Survival and apoptosis: a dysregulated balance in liver cancer

Dysregulation of the balance between proliferation and cell death represents a protumorigenic principle in human hepatocarcinogenesis. This article aims to provide a review of the current findings about how physiological hepatocyte apoptosis is regulated and whether or not its dysregulation might contribute to the progression towards a hepatocellular carcinoma (HCC) process.

Although some physiological proapoptotic molecules are downregulated or inactivated in HCC, such as Fas, p53, Bax or Bid, dysregulation of the balance between death and survival is mainly due to overactivation of antiapoptotic signals. Thus, some growth factors that mediate cell survival are upregulated in HCC, as well as the molecules involved in the machinery responsible for cleavage of their proforms to an active peptide. The expression of the pten gene is reduced or absent in almost half the HCCs and the Spred family of Ras/ERK inhibitors is also dysregulated in HCC, which consequently lead to the overactivation of relevant survival kinases: AKT and ERKs. Alterations in the expression and/or activity of molecules involved in counteracting apoptosis, such as NF-kappaB, Bcl-X(L), Mcl-1 or c-IAP1, have also been observed in HCC.

Therefore, therapeutic strategies to inhibit selectively antiapoptotic signals in tumour cells have the potential to provide powerful tools to treat liver cancer.