Roles of hepatoma-derived growth factor (HDGF) on liver development, regeneration and hepatocellular carcinogenesis

肝细胞源性生长因子（HDGF）在肝脏发育、再生和肝细胞癌变中的作用

• 批准号: 12670484
• 负责人: NAKAMURA Hideji
• 金额: $ 2.18万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670484/
• 关键词: HDGF; Liver development; Liver regeneration; Fetal hepatocyte; Hepatocyte proliferation; Hepatocellular carcinogenesis; FLS mouse; CDAA rat

HDGF (Hepatoma-derived growth factor) is a heparin-binding protein, which has been purified from the conditioned media of HuH-7 hepatoma cells. Recent studies have suggested the involvement of HDGF in the development of the kidney and cardiovascular systems. In the present study, we investigated the possibility that HDGF was also involved in the liver development and regeneration. HDGF expression was strongly detected in the fetal liver of the mid-gestation stage and was markedly decreased near birth. Its expression was mainly detected in immature hepatocytes and was remarkably decreased with their differentiation. Administration of recombinant HDGF enhanced the growth of primary cultured fetal hepatocytes. Adenovirally introduction of HDGF antisense cDNA into the fetal hepatocytes significantly suppressed their proliferation. The growth inhibitory effects of the HDGF antisense virus were recovered by exogenous HDGF. HDGF expression was induced in liver regeneration after partial hepat … More ectomy and CCl_4-induced liver damage. In both models, HDGF expression was induced before the peak of DNA synthesis. Expression of the HDGF gene in the regenerating liver was dominantly detected in parenchymal hepatocytes. These findings suggest that HDGF plays an important role in the liver development and regeneration as an autocrine factor, especially in the hepatocyte proliferation. Next, we investigated the roles of HDGF on hepatocellular carcinogenesis. In human samples, the expression of HDGF mRNA and proteins were elevated in HCC as compared to the adjacent non-cancerous tissues. In rodent models of hepatic carcinogenesis, HDGF expressed more abundantly in HCC, which developed in FLS mouse or CDAA-feeding rat than the non-cancerous tissues by Western blotting and immunohistochemistry. During the aging from the birth, HDGF mRNA expression started to increase earlier than the development of HCC in FLS mouse, and also HDGF-highly expressing foci (HEF) appeared in the stage before the development of HCC. The HEF could not be distinct from the normal hepatocytes by Hematoxylin-Eosine staining. These findings suggest that HDGF would become a marker for precancerous lesions and that HDGF play an important role on hepatic carcinogenesis as one of the important factors. Less

HDGF是一种肝素结合蛋白，从HH-7肝癌细胞的条件培养液中纯化而来。最近的研究表明，HDGF参与了肾脏和心血管系统的发育。在本研究中，我们研究了HDGF也参与肝脏发育和再生的可能性。HDGF在妊娠中期胎肝组织中有较强的表达，出生时表达明显降低。其表达主要在未成熟肝细胞中表达，随着分化程度的增加，其表达明显减弱。重组HDGF可促进原代培养胎肝细胞的生长。腺病毒介导的HDGF反义基因可显著抑制胎肝细胞的增殖。外源HDGF可恢复HDGF反义病毒的生长抑制作用。肝细胞生长因子在部分Hepat…肝再生中的诱导表达更多的切除和CCl_4所致的肝损伤。在两种模型中，HDGF的表达都是在DNA合成高峰之前被诱导的。在再生肝中，HDGF基因主要在肝实质细胞中表达。提示HDGF作为一种自分泌因子在肝脏发育和再生中发挥重要作用，尤其是在肝细胞增殖中起重要作用。接下来，我们研究了HDGF在肝细胞癌发生中的作用。在人肝细胞癌组织中，与癌旁组织相比，肝细胞癌组织中HDGF mRNA和蛋白的表达均升高。在大鼠肝癌变模型中，免疫印迹和免疫组织化学显示HDGF在FLS小鼠和CDAA饲养的大鼠肝细胞癌组织中的表达明显高于非癌组织。在FLS小鼠出生后的增龄过程中，HDGF mRNA的表达早于肝细胞癌的发生发展，高表达灶(Hef)也出现在肝细胞癌发生前的阶段。苏木精-伊红染色不能将HEF与正常肝细胞区分开来。提示HDGF可作为癌前病变的标志物，在肝癌的发生发展过程中发挥重要作用。较少

项目成果

Enomoto H.,Kishima Y. et al.: "Hepatoma-derived growth factor : Involvement in liver development and regeneration"Hepatology and Gastroenterology. (発表予定).

Enomoto H.、Kishima Y. 等人：“肝癌衍生生长因子：参与肝脏发育和再生”肝病学和胃肠病学（待提交）。

Enomoto H., Yoshida K., Kishima Y., Okuda Y., Nakamura H.: "Participation of hepatoma-derived growth factor (HDGE) in the regulation of fetal hepatocyte proliferation"Journal of Gastroenterology. (in press). (2002)

Enomoto H.、Yoshida K.、Kishima Y.、Okuda Y.、Nakamura H.：“肝癌源性生长因子（HDGE）参与胎儿肝细胞增殖的调节”胃肠病学杂志。

Enomoto H., Yoshida K., Kishima Y., Okuda Y., Nakamura H.: "Participation of hepatoma-derived growth factor (HDGF) in the regulation of fetal hepatocyte proliferation"Journal of Gastroenterology. (in press). (2002)

Enomoto H.、Yoshida K.、Kishima Y.、Okuda Y.、Nakamura H.：“肝癌衍生生长因子（HDGF）参与胎儿肝细胞增殖的调节”胃肠病学杂志。

Kishima Y, Yoshida K., Enomoto H., Yamamoto M., Kuroda T., Okuda Y., Uyama H., Yoshizaki K., Nakamura H.: "Antisense oligonucleotides of hepatoma-derived growth factor (HDGF) suppress the proliferation of hepatoma cells"Hepato-Gastroenterol. (in press). (

Kishima Y、Yoshida K.、Enomoto H.、Yamamoto M.、Kuroda T.、Okuda Y.、Uyama H.、Yoshizaki K.、Nakamura H.：“肝细胞源性生长因子 (HDGF) 的反义寡核苷酸抑制增殖

Kishima Y., Yoshida K., Enomoto H., Yamamoto M., Kuroda T., Okuda Y., Uyama H., Yoshizaki K., Nakamura H.: "Antisense oligonucleotides of hepatoma-derived growth factor (HDGF) suppress the proliferation of hepatoma cells"Hepato-Gastroenterol.. (in press).

Kishima Y.、Yoshida K.、Enomoto H.、Yamamoto M.、Kuroda T.、Okuda Y.、Uyama H.、Yoshizaki K.、Nakamura H.：“肝细胞源性生长因子 (HDGF) 的反义寡核苷酸抑制