Transcriptome Analysis Uncovers a Growth-Promoting Activity of Orosomucoid-1 on Hepatocytes

• Published in: EBioMedicine Vol. 24; no. C; pp. 257 - 266
• Main Authors: Qin, Xian-Yang, Hara, Mitsuko, Arner, Erik, Kawaguchi, Yoshikuni, Inoue, Ikuyo, Tatsukawa, Hideki, Furutani, Yutaka, Nagatsuma, Keisuke, Matsuura, Tomokazu, Wei, Feifei, Kikuchi, Jun, Sone, Hideko, Daub, Carsten, Kawaji, Hideya, Lassmann, Timo, Itoh, Masayoshi, Suzuki, Harukazu, Carninci, Piero, Hayashizaki, Yoshihide, Kokudo, Norihiro, Forrest, Alistair R.R., Kojima, Soichi
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-10-2017; Elsevier
• Subjects: Animals; Bioinformatics; Cell Cycle; Cell Proliferation; Gene Expression Profiling - methods; Gene Regulatory Networks; Hepatectomy; Hepatocyte proliferation; Hepatocytes - cytology; Hepatocytes - metabolism; Humans; Lipocalin; Liver Neoplasms - blood; Liver Neoplasms - genetics; Liver Neoplasms - surgery; Liver Regeneration; Medicin och hälsovetenskap; Mice; Oligonucleotide Array Sequence Analysis - methods; Orosomucoid - genetics; Orosomucoid - metabolism; Orosomucoid-1; Research Paper; Signal Transduction; Up-Regulation; Hepatocyte proliferation; Bioinformatics; Lipocalin; Cell cycle; Orosomucoid-1
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2017.09.008

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.