| [ Summary ] |
The prognosis for patients with hepatocellular carcinoma (HCC) is poor because even in early stage cases when surgical treatment may be expected to be curative, the incidence of recurrence in patients with underlying cirrhosis is very high. Therefore, strategies to prevent recurrence and second primary HCC are required to improve the prognosis for patients with HCC. One of the most practical approaches to prevent the development of HCC is "clonal deletion" therapy, which is defined as the removal of the latent (i. e. invisible) (pre) malignant clones from the livers which are in a hypercarcinogenic state. A malfunction of retinoid X receptor-alpha (RXRalpha) due to phosphorylation by the Ras/MAPK signaling pathway is associated with the development of HCC and thus may be a critical target for HCC chemoprevention. Acyclic retinoid (ACR), which has been shown to reduce the incidence of a post-therapeutic recurrence of HCC, can inhibit the Ras activity and phosphorylation of the RXRalpha protein. The combination of ACR plus interferon or vitamin K2 synergistically inhibited the growth of HCC cells. In conclusion, the inhibition of RXRalpha phosphorylation and the restoration of its physiological function as a master regulator for nuclear receptors may be a potentially effective and critical strategy for HCC chemoprevention. ACR, which targets phosphorylated RXRalpha, may play a critical role in preventing the development of HCC. In addition, the combination therapy using ACR may therefore be effective for chemoprevention of HCC. |