Lentiviral vector-based insertional mutagenesis identifies new clinically relevant cancer genes involved in the pathogenesis of hepatocellular carcinoma

We devised a novel insertional mutagenesis approach based on lentiviral vectors to induce hepatocellular carcinoma in three mouse models and identified four novel cancer initiating genes. Two genes are the well characterized Braf and Sos1, while the other two are Fign, encoding an AAA ATPase whose functions are poorly understood, and the complex Dlk1-Dio3 imprinted region which has been recently implicated in cancer and stemness. Activation of Fign or Braf and upregulation of the Dlk1-Dio3 imprinted region are functionally interconnected and may altogether control cell transformation, stemness and energy metabolism. Moreover, all the genes identified play a relevant role in human hepatocarcinogenesis as their expression levels and/or transcriptional signatures induced by their deregulation predict a different clinical outcome in hepatocellular carcinoma patients. These series consists of mRNA expression microarray data (The GeneChip® Mouse Gene 1.0 ST Array, Affymetrix) from 8 non-tumoral liver and 21 hepatocellular carcinoma induced by insertional mutagenesis. LV.ET.LTR was administered to newborn mice with 3 different genetic backgrounds. Hepatocellular carcinomas were induced in all the mouse models. Vector integrations were retrieved form each single liver mass. From 21 liver masses, RNA was collected to perform whole transcriptome analysis.