Functional analysis of osteoactivin and its role in hepatocarcinogenesis

骨激活素的功能分析及其在肝癌发生中的作用

• 批准号: 14570484
• 负责人: IDO Akio
• 金额: $ 2.24万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570484/
• 关键词: osteoactivin; choline deficient, L-amino acid-defined (CDAA) diet; haepatocarcinogenesis; hepatocellular carcinoma; liver cirrhosis; invasion; metastasis; growth factor

Hepatocellular carcinoma (HCC) is closely associated with chronic liver disease, particularly cirrhosis. The aim of this study is to identify genes associated with early cirrhosis-associated hepatocarcinogenesis. First, we examined sequential changes in expression of growth factors, and hepatocyte proliferation and apoptosis during hepatocarcinogenesis in rats fed a choline-deficient, L-amino acid-defined (CDAA) diet. In this rat model, HCCs occur in conjunction with fatty liver, hepatocyte death and subsequent regeneration, fibrosis, and eventual cirrhosis. Expression of hepatocyte growth factor (HGF) was stimulated at about the same time as CDAA diet-induced liver injury within 1 week. HGF reached a maximum level of expression from 4 to 8 weeks. Although hepatocyte proliferation continued to be stimulated throughout the experimental period, the number of apoptotic hepatocytes was markedly reduced after peaking at 8 weeks. These findings suggest that a disruption of the normal balance between hepatocyte proliferation and apoptosis early in the CDAA diet promotes the survival of cells capable of malignant transformation. Therefore, we next examined genes differentially expressed in the livers of normal rats and rats fed the CDAA diet for 8 weeks, and isolated, osteoactivin (OA) cDNA. OA mRNA was strongly expressed in the livers of rats fed the CDAA diet for 1-3 months. Moderate expression was sustained for 18 months. OA overexpression increased the invasiveness and metastasis of rat hepatoma cells. In humans, while GA transcripts were detectable in cirrhotic nontumorous liver tissues surrounding HCCs, the majority of HCC tissue samples exhibited higher levels of OA expression than the surrounding normal tissue. These results indicate that OA is a novel factor involved in the progression of HCC via stimulation of tumor invasiveness and metastatic potential.

肝细胞癌（HCC）与慢性肝病，特别是肝硬化密切相关。本研究的目的是鉴定与早期肝癌相关的基因。首先，我们研究了连续的变化，生长因子的表达，肝细胞增殖和细胞凋亡在大鼠喂养胆碱缺乏，L-氨基酸定义（CDAA）饮食的肝癌发生。在该大鼠模型中，HCC与脂肪肝、肝细胞死亡和随后的再生、纤维化和最终的肝硬化一起发生。肝细胞生长因子（HGF）的表达在大约相同的时间刺激CDAA饮食诱导的肝损伤1周内。HGF在4 ~ 8周表达最高。虽然肝细胞增殖在整个实验期间继续受到刺激，但凋亡肝细胞的数量在8周达到峰值后显著减少。这些发现表明，CDAA饲料中肝细胞增殖和凋亡之间的正常平衡早期被破坏，促进了能够恶性转化的细胞的存活。因此，我们接下来检查了在正常大鼠和喂食CDAA饮食8周的大鼠的肝脏中差异表达的基因，并分离了骨激活素（OA）cDNA。OA mRNA在喂食CDAA饲料1-3个月的大鼠肝脏中强烈表达。中度表达持续18个月。OA过表达增加大鼠肝癌细胞的侵袭和转移能力。在人类中，虽然GA转录本在HCC周围的非肿瘤性肝组织中可检测到，但大多数HCC组织样本表现出比周围正常组织更高水平的OA表达。这些结果表明，OA是一个新的因素参与肝癌的进展，通过刺激肿瘤的侵袭性和转移潜力。

项目成果

Onaga M, Ido A, Hasuike S, et al.: "Osteoactivin, expressed during cirrhosis development in rats fed a choline-deficient, L-amino acid-defined diet, accelerates motility of hepatoma cells"Journal of Hepatology. 39巻. 779-785 (2003)

Onaga M、Ido A、Hasuike S 等人：“在喂食缺乏胆碱、L-氨基酸限定饮食的大鼠中，在肝硬化发展过程中表达的骨激活素可加速肝癌细胞的运动”《肝脏病学杂志》39. 779 -。 785 (2003)

Hori T, Nagata K, Hasuike S, et al.: "Risk factors for the local recurrence of hepatocellular carcinoma after a single session of percutaneous radiofrequency ablation."Journal of Gastroenterology. 38巻10号. 977-981 (2003)

Hori T、Nagata K、Hasuike S 等人：“单次经皮射频消融术后肝细胞癌局部复发的风险因素。”胃肠病学杂志，第 38 卷，第 10 期。977-981（2003 年）。 ）

Hori T, Ido A, Uto H, et al.: "Activation of hepatocyte growth factor in monkey stomach following gastric mucosal injury."Journal of Gastroenterology. 39巻2号. 133-139 (2004)

Hori T、Ido A、Uto H 等人：“胃粘膜损伤后猴胃中肝细胞生长因子的激活”，《胃肠病学杂志》，第 39 卷，第 2 期，第 133-139 期（2004 年）。

Hori T, Ido A, Uto H, et al.: "Activation of hepatocyte growth factor in monkey stomach following gastric mucosal injury."Journal of Gastroenterology. 39(2). 133-139 (2004)

Hori T、Ido A、Uto H 等人：“胃粘膜损伤后猴胃中肝细胞生长因子的激活。”胃肠病学杂志。

Onaga M, Ido A, Hasuike S, et al.: "Enhanced expression of growth factors and imbalance between hepatocyte proliferation and apoptosis in the livers of rats fed a choline-deficient, L-amino acid-defined diet."Hepatology Research. 28巻2号. 94-101 (2004)

Onaga M、Ido A、Hasuike S 等人：“喂食缺乏胆碱、L-氨基酸的饮食的大鼠肝脏中生长因子的表达增强以及肝细胞增殖和凋亡之间的不平衡。”肝病学研究 28。第 2 卷. 94-101 (2004)