Conflicting Roles of Molecules in Hepatocarcinogenesis: Paradigm or Paradox

Abstract

Summary In delineating the molecular pathogenesis of hepatocellular carcinoma (HCC), recent experiments on mouse tumor models have revealed unexpected tumor-suppressing effect in genes previously identified as pro-oncogenic. This contradiction underscores the complexity of hepatocarcinogenesis and predicts uncertainty in targeting these molecules for HCC therapy. Deciphering the underlying mechanisms for these paradoxical functions will elucidate the complex molecular and cellular communications driving HCC development, and will also suggest more thoughtful therapeutic strategies for this deadly disease.

Acquisition of an immunosuppressive protumorigenic macrophage phenotype depending on c-Jun phosphorylation

“…One concept emerging from these studies is that JNK signaling in hepatocytes promotes survival of hepatocytes via abrogating p53-induced apoptosis and up-regulation of c-Myc (22,24). Interestingly, JNK signaling was shown to play opposing roles in DEN-induced HCC; whereas deletion of JNK1 and JNK2 in both hepatocytes and nonparenchymal cells resulted in reduced tumorigenesis, deletion of these isoforms in hepatocytes alone increased tumorigenesis (20,31). The JNK1/2 targets that It is now well appreciated that mouse models of inflammationinduced HCC are significantly different from carcinogen models (20).…”

“…However, JNK functions in cancer have been difficult to predict because JNK is involved both in cell proliferation and cell survival as well as in cell death (19). The role of JNK kinases in HCC is controversial, with different models showing protumorigenic and antitumorigenic roles for JNK (20). We therefore set out to study the role of c-Jun N-terminal phosphorylation (JNP) in inflammationassociated HCC.…”

Overexpression of the Transcription Factor MEF2D in Hepatocellular Carcinoma Sustains Malignant Character by Suppressing G2–M Transition Genes

“…However, current knowledge about molecular pathogenesis of hepatocellular carcinoma is far from complete elucidation. Therefore, identification of new genes participating in hepatocarcinogenesis is critical for the development of novel targeted therapeutic strategies in hepatocellular carcinoma (5).…”

Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis

“…Abnormal activation of the Wnt/β-catenin pathway causes many types of tumors in humans including hepatoblastoma and HCC (27). In mice, hepatocyte-specific expression of active β-catenin resulted in hepatomegaly and HCC development when induced by the chemical carcinogen diethylnitrosamine (DEN) (27)(28)(29)(30), and DEN injection is required in many genetic liver tumor models (1,31). Importantly, HCC forms in 100% of Mst1/2 double-mutant mouse livers by the age of 4 months, without chemical induction, while 50% of transgenic mice overexpressing TGF-α or E2F1 develop HCCs when older than 12 months (32,33).…”