Differentiation therapy of hepatocellular carcinoma in mice with recombinant adenovirus carrying hepatocyte nuclear factor-4α gene

Abstract

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 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 anticancer 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 Abbreviations: CSC, cancer stem cell; GFP, green fluorescent protein; HCC, hepatocellular carcinoma; HNF4␣, mRNA, messenger RNA; PBS, PCR, polymerase chain reaction; From the

The reprogramming factors of human somatic cells are novel targets for human hepatocellular carcinoma therapy

“…Therefore, first, I reviewed the gene expression of the four factors between human iPS cells established from healthy humans by using the four factors 2,3 and human hepatoma cells. 1 As a result, the gene expression levels of c-Myc and Klf4 were lower than that of Oct3/4 and Sox2 in human iPS cells. 2,3 However, the gene expression levels of c-Myc and Klf4 were higher than that of Oct3/4 and Sox2 in Hep3B and HepG2 human hepatoma cell lines.…”

“…2,3 However, the gene expression levels of c-Myc and Klf4 were higher than that of Oct3/4 and Sox2 in Hep3B and HepG2 human hepatoma cell lines. 1 On the other hand, the relative ratio of Oct3/4 and Sox2 was 1:1 in human iPS cells derived from neonatal foreskin fibroblasts, adult dermal fibroblasts, and CD 34ϩ mobilized human peripheral blood cells, generally. 2,3 However, for example, the relative ratio of Oct3/4 and Sox2 was 4:1 in Hep3B or HepG2 cells, generally.…”

“…I read with interest the article by Yin et al 1 on differentiation therapy of hepatocellular carcinoma (HCC). The study by Yin et al 1 showed that a differentiation therapy with hepatocyte nuclear factor 4 alpha induced the differentiation of hepatoma cells into hepatocytes by the dramatic decrease of gene expression of four transcription factors (Oct3/4 [octamer 3/octamer 4], Sox2 [sexdetermining region Y box 2], Klf4 [Kruppel-like factor 4], and c-Myc) which are known reprogramming factors.…”

“…The study by Yin et al 1 showed that a differentiation therapy with hepatocyte nuclear factor 4 alpha induced the differentiation of hepatoma cells into hepatocytes by the dramatic decrease of gene expression of four transcription factors (Oct3/4 [octamer 3/octamer 4], Sox2 [sexdetermining region Y box 2], Klf4 [Kruppel-like factor 4], and c-Myc) which are known reprogramming factors. [2][3][4] The results by Yin et al 1 may be helpful in order to understand the differences between human induced pluripotent stem (iPS) cells and human hepatoma cells or to develop novel HCC therapy. Therefore, first, I reviewed the gene expression of the four factors between human iPS cells established from healthy humans by using the four factors 2,3 and human hepatoma cells.…”

“…2,3 However, for example, the relative ratio of Oct3/4 and Sox2 was 4:1 in Hep3B or HepG2 cells, generally. 1 Thus, the gene expression levels of the four factors or the relative ratio of Oct3/4 and Sox2 in human hepatoma cells were inappropriate in comparison with the cases of human iPS cells. Therefore, I found that the differences between human iPS cells and human hepatoma cells can be explained by the gene expression levels of the four factors or the relative ratio of Oct3/4 and Sox2.…”