Department of Medicine, Leon H. Charney Division of Cardiology and Cell Biology and Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, NY, USA.
Cell Cycle. 2012 Mar 1;11(5):922-33. doi: 10.4161/cc.11.5.19421.
Cholesterol metabolism is tightly regulated at the cellular level and is essential for cellular growth. microRNAs (miRNAs), a class of noncoding RNAs, have emerged as critical regulators of gene expression, acting predominantly at posttranscriptional level. Recent work from our group and others has shown that hsa-miR-33a and hsa-miR-33b, miRNAs located within intronic sequences of the Srebp genes, regulate cholesterol and fatty acid metabolism in concert with their host genes. Here, we show that hsa-miR-33 family members modulate the expression of genes involved in cell cycle regulation and cell proliferation. MiR-33 inhibits the expression of the cyclin-dependent kinase 6 (CDK6) and cyclin D1 (CCND1), thereby reducing cell proliferation and cell cycle progression. Overexpression of miR-33 induces a significant G 1 cell cycle arrest in Huh7 and A549 cell lines. Most importantly, inhibition of miR-33 expression using 2'fluoro/methoxyethyl-modified (2'F/MOE-modified) phosphorothioate backbone antisense oligonucleotides improves liver regeneration after partial hepatectomy (PH) in mice, suggesting an important role for miR-33 in regulating hepatocyte proliferation during liver regeneration. Altogether, these results suggest that Srebp/miR-33 locus may cooperate to regulate cell proliferation, cell cycle progression and may also be relevant to human liver regeneration.
胆固醇代谢在细胞水平上受到严格调控，对细胞生长至关重要。microRNAs（miRNAs）是一类非编码 RNA，作为基因表达的关键调节剂而出现，主要在转录后水平发挥作用。我们小组和其他小组的最近研究表明，位于 Srebp 基因内含子序列中的 hsa-miR-33a 和 hsa-miR-33b 与它们的宿主基因一起调节胆固醇和脂肪酸代谢。在这里，我们表明 hsa-miR-33 家族成员调节参与细胞周期调控和细胞增殖的基因的表达。miR-33 抑制细胞周期蛋白依赖性激酶 6（CDK6）和细胞周期蛋白 D1（CCND1）的表达，从而减少细胞增殖和细胞周期进程。miR-33 的过表达在 Huh7 和 A549 细胞系中诱导显著的 G1 细胞周期停滞。最重要的是，使用 2'氟/甲氧基乙基修饰（2'F/MOE 修饰）硫代磷酸酯骨架反义寡核苷酸抑制 miR-33 的表达可改善小鼠部分肝切除（PH）后的肝再生，表明 miR-33 在调节肝再生期间肝细胞增殖中起重要作用。总之，这些结果表明 Srebp/miR-33 基因座可能共同调节细胞增殖、细胞周期进程，并且也与人类肝再生相关。
