Dysregulation of Bmi1 promotes malignant transformation of hepatic progenitor cells.
Dysregulation of Bmi1 promotes malignant transformation of hepatic progenitor cells.
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Bmi1失调促进肝祖细胞恶性转化
DOI：
10.1038/oncsis.2016.6
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发表时间：
2016-02-29
期刊：
影响因子：
6.2
通讯作者：
Liu, C.
中科院分区：
文献类型：
--
作者：
Zhang, R.;Wu, W. R.;Shi, X. D.;Xu, L. B.;Zhu, M. S.;Zeng, H.;Liu, C.
成体肝祖细胞（HPC）参与了广泛的人类肝脏疾病，包括肝细胞癌（HCC）。据报道，Bmi 1在干细胞自我更新和致癌中具有重要作用。我们先前已经证明Bmi 1在伴有胆管癌栓的HCC中上调，胆管癌栓是HCC的一种亚型，其特征在于肝干细胞标志物的大量表达。然而，Bmi 1在HPC中的功能尚未得到很好的阐明。本研究旨在探讨Bmi 1对大鼠HPC生物学特性的影响。为了实现这一点，Bmi 1沉默或增强在两个HPC细胞系（WB-F344和OC 3），分别使用小干扰RNA对Bmi 1或强制Bmi 1表达逆转录病毒载体。通过细胞增殖试验、集落形成试验、细胞周期分析和侵袭试验以及异种移植物形成试验研究了Bmi 1在HPC中的生物学功能。在这项研究中，Bmi 1基因缺失抑制细胞增殖，集落形成和侵袭在两个评估的HPC细胞系相对于对照。相反，在两种HPC细胞系中强制表达Bmi 1促进细胞增殖、集落形成和体外侵袭。醛脱氢酶（ALDH）检测显示，ALDH阳性细胞的数量显着增加后，强制表达Bmi 1在HPC。最重要的是，将强制表达Bmi 1的HPC移植到裸鼠中导致形成具有低分化HCC的组织学特征的肿瘤。综上所述，我们的研究结果表明，Bmi 1的强制表达促进了HPC的恶性转化，这表明Bmi 1可能是治疗HCC的潜在分子靶点。
Adult hepatic progenitor cells (HPCs) are involved in a wide range of human liver diseases, including hepatocellular carcinoma (HCC). Bmi1 has been reported to have vital roles in stem cell self-renewal and carcinogenesis. We have previously demonstrated that Bmi1 is upregulated in HCC with bile duct tumor thrombi, a subtype of HCC characterized by profuse expression of hepatic stem cell markers. However, the function of Bmi1 in HPCs has not yet been well elucidated. The current study was designed to investigate the effects of Bmi1 on the biological properties of rat HPCs. To accomplish this, Bmi1 was silenced or enhanced in two HPC cell lines (WB-F344 and OC3) by, respectively, using either small interfering RNA against Bmi1 or a forced Bmi1 expression retroviral vector. The biological functions of Bmi1 in HPCs were investigated through cell proliferation assays, colony-formation assays, cell cycle analysis and invasion assays, as well as through xenograft-formation assays. In this study, genetic depletion of Bmi1 repressed cell proliferation, colony formation and invasion in both assessed HPC cell lines relative to controls. Conversely, forced expression of Bmi1 in two HPCs cell lines promoted cell proliferation, colony formation and invasion in vitro. Aldehyde dehydrogenase (ALDH) assay revealed a significant increase in the number of ALDH-positive cells following the forced expression of Bmi1 in HPCs. Most importantly, transplantation of forced Bmi1 expression HPCs into nude mice resulted in the formation of tumors with histological features of poorly differentiated HCC. Taken together, our findings indicate that forced expression of Bmi1 promotes the malignant transformation of HPCs, suggesting Bmi1 might be a potential molecular target for the treatment of HCC.
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