Lazarevich N L, Shavochkina D A, Fleishman D I, Kustova I F, Morozova O V, Chuchuev E S, Patyutko Y I
Department of Immunochemistry, Institute of Carcinogenesis, NN Blokhin Russian Cancer Research Center, Kashirskoye sh 24, Moscow 115478, Russia.
Exp Oncol. 2010 Sep;32(3):167-71.
Tissue-specific transcription factors forming the regulatory cascades which determine the specification and differentiation of epithelial cells during embryogenesis, play the central role in the control of functional and morphological properties of different cell types. Hepatocyte nuclear factors (HNFs) network is one of the most investigated tissue-specific regulatory systems which controls the specification and maintenance of differentiation of several epithelial cell types. Nuclear receptor HNF4α is one of the central elements of this regulatory network in the liver. We have found that deregulation of this gene is associated with rodent and human hepatocellular carcinoma (HCC) progression and induces the increase of proliferation rate, loss of epithelial morphology, dedifferentiation and metastasis. Restoration of HNF4α expression in dedifferentiated cells induced partial reversion of highly malignant phenotype both in vitro and in vivo. In human HCC samples HNF4α transcription was completely lost or significantly decreased in about 70% of HCCs, not associated with hepatitis B virus infection. Decrease of HNF4α isoforms expression correlated with poor prognosis. Thus we propose HNF4α is a candidate tumor suppressor for hepatic cells. Dysfunction of different HNFs was also reported in other epithelial tumors. We suppose that tissue-specific transcription factors which control the key steps of definite differentiation programs and are capable to receive and modulate extracellular signals can be considered as promising tumor suppressor candidates for their corresponding tissues.
组织特异性转录因子形成调节级联，决定胚胎发育过程中上皮细胞的特化和分化，在控制不同细胞类型的功能和形态特性方面发挥核心作用。肝细胞核因子（HNFs）网络是研究最多的组织特异性调节系统之一，它控制着几种上皮细胞类型的特化和分化维持。核受体HNF4α是肝脏中这个调节网络的核心元件之一。我们发现该基因的失调与啮齿动物和人类肝细胞癌（HCC）的进展相关，并导致增殖率增加、上皮形态丧失、去分化和转移。在去分化细胞中恢复HNF4α表达在体外和体内均诱导高度恶性表型的部分逆转。在人类HCC样本中，约70%的HCC中HNF4α转录完全丧失或显著降低，且与乙型肝炎病毒感染无关。HNF4α亚型表达的降低与预后不良相关。因此我们提出HNF4α是肝细胞的候选肿瘤抑制因子。在其他上皮肿瘤中也报道了不同HNFs的功能障碍。我们认为，控制特定分化程序关键步骤并能够接收和调节细胞外信号的组织特异性转录因子可被视为其相应组织有前景的候选肿瘤抑制因子。
