Transcriptome Analysis Uncovers a Growth-Promoting Activity of Orosomucoid-1 on Hepatocytes.
Transcriptome Analysis Uncovers a Growth-Promoting Activity of Orosomucoid-1 on Hepatocytes.
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DOI：
10.1016/j.ebiom.2017.09.008
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发表时间：
2017-10
期刊：
影响因子：
11.1
通讯作者：
Kojima S
中科院分区：
文献类型：
--
作者：
Qin XY;Hara M;Arner E;Kawaguchi Y;Inoue I;Tatsukawa H;Furutani Y;Nagatsuma K;Matsuura T;Wei F;Kikuchi J;Sone H;Daub C;Kawaji H;Lassmann T;Itoh M;Suzuki H;Carninci P;Hayashizaki Y;FANTOM consortium;Kokudo N;Forrest ARR;Kojima S
急性期蛋白orosomucoid-1 （Orm1）主要在应激条件下由肝细胞（HPCs）表达。然而，其具体功能尚不完全清楚。在这里，我们报道了Orm1作为HPC增殖的执行者的作用。在肝癌手术切除患者和部分肝切除术（PH）小鼠中观察到血清Orm1水平升高。转录组研究表明，ph后再生小鼠肝组织分离的HPCs中Orm1含量最高。体外和体内sirna诱导的Orm1敲低均抑制小鼠再生HPCs和人肝细胞的增殖。对再生小鼠肝脏的微阵列分析显示，在Orm1敲低后，控制染色质复制的信号通路，特别是小染色体维持蛋白复合物基因均下调。这些数据表明，Orm1在肝损伤时被诱导，并通过激活HPCs的细胞周期进程来实现肝脏再生。在人类和小鼠部分肝切除术后，血清Orm1水平增加了约1.3- 2.5倍。转录组分析显示Orm1主要诱导于肝细胞，作为小鼠肝脏再生的调节因子。Orm1敲低小鼠肝脏再生受损，肝细胞生长不良，细胞周期信号传导受到抑制。Orosomucoid-1 （Orm1）是一种急性期蛋白，主要在应激条件下由肝细胞表达。从发现Orm1在人类和小鼠部分肝切除后被诱导开始，我们通过转录组分析和随后的培养和动物实验发现Orm1在肝切除小鼠的再生肝细胞中富集。小鼠中Orm1的敲低导致肝细胞生长减少，同时抑制控制染色质复制的信号传导。因此，通过新发现的刺激再生肝细胞细胞周期的能力，Orm1将成为肝脏疾病的潜在治疗和预后生物标志物，特别是在手术切除肝癌肝后。
The acute phase protein orosomucoid-1 (Orm1) is mainly expressed by hepatocytes (HPCs) under stress conditions. However, its specific function is not fully understood. Here, we report a role of Orm1 as an executer of HPC proliferation. Increases in serum levels of Orm1 were observed in patients after surgical resection for liver cancer and in mice undergone partial hepatectomy (PH). Transcriptome study showed that Orm1 became the most abundant in HPCs isolated from regenerating mouse liver tissues after PH. Both in vitro and in vivo siRNA-induced knockdown of Orm1 suppressed proliferation of mouse regenerating HPCs and human hepatic cells. Microarray analysis in regenerating mouse livers revealed that the signaling pathways controlling chromatin replication, especially the minichromosome maintenance protein complex genes were uniformly down-regulated following Orm1 knockdown. These data suggest that Orm1 is induced in response to hepatic injury and executes liver regeneration by activating cell cycle progression in HPCs. Serum Orm1 levels increased approximately 1.3- to 2.5-folds in both humans and mice after partial hepatectomy. Transcriptome analysis revealed that Orm1 mostly induced in hepatocytes as a regulator of mouse liver regeneration. Orm1 knockdown in mice impaired liver regeneration with poor hepatocyte growth and suppressed cell cycle signaling. Orosomucoid-1 (Orm1) is an acute phase protein mainly expressed by hepatocytes under stress conditions. Beginning from the finding that Orm1 was induced after partial hepatectomy in humans and mice, we showed enrichment of Orm1 in regenerating hepatocytes of hepatectomized mice by transcriptome analysis and following culture and animal experiments. Knockdown of Orm1 in mice resulted in decreases in hepatocyte growth accompanying suppressed signaling in controlling chromatin replication. Therefore, Orm1 would be a potential therapeutic and prognostic biomarker for liver diseases, especially after surgical resection of cancer-bearing liver, through its newly found ability to stimulate the cell cycle in regenerating hepatocytes.
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影响因子：
56.9
作者：
Carninci, P;Kasukawa, T;Hayashizaki, Y
通讯作者：
Hayashizaki, Y
影响因子：
--
作者：
Hara M;Kirita A;Kondo W;Matsuura T;Nagatsuma K;Dohmae N;Ogawa S;Imajoh-Ohmi S;Friedman SL;Rifkin DB;Kojima S
通讯作者：
Kojima S
DOI：
10.1126/science.1259418
发表时间：
2015-02-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Arner E;Daub CO;Vitting-Seerup K;Andersson R;Lilje B;Drabløs F;Lennartsson A;Rönnerblad M;Hrydziuszko O;Vitezic M;Freeman TC;Alhendi AM;Arner P;Axton R;Baillie JK;Beckhouse A;Bodega B;Briggs J;Brombacher F;Davis M;Detmar M;Ehrlund A;Endoh M;Eslami A;Fagiolini M;Fairbairn L;Faulkner GJ;Ferrai C;Fisher ME;Forrester L;Goldowitz D;Guler R;Ha T;Hara M;Herlyn M;Ikawa T;Kai C;Kawamoto H;Khachigian LM;Klinken SP;Kojima S;Koseki H;Klein S;Mejhert N;Miyaguchi K;Mizuno Y;Morimoto M;Morris KJ;Mummery C;Nakachi Y;Ogishima S;Okada-Hatakeyama M;Okazaki Y;Orlando V;Ovchinnikov D;Passier R;Patrikakis M;Pombo A;Qin XY;Roy S;Sato H;Savvi S;Saxena A;Schwegmann A;Sugiyama D;Swoboda R;Tanaka H;Tomoiu A;Winteringham LN;Wolvetang E;Yanagi-Mizuochi C;Yoneda M;Zabierowski S;Zhang P;Abugessaisa I;Bertin N;Diehl AD;Fukuda S;Furuno M;Harshbarger J;Hasegawa A;Hori F;Ishikawa-Kato S;Ishizu Y;Itoh M;Kawashima T;Kojima M;Kondo N;Lizio M;Meehan TF;Mungall CJ;Murata M;Nishiyori-Sueki H;Sahin S;Nagao-Sato S;Severin J;de Hoon MJ;Kawai J;Kasukawa T;Lassmann T;Suzuki H;Kawaji H;Summers KM;Wells C;FANTOM Consortium;Hume DA;Forrest AR;Sandelin A;Carninci P;Hayashizaki Y
通讯作者：
Hayashizaki Y
影响因子：
3.5
作者：
Agra, Rosa M.;Varela-Roman, Alfonso;Eiras, Sonia
通讯作者：
Eiras, Sonia
影响因子：
3.7
作者：
de Graaf, Wilmar;van den Esschert, Jacomina W.;van Gulik, Thomas M.
通讯作者：
van Gulik, Thomas M.