Micol Ravà

The molecular mechanisms and pathways responsible for the progression of hepatocellular carcinoma (HCC) remain to be fully characterized. Among the genetic lesions associated with HCC progression, Shukla et al. (2013) identified insertions of the L1 transposon proximal to the gene encoding the zinc-finger DNA-binding protein ST18 (suppression of tumorigenicity 18) and suggested that this actually functions as an oncogene in HCC. However, functional evidence for a cancer-promoting activity of ST18 and insight into its mode of action are missing. Here, I pursued the functional characterization of ST18 in a mouse model of HCC based on ex vivo transformation and subcutaneous transplantation of embryonic hepatoblasts. ST18 was undetectable in either normal liver or cultured hepatoblasts, but was induced in the subcutaneous tumors. ST18 was also expressed in either chronically or acutely inflamed mouse livers (as assessed in Mdr2-/- or LPS-treated mice) as well as in human Progressive Familial Intrahepatic Cholestasis 2 (PFIC2: a condition associated with chronic inflammation), suggesting its induction by inflammatory stimuli. The knockdown of ST18 delayed tumor formation or, if induced in already formed tumors, led to rapid hemorrhage, pervasive morphological changes in the tumor cells reminiscent of an epithelial-to-mesenchymal transition (EMT) and eventually tumor regression. RNA profiling revealed that ST18 silencing caused expression of EMT-associated genes, among others. Previous studies have linked inflammation to the induction of EMT in other epithelia: we hypothesize that the concomitant activation of ST18 constitutes a safeguard against EMT, inactivation of this control mechanism causing the dramatic phenotypic switch observed in our model. These data warrant further evaluation of the mode of action of ST18 and of its potential value as a therapeutic target in HCC.