Malignant transformation, invasion and angiogenesis rely on the coordinated reprogramming of gene expression in the cells from which the tumor originated. Although deregulated gene expression has been extensively studied at genomic and epigenetic scales, the contribution of the regulation of mRNA-specific translation to this reprogramming is not well understood. Here we show that cytoplasmic polyadenylation element binding protein 4 (CPEB4), an RNA binding protein that mediates meiotic mRNA cytoplasmic polyadenylation and translation, is overexpressed in pancreatic ductal adenocarcinomas and glioblastomas, where it supports tumor growth, vascularization and invasion. We also show that, in pancreatic tumors, the pro-oncogenic functions of CPEB4 originate in the translational activation of mRNAs that are silenced in normal tissue, including the mRNA of tissue plasminogen activator, a key contributor to pancreatic ductal adenocarcinoma malignancy. Taken together, our results document a key role for post-transcriptional gene regulation in tumor development and describe a detailed mechanism for gene expression reprogramming underlying malignant tumor progression.

We have identified a sine oculis gene in the planarian Girardia tigrina (Platyhelminthes; Turbellaria; Tricladida). The planarian sine oculis gene (Gtso) encodes a protein with a sine oculis (Six) domain and a homeodomain that shares significant sequence similarity with so proteins assigned to the Six-2 gene family. Gtso is expressed as a single transcript in both regenerating and fully developed eyes. Whole-mount in situ hybridization studies show exclusive expression in photoreceptor cells. Loss of function of Gtso by RNA interference during planarian regeneration inhibits eye regeneration completely. Gtso is also essential for maintenance of the differentiated state of photoreceptor cells. These results, combined with the previously demonstrated expression of Pax-6 in planarian eyes, suggest that the same basic gene regulatory circuit required for eye development in Drosophila and mouse is used in the prototypic eye spots of platyhelminthes and, therefore, is truly conserved during evolution.homeobox ͉ eye morphogenesis ͉ platyhelmint ͉ eye evolution T he study of the genetic network that regulates the development of the Drosophila visual system has resulted in the identification of several transcription factors and other nuclear proteins that are required for the specification of early eye morphogenesis (1-4). These factors seem to act in a hierarchy in which sine oculis (so) is regulated directly by Pax-6 (5, 6), the master control function. In turn, so requires eyes absent (eya), encoding a nuclear protein (7), to induce ectopic eyes (4). This genetic pathway has been established in Drosophila (8), but homologous proteins also regulate eye development in vertebrates, suggesting that this regulatory network is old, is conserved in evolution, and has been adapted to the control of development of different visual systems found in both clades (9). Both the identification and functional characterization of homologous genes in more primitive organisms, such as the platyhelminthes, will help to clarify the age and extent of conservation of this genetic cascade.Sine oculis is a homeobox-containing gene that is required for the development of the visual system in Drosophila (10, 11). A murine homologue, Six3, is expressed in the developing eye (12). In both of these model systems, so and Six are expressed early in eye development as well as in other structures. Combined overexpression of so and eya in Drosophila induces ectopic eyes (4), whereas, in vertebrates, Six3 overexpression results in ectopic lens formation (13,14). Planarians (Platyhelminthes; Turbellaria; Tricladida) are located at the base of the Lophotrochozoa Protostomia clade (15, 16). The eye spots of planarians are one of the most ancestral and simple types of visual systems, close to the prototypic eye proposed by Charles Darwin (see ref.8). The planarian eye spots consist of two cell types: a bipolar nerve cell with a rhabdomere as a photoreceptive structure and a cup-shaped structure composed of pigment cells (17). During head regeneration, new e...