SUMMARY The human gene PTPN11, which encodes the tyrosine phosphatase Shp2, may act as a proto-oncogene, as dominantly activating mutations have been detected in several types of leukemia. Herein we report a tumor suppressor function of Shp2. Hepatocyte-specific deletion of Shp2 promotes inflammatory signaling through the Stat3 pathway and hepatic inflammation/necrosis, resulting in regenerative hyperplasia and development of tumors in aged mice. Furthermore, Shp2 ablation dramatically enhanced diethylenenitrite (DEN)-induced hepatocellular carcinoma (HCC) development, which was abolished by concurrent deletion of Shp2 and Stat3 in hepatocytes. Decreased Shp2 expression was detected in a sub-fraction of human HCC specimens. Thus, in contrast to the leukemogenic effect of dominant active mutants, PTPN11/Shp2 has a tumor suppressor function in liver.

Invasiveness underlies cancer aggressiveness and is a hallmark of malignancy. Most malignant tumors have elevated levels of Tn, an O-GalNAc glycan. Mechanisms underlying Tn up-regulation and its effects remain unclear. Here we show that Golgi-to-endoplasmic reticulum relocation of polypeptide N-acetylgalactosamine-transferases (GalNAc-Ts) drives high Tn levels in cancer cell lines and in 70% of malignant breast tumors. This process stimulates cell adhesion to the extracellular matrix, as well as migration and invasiveness. The GalNAc-Ts lectin domain, mediating high-density glycosylation, is critical for these effects. Interfering with the lectin domain function inhibited carcinoma cell migration in vitro and metastatic potential in mice. We also show that stimulation of cell migration is dependent on Tn-bearing proteins present in lamellipodia of migrating cells. Our findings suggest that relocation of GalNAc-Ts to the endoplasmic reticulum frequently occurs upon cancerous transformation to enhance tumor cell migration and invasiveness through modification of cell surface proteins.

Ecotropic viral integration site 1 (EVI1) is an oncogenic dual domain zinc finger transcription factor that plays an essential role in the regulation of hematopoietic stem cell renewal, and its overexpression in myeloid leukemia and epithelial cancers is associated with poor patient survival. Despite the discovery of EVI1 in 1988 and its emerging role as a dominant oncogene in various types of cancer, few EVI1 target genes are known. This lack of knowledge has precluded a clear understanding of exactly how EVI1 contributes to cancer. Using a combination of ChIP-Seq and microarray studies in human ovarian carcinoma cells, we show that the two zinc finger domains of EVI1 bind to DNA independently and regulate different sets of target genes. Strikingly, an enriched fraction of EVI1 target genes are cancer genes or genes associated with cancer. We also show that more than 25% of EVI1-occupied genes contain linked EVI1 and activator protein (AP)1 DNA binding sites, and this finding provides evidence for a synergistic cooperative interaction between EVI1 and the AP1 family member FOS in the regulation of cell adhesion, proliferation, and colony formation. An increased number of dual EVI1/AP1 target genes are also differentially regulated in late-stage ovarian carcinomas, further confirming the importance of the functional cooperation between EVI1 and FOS. Collectively, our data indicate that EVI1 is a multipurpose transcription factor that synergizes with FOS in invasive tumors. E cotropic viral integration site 1 (EVI1) is a zinc finger (ZNF) transcription factor (TF), and its overexpression in myeloid leukemia (1-3) and epithelial cancers (1, 2, 4-9) has been extensively studied and correlated with adverse patient outcome (7, 10, 11). EVI1 also controls several aspects of embryonic development, including hematopoiesis, angiogenesis, and heart and neural development (12). Three major alternative splice forms of the MDS1 and EVI1 complex locus (MECOM) locus have been identified, including EVI1, EVI1Δ324, and MDS1-EVI1. The PRDI-BF1 and RIZ homology domain containing Myelodysplastic syndrome (MDS)1-EVI1 isoform acts as a tumor suppressor gene, whereas the shorter isoforms, EVI1 and EVI1Δ324, that lack this domain display oncogenic functions (13). The most oncogenic isoform, EVI1, encodes a 1,051-aa protein containing two DNA binding ZNF domains of seven and three motifs. The N-terminal ZNF domain binds to a GATA-like consensus motif (14), whereas the distal ZNF domain binds to an v-ets erythroblastosis virus E26 oncogene homolog (ETS)-like motif (15). EVI1Δ324 lacks ZNFs motifs 6 and 7, which prevents its binding to GATA-like sites.Despite its discovery in 1988 (16, 17), very few EVI1 target genes have been identified, and most of these loci are known to be bound by EVI1 . This lack of knowledge regarding the genes transcriptionally regulated by EVI1 has precluded a complete understanding of EVI1's role in development and cancer. In general, these biological processes are triggered by gene expression changes coordinate...

The most common risk factor for developing hepatocellular carcinoma (HCC) is chronic infection with hepatitis B virus (HBV). To better understand the evolutionary forces driving HCC we performed a near saturating transposon mutagenesis screen in a mouse HBV model of HCC. This screen identified 21 candidate early stage drivers, and a bewildering number (2860) of candidate later stage drivers, that were enriched for genes mutated, deregulated, or that function in signaling pathways important for human HCC, with a striking 1199 genes linked to cellular metabolic processes. Our study provides a comprehensive overview of the genetic landscape of HCC.