Dedifferentiation of hepatocellular carcinoma: molecular mechanisms and therapeutic implications

Hepatocellular carcinoma (HCC) is a common cancer with high morbidity and mortality. Poorer differentiation status indicates worse prognosis of HCC patients. Regain of better differentiation status may improve the prognosis. Differentiation therapy for HCC is based on the fact that agents may reverse the dedifferentiation process from hepatocytes to HCC cells and thus improve tumor differentiation status. Reversal of progenitor-like property and restoration of hepatic characteristics are main objectives of HCC differentiation therapy. Comprehending the mechanisms of HCC dedifferentiation provides ideas for drug design. Diverse dysregulated molecules and signalings cooperatively cause HCC dedifferentiation. Dysregulation of liver enriched transcription factors, especially hepatocyte nuclear factor 4 alpha, was a critical determinant of HCC dedifferentiation. Aberrant pivotal signaling molecules such as transforming factor-beta, beta-catenin and Yes-associated protein caused disordered signalings, which promoted HCC dedifferentiation. Loss of epithelial morphology during epithelial-mesenchymal transition (EMT) concurred with HCC dedifferentiation. Some EMT-related molecules exerted double-sided role in concurrently inducing EMT and HCC dedifferentiation. Besides, microRNAs (e.g. miR-122 and miR-148a) as well as some impressive proteins (i.e. KLF4, gankyrin and CHD1L) functioned in manipulating HCC differentiation status. Restoring normal expression levels of these molecules could induce HCC differentiation and inhibited malignant tumor behaviors. Based on the knowledge above, some agents have been found effective in lab, but need more data to support their reliability. Additionally, peretinoin as a potential drug is in progress of several phase III clinical trials. It's promising that differentiation therapy for HCC may be a part of options in future HCC treatment.