Figure 6. Overall mechanism of HCC progression from stage I to stage IV via miRNA deregulation and DNA methylation.

Figures 3 to 5 summarize the overall mechanism of HCC progression from stage I to stage IV. The pathway members are all influenced by miRNA regulation and/or epigenetic DNA methylation; the members in brown were only affected by miRNA. miRNA deregulation and DNA methylation lead to distortion of the ErbB and MAPK signaling pathways, inducing distortions in the cell cycle, apoptosis, and cell proliferation processes, resulting in the progression of HCC from stage I to stage II. Similarly, induced distortions in the MAPK and TGF-β signaling pathway caused metastasis and cell cycle, apoptosis, and cell proliferation dysfunction, resulting in HCC progression from stage II to stage III. miRNA dysregulation and DNA methylation changes were also responsible for distortions in the MAPK, TGF-β, and JAK-STAT signaling pathways, resulting in metastasis and cell cycle, apoptosis, and cell proliferation dysfunction, which in turn induces HCC progression from stage III to stage IV. As a whole, miRNA and DNA methylation dysregulation of the various downstream genes in tumor cells could induce changes in the various signaling pathways, resulting in aberrant cell response, which favors HCC progression.