Recombinant adenovirus carrying the hepatocyte nuclear factor-1alpha gene inhibits hepatocellular carcinoma xenograft growth in mice
| Autor: | Qing Zhang, Wei-Fen Xie, Jun-Ping Zhang, Lei Qiu, Bei-Fang Ning, Yong Lin, Xiao-Ran Qin, Chuan Yin, Xin Zeng, Xin Zhang, Yue-Xiang Chen |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Male
endocrine system Pathology medicine.medical_specialty Carcinoma Hepatocellular Transplantation Heterologous Adenoviridae Mice Antigens CD Antigens Neoplasm Differentiation therapy Cell Line Tumor medicine Animals Humans AC133 Antigen Hepatocyte Nuclear Factor 1-alpha Clonogenic assay Glycoproteins Hepatocyte differentiation Severe combined immunodeficiency Hepatology Cluster of differentiation biology Liver Neoplasms Cell Cycle Checkpoints Transforming growth factor beta Epithelial Cell Adhesion Molecule medicine.disease digestive system diseases MicroRNAs medicine.anatomical_structure p21-Activated Kinases Cell culture Hepatocyte biology.protein Cancer research Peptides Cell Adhesion Molecules Neoplasm Transplantation |
| Zdroj: | Hepatology. 54:2036-2047 |
| ISSN: | 0270-9139 |
| Popis: | Hepatocyte nuclear factor-1alpha (HNF1a) is one of the key transcription factors of the HNF family, which plays a critical role in hepatocyte differentiation. Substantial evidence has suggested that down-regulation of HNF1a may contribute to the development of hepatocellular carcinoma (HCC). Herein, human cancer cells and tumor-associated fibroblasts (TAFs) were isolated from human HCC tissues, respectively. A recombinant adenovirus carrying the HNF1a gene (AdHNF1a) was constructed to determine its effect on HCC in vitro and in vivo. Our results demonstrated that HCC cells and HCC tissues revealed reduced expression of HNF1a. Forced reexpression of HNF1a significantly suppressed the proliferation of HCC cells and TAFs and inhibited the clonogenic growth of hepatoma cells in vitro. In parallel, HNF1a overexpression reestablished the expression of certain liver-specific genes and microRNA 192 and 194 levels, with a resultant increase in p21 levels and induction of G2/M arrest. Additionally, AdHNF1a inhibited the expression of cluster of differentiation 133 and epithelial cell adhesion molecule and the signal pathways of the mammalian target of rapamycin and transforming growth factor beta/Smads. Furthermore, HNF1a abolished the tumorigenicity of hepatoma cells in vivo. Most interestingly, intratumoral injection of AdHNF1a significantly inhibited the growth of subcutaneous HCC xenografts in nude mice. Systemic delivery of AdHNF1a could eradicate the orthotopic liver HCC nodules in nonobese diabetic/severe combined immunodeficiency mice. Conclusion: These results suggest that the potent inhibitive effect of HNF1a on HCC is attained by inducing the differentiation of hepatoma cells into mature hepatocytes and G2/M arrest. HNF1a might represent a novel, promising therapeutic agent for human HCC treatment. Our findings also encourage the evaluation of differentiation therapy for tumors of organs other than liver using their corresponding differentiation-determining transcription factor. (HEPATOLOGY 2011;54:2036-2047) |
| Databáze: | OpenAIRE |
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