Highlights of This Issue

Abstract

Mixed lineage leukemia (MLL) gene–associated disease accounts for more than 70% of infantile and 5% to 10% of acute leukemias and often has a poor prognosis. Although a number of microRNA signatures have been exposed using molecular profiling, only a few of them have been investigated for their regulatory mechanism in the context of MLL-associated leukemia. Bousquet and colleagues discovered a new MLL-leukemic tumor suppressor, miR-150, that exerts profound antileukemic effects in MLL-associated disease. Expression of miR-150 inhibited blast colony formation and cellular growth and induced apoptosis in vitro, whereas in vivo transplantation studies determined that miR-150 blocked the transforming properties of the MLL–AF9 fusion protein. Using genomic profiling, it was determined that miR-150 modulates an entire leukemic network and that knockdown of two newly identified miR-150 targets, Cbl and Egr2, recapitulated the mir-150–induced apoptosis. The findings of this study identify miR-150 as a potent tumor suppressor that impinges upon multiple oncogenes in MLL-associated leukemia.The key cell-cycle regulators p14ARF and p16INK4A are encoded by the IN4A–ARF locus, which is frequently altered in many cancers. It has long been suspected that the unusual organization of these two alternative transcripts from the same locus might reflect their coordinate regulation. In this Rapid Impact article, Kobayashi and colleagues demonstrate that ARF regulates p16 protein expression levels by influencing its protein stability. Notably, the reciprocal relationship of ARF and p16 is associated with disease outcome in at least two major tumor types, namely bladder and prostate. ARF regulates p16 stability through a REGγ-dependent proteasome degradation mechanism. These data provide significant insight into the coordinate roles of ARF and p16 in cancer, as well as the role of ARF-mediated regulation of proteasome degradation and cell-cycle and growth control.Helicobacter pylori bacterial infections are fairly common worldwide and are often asymptomatic but are strongly implicated in diseases involving the human gastric mucosa. However, the mechanism through which H. pylori promotes gastric disease is still unclear. Feng and colleagues show that the transcriptional activator FoxM1 is increased, whereas miR-370 is decreased as a function of human gastric disease stage. H. pylori infection or its key virulence factor CagA were sufficient to upregulate FoxM1 and downregulate the cell-cycle inhibitor p27Kip1 (CDKN1B), which promoted cellular proliferation. H. pylori and CagA increased FoxM1 expression by downregulating miR-370, which was shown to directly target FoxM1. These authors are the first to report that H. pylori or CagA may induce gastric carcinogenesis through upregulation of FoxM1 in a miR-370-dependent manner and suppress p27Kip1 to promote cellular proliferation.Lung cancer is the most common cause of cancer-related death in the world, and development of new molecular targeting drugs is urgently awaited. Systematic screening identified Ras and EF-hand domain containing (RASEF) as transactivated in the majority of lung cancers. Oshita and colleagues validate the elevated expression of RASEF in clinical lung specimens and show that its strong expression is associated with poor prognosis. Furthermore, RASEF promotes lung cancer cell growth through its interaction with extracellular signal–regulated kinase (ERK) 1/2. Critically, inhibition of the interaction between RASEF and ERK1/2 using a cellpermeable peptide, corresponding to the ERK1/2-interacting site of RASEF, suppressed growth of lung cancer cells. Overall, RASEF could be a prognostic biomarker, and its interaction with ERK 1/2 could be a new molecular target.