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 [sex-determining region Y box 2], Klf4 [Kruppel-like factor 4], and c-Myc) which are known reprogramming factors.2–4 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 factors2, 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.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 34+ 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.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.
On the other hand, a recent study showed that gene expression for the four factors in human cancers was overexpressed compared to normal tissues and the expression levels were associated with tumor progression or bad prognosis.5 Furthermore, after undergoing the differentiation therapy of Yin et al.,1 the gene expression levels of c-Myc and Klf4 became lower than that of Oct3/4 and Sox2. This was comparable to the cases of human iPS cells.
Therefore, if the gene expression levels for the four factors in human hepatoma cells can be decreased and can be compared with the levels in human normal cells and/or tissues, the efficacy of human HCC therapy could be increasingly improved. Furthermore, the gene expression levels for the four factors may serve as a basis for detecting and/or monitoring the effect of potential therapeutic agents on human HCC.
In conclusion, the four factors are not only reprogramming factors of human somatic cells but also novel targets for human HCC therapy.