Differentiation therapy of hepatocellular carcinoma in mice with recombinant adenovirus carrying hepatocyte nuclear factor-4α gene
✍ Scribed by Chuan Yin; Yong Lin; Xin Zhang; Yue-Xiang Chen; Xin Zeng; Hai-Yan Yue; Jun-Liang Hou; Xing Deng; Jun-Ping Zhang; Ze-Guang Han; Wei-Fen Xie
- Publisher
- John Wiley and Sons
- Year
- 2008
- Tongue
- English
- Weight
- 844 KB
- Volume
- 48
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
Previous studies have shown that hepatocyte nuclear factor-4␣ (HNF4␣) is a central regulator of differentiated hepatocyte phenotype and forced expression of HNF4␣ could promote reversion of tumors toward a less invasive phenotype. However, the effect of HNF4␣ on cancer stem cells (CSCs) and the treatment of hepatocellular carcinoma (HCC) with HNF4␣ have not been reported. In this study, an adenovirus-mediated gene delivery system, which could efficiently transfer and express HNF4␣, was generated to determine its effect on hepatoma cells (Hep3B and HepG2) in vitro and investigate the anti-tumor effect of HNF4␣ in mice. Our results demonstrated that forced re-expression of HNF4␣ induced the differentiation of hepatoma cells into hepatocytes, dramatically decreased "stemness" gene expression and the percentage of CD133 ؉ and CD90 ؉ cells, which are considered as cancer stem cells in HCC. Meanwhile, HNF4␣ reduced cell viability through inducing apparent apoptosis in Hep3B, while it induced cell cycle arrest and cellular senescence in HepG2. Moreover, infection of hepatoma cells by HNF4␣ abolished their tumorigenesis in mice. Most interestingly, systemic administration of adenovirus carrying the HNF4␣ gene protected mice from liver metastatic tumor formation, and intratumoral injection of HNF4␣ also displayed significant antitumor effects on transplanted tumor models. Conclusion: The striking suppression effect of HNF4␣ on tumorigenesis and tumor development is attained by inducing the differentiation of hepatoma cells-especially CSCsinto mature hepatocytes, suggesting that differentiation therapy with HNF4␣ may be an effective treatment for HCC patients. Our study also implies that differentiation therapy may present as one of the best strategies for cancer treatment through the induction of cell differentiation by key transcription factors. (HEPATOLOGY 2008;48:1528-1539.)
H epatocellular carcinoma (HCC) is one of the most common cancers worldwide, and in the United States its incidence has increased by more than 90% in the past three decades. 1 Despite great advances in detection and treatment of the disease, the mortality rate remains high-especially in the advanced stage, when the disease is usually diagnosed. Even if anti-cancer therapies could shrink primary and metastatic tumors, such effects are usually transient, and most metastatic cancers relapse frequently.
Recent evidence has demonstrated that tumors are organized in a hierarchy of heterogeneous cell populations with different biologic properties and that the populations consist of cancer stem cells (CSCs), proliferating