Role of microRNA-155 at early stages of hepatocarcinogenesis induced by choline-deficient and amino acid-defined diet in C57BL/6 mice.
Role of microRNA-155 at early stages of hepatocarcinogenesis induced by choline-deficient and amino acid-defined diet in C57BL/6 mice.
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DOI：
10.1002/hep.23100
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发表时间：
2009-10
期刊：
影响因子：
13.5
通讯作者：
Jacob, Samson T.
中科院分区：
文献类型：
--
作者：
Wang, Bo;Majumder, Sarmila;Nuovo, Gerard;Kutay, Huban;Volinia, Stefano;Patel, Tushar;Schmittgen, Thomas D.;Croce, Carlo;Ghoshal, Kalpana;Jacob, Samson T.
MicroRNA是保守的小（20-25个核苷酸）非编码RNA，其在转录后水平负调节mRNA的表达。某些microRNA的异常表达在肿瘤发生中起着因果作用。在这里，我们报告了在喂养C57 BL/6小鼠胆碱缺乏和氨基酸定义（CDAA）饮食的早期阶段失调的肝脏microRNA的鉴定，该饮食已知在84周后促进非酒精性脂肪性肝炎（NASH）诱导的肝癌发生。微阵列分析确定了30种肝脏microRNA，与喂食胆碱充足和氨基酸定义饮食的小鼠相比，喂食CDAA饮食6、18、32和65周的小鼠中有显著（P≤0.01）改变。实时RT-PCR分析显示，在肝癌发生的早期阶段，致癌miR-155、miR-221/222和miR-21上调，而最丰富的肝脏特异性miR-122下调。Western blot分析显示，在这些小鼠中，在早期阶段，肝脏PTEN和C/EBPβ各自的miR-21和miR-155靶点的表达降低。在喂食CDAA饲料的小鼠的肝核提取物中，反式激活miR-155基因的NF-κ B的DNA结合活性显著升高（P=0.002）。此外，通过原位杂交和实时RT-PCR测量的miR-155的表达与饮食诱导的肝脏组织病理学变化相关。miR-155的异位表达促进HCC细胞的生长，而其缺失抑制细胞生长。值得注意的是，与匹配的肝组织相比，miR-155在原发性人HCC中显著上调（P=0.0004），伴随C/EBPβ水平降低（P=0.02）。microRNA谱的时间变化发生在CDAA饮食诱导的肝癌发生的早期阶段。特异性oncomirs及其肿瘤抑制靶点的相互调节暗示它们在NASH诱导的肝癌发生中的作用，并建议它们在肝癌的诊断、预后和治疗中的用途。
MicroRNAs are conserved, small (20–25 nucleotide) noncoding RNAs that negatively regulate expression of mRNAs at the post-transcriptional level. Aberrant expression of certain microRNAs plays a causal role in tumorigenesis. Here, we report identification of hepatic microRNAs that are dysregulated at early stages of feeding C57BL/6 mice choline deficient and amino acid defined (CDAA) diet that is known to promote nonalcoholic steatohepatitis (NASH)-induced hepatocarcinogenesis after 84 weeks. Microarray analysis identified 30 hepatic microRNAs that are significantly (P≤0.01) altered in mice fed CDAA diet for 6, 18, 32 and 65 weeks compared to those fed choline sufficient and amino acid defined diet. Real-time RT-PCR analysis demonstrated upregulation of oncogenic miR-155, miR-221/222 and miR-21 and downregulation of the most abundant liver specific miR-122 at early stages of hepatocarcinogenesis. Western blot analysis showed reduced expression of hepatic PTEN and C/EBPβ respective targets of miR-21 and miR-155, in these mice at early stages. DNA binding activity of NF-kB that transactivates miR-155 gene was significantly (P=0.002) elevated in the liver nuclear extract of mice fed CDAA diet. Further, the expression of miR-155, as measured by in situ hybridization and real-time RT-PCR, correlated with diet-induced histopathological changes in the liver. Ectopic expression of miR-155 promoted growth of HCC cells whereas its depletion inhibited cell growth. Notably, miR-155 was significantly (P=0.0004) upregulated in primary human HCCs with concomitant decrease (P=0.02) in C/EBPβ level compared to matching liver tissues. Temporal changes in microRNA profile occur at early stages of CDAA diet-induced hepatocarcinogenesis. Reciprocal regulation of specific oncomirs and their tumor suppressor targets implicate their role in NASH-induced hepatocarcinogenesis and suggest their use in the diagnosis, prognosis and therapy of liver cancer.
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影响因子：
64.5
作者：
Eulalio, Ana;Huntzinger, Eric;Izaurralde, Elisa
通讯作者：
Izaurralde, Elisa
DOI：
10.1073/pnas.0602266103
发表时间：
2006-05-02
影响因子：
11.1
作者：
Costinean, S;Zanesi, N;Croce, CM
通讯作者：
Croce, CM
影响因子：
4
作者：
Kutay, Huban;Bai, Shoumei;Ghoshal, Kalpana
通讯作者：
Ghoshal, Kalpana
DOI：
10.1111/j.1349-7006.2002.tb01250.x
发表时间：
2002-03
期刊：
Japanese journal of cancer research : Gann
影响因子：
--
作者：
Denda A;Kitayama W;Kishida H;Murata N;Tsutsumi M;Tsujiuchi T;Nakae D;Konishi Y
通讯作者：
Konishi Y
影响因子：
5.3
作者：
Ghoshal, K;Majumder, S;Jacob, ST
通讯作者：
Jacob, ST