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Juan Su, Pu You,
Jun-Peng Zhao,
Shou-Long Zhang,
Shao-Hua Song,
Zhi-Ren Fu,
Li-Wei Ye,
Xiao-Yuan Zi,
Dong-Fu Xie,
Ming-Hua Zhu,
Yi-Ping Hu
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ABSTRACT: Hepatocellular carcinoma (HCC), the most common primary malignant tumor of the liver, often associated with the dysregulation of transcriptional pathways involved in cell growth and differentiation. The hematopoietically expressed homeobox protein (Hhex) is an important transcription factor throughout liver development and is essential to liver bud formation and hepatoblast differentiation. Here, we report a relationship between Hhex expression and HCC. First, adenovirus-mediated Hhex delivery into the hepatoma cell line, Hepa1-6, resulted in decreased expression of several proto-oncogenes (c-Jun and Bcl2), increased expression of some tumor suppressor genes (P53 and Rb), and enhanced expression of a cluster of hepatocytic and bile ductular markers. Second, Hhex expression significantly attenuated Hepa1-6 tumorigenicity in nude mice. Third, we report a correlation between Hhex expression and the differentiation state of human HCC. In 24 cases of clinical specimens, there was a significant difference in Hhex expression between poorly differentiated HCC and well-differentiated HCC (P < 0.001). Taken together, these results indicate that Hhex is a potential candidate molecular marker for HCC pathological evaluation, suggesting a need to evaluate Hhex as a potential target for therapeutic intervention.
Medical Oncology 06/2011; 29(2):1059-67. · 2.14 Impact Factor
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Juan Su, Pu You,
Wen-Lin Li,
Xin-Rong Tao,
Hai-Ying Zhu,
Yu-Cheng Yao,
Hong-Yu Yu,
Qing-Wang Han,
Bing Yu,
Fang-Xia Liu,
Jun Xu,
Joseph T Y Lau,
Yi-Ping Hu
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ABSTRACT: During early stage of embryonic development, the liver bud, arising from the foregut endoderm, is the beginning for the formation of future liver three-dimensional structure. While the gene expression profiles associated with this developmental stage have been well explored, the detailed cellular events are not as clear. Epithelial-mesenchymal transition (EMT) was thought to be essential for cell migration in the early vertebrate embryo but seldom demonstrated in human liver development. In this study, we tried to identify the cell populations with both stem cell and EMT features in the human liver bud. Our in situ studies show that the phenotype of EMT occurs at initiation of human liver development, accompanied by up-regulation of EMT associated genes. A human liver bud derived stem cell line (hLBSC) was established, which expressed not only genes specific to both mesenchymal cells and hepatic cells, but also octamer-binding protein 4 (OCT4) and nanog. Placed in appropriate media, hLBSC differentiated into hepatocytes, adipocytes, osteoblast-like cells and neuron-like cells in vitro. When transplanted into severe combined immunodeficiency mice pre-treated by carbon tetrachloride, hLBSC engrafted into the liver parenchyma and proliferated. These data suggests that there are cell populations with stem cell and EMT-like properties in the human liver bud, which may play an important role in the beginning of the spatial structure construction of the liver.
The international journal of biochemistry & cell biology 09/2010; 42(12):2047-55. · 4.89 Impact Factor
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Qian Wang,
Wen-Lin Li, Pu You,
Juan Su,
Ming-Hua Zhu,
Dong-Fu Xie,
Hai-Yin Zhu,
Zhi-Ying He,
Jian-Xiu Li,
Xiao-Yan Ding,
Xin Wang,
Yi-Ping Hu
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ABSTRACT: BMI-1 (B-cell-specific Moloney murine leukemia virus integration site 1), a novel oncogene, has attracted much attention in recent years for its involvement in the initiation of a variety of tumors. Recent evidence showed that BMI-1 was highly expressed in neoplastic skin lesions. However, whether dysregulated BMI-1 expression is causal for the transformation of skin cells remains unknown. In this study, we stably expressed BMI-1 in a human keratinocyte cell line, HaCaT. The expression of wild-type BMI-1 induced the malignant transformation of HaCaT cells in vitro. More importantly, we found that expression of BMI-1 promoted formation of squamous cell carcinomas in vivo. Furthermore, we showed that BMI-1 expression led to the downregulation of tumor suppressors, such as p16INK4a and p14ARF, cell adhesion molecules, such as E-Cadherin, and differentiation related factor, such as KRT6. Therefore, our findings demonstrated that dysregulated BMI-1 could indeed lead to keratinocytes transformation and tumorigenesis, potentially through promoting cell cycle progression and increasing cell mobility.
Journal of Cellular Biochemistry 12/2008; 106(1):16-24. · 2.87 Impact Factor
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ABSTRACT: The liver regenerates by progenitor cells when it is damaged in chronic liver diseases and extensive damage. The progenitor cells, also termed "oval cells" according to their morphological traits, can differentiate into hepatocytes and bile duct cells in vivo. To better understand the transcriptional pattern that accompanies the hepatic differentiation of oval cells, we applied cDNA microarray to analyze the oval cell-derived liver epithelial progenitor cells (LEPCs) during in vitro induced differentiation. Upon exposure to sodium butyrate, a histone deacetylase inhibitor, cultured LEPCs differentiate and express functional hepatocyte markers albumin, tryptophan 2, 3-dioxygenase and alcohol dehydrogenase. For expression profiling, cells were harvested at 6 h, 12 h, 1 d, 3 d and 7 d after exposure to sodium butyrate. After analyzing the microarray data by SOM clustering, total of 796 differentially regulated genes were grouped into 48 clusters. Consistent with the phenotype change of LEPCs after sodium butyrate treatment, many hepatocyte functional genes are revealed by analyzing the clusters containing genes up-regulated through all the time points. The clusters, containing down-regulated genes immediately after the induction, are also analyzed. The microarray data was validated by analyzing the expression of selected genes by quantitative real-time PCR. A set of genes expressed synergistically in these clusters may play a central role during the process of differentiation. Sodium butyrate decreases cyclin B1 and Cdk4 expression, which would be associated with LEPCs growth arrest shortly after treatment. Bmi1, a polycomb group protein, is also down-regulated immediately after treatment and remains at a low level during the induction. These findings highlight the key molecular mechanisms by which sodium butyrate, mediates its effects on cell growth arrest and induction of differentiation. In conclusion, our data reflect a global view of gene expression during hepatic differentiation of LEPCs induced by sodium butyrate.
Frontiers in Bioscience 02/2007; 12:1691-8. · 3.52 Impact Factor
