These data further demonstrated that the tumorigenic potential was restored in the reprogrammed ES-Hepa hybrids upon differentiation. TABLE 2 Tumorigenic selleck Veliparib potential of ES cells, Hepa1�C6 cells, ES-lymphocyte hybrids, and ES-Hepa hybrids (D0, D7, and D14) DISCUSSION Silencing of p16INK4a is a common event in both human and mouse cancers through losing control of cell cycle arrest and abnormal cell proliferation (32). Early epigenetic events that occur in the silencing course of p16INK4a may be considered to predict cancer development, thus providing means for pre-diagnosis. In the current study, epigenetic silencing of p16INK4a in mouse HCC cells can be reactivated by fusion with mouse embryonic stem cells.

Upon differentiation, the hybrid regained the original histone methylation pattern of the p16INK4a silencing program, associated with a strong tumorigenic potential after transplanted subcutaneously into the immunodeficient nude mice. Because the early epigenetic events in silencing of p16INK4a remain largely unknown, our study provides novel insights in this course. We still do not know the specific reasons why the differentiated reprogrammed cancer cells re-established malignant programs like the former cancer cells. In our speculation, there are two reasons that could explain this fact. First, some genes refuse to be reprogrammed. In this research, c-jun escaped from the reprogramming mode and exhibited an expression level similar to that in Hepa1�C6 cells. The transcription factor c-jun was reported as an essential oncogene in HCC development and progression by cooperation with Ras and repression of p53 in cell proliferation and anti-apoptosis (33).

The anti-reprogramming effect of c-jun revealed it might be one of the genes that contribute to the tumorigenic course of the ES-Hepa hybrids upon differentiation. AV-951 Second, genetic mutations in cancer cells cannot be changed by means of epigenetic reprogramming effects. These inappropriate intrinsic genetic alterations inside a cell may predispose the cell to malignant epigenetic modulations after response to the extrinsic signals. The bidirectional cellular communication with the microenvironment of the cancer cell is related to the ability of progression and development. Previous studies have proven that embryonic microenvironments would change aggressive cancer malignancy by reducing tumorigenesis and metastasis (34,�C36). Tumors may develop in a particular developmental pattern, in which epigenetic modulation may contribute to tumorigenesis through its effects on differentiation.