregulated in ICC and some of them were associated with aberrant
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