Hepatocellular carcinoma (HCC) is a major health care problem worldwide. The prognosis of patients with HCC is poor because even in the early stages when surgical treatment might be expected to be curative, the incidence of recurrence in patients with underlying
cirrhosis is very high due to multicentric
carcinogenesis. Therefore, strategies to prevent recurrence and second primary HCC are required to improve the prognosis. One of the most practical approaches to prevent the multicentric development of HCC is 'clonal deletion'
therapy, which is defined as the removal of latent (i.e. invisible) (pre)malignant clones from the liver in a hypercarcinogenic state.
Retinoids, a group of structural and functional analogs of
vitamin A, exert their
biological function primarily through two distinct
nuclear receptors,
retinoic acid receptors and
retinoid X receptors (RXR), and abnormalities in the expression and function of these receptors are highly associated with the development of various
cancers, including HCC. In particular, a malfunction of RXRalpha due to phosphorylation by the Ras-
mitogen-activated protein kinase signaling pathway is profoundly associated with the development of HCC and thus may be a critical target for HCC
chemoprevention.
Acyclic retinoid, which has been clinically shown to reduce the incidence of a post-therapeutic recurrence of HCC, can inhibit Ras activity and phosphorylation of the
extracellular signal-regulated kinase and RXRalpha
proteins. 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 strategy for HCC
chemoprevention and clonal deletion.
Acyclic retinoid, which targets phosphorylated RXRalpha, may thus play a critical role in preventing the development of multicentric HCC.