Insights into developmental mechanisms and cancers in the mammalian intestine derived from serial analysis of gene expression and study of the hepatoma-derived growth factor (HDGF)

Abstract

The vertebrate intestine is a model for investigating inductive cellular interactions and the roles of epithelial stem cells in tissue regeneration,and for understanding parallels between development and cancer. We have used serial analysis of gene expression to measure transcript levels across stages in mouse intestine development. The data(http://genome.dfci.harvard.edu/GutSAGE)identify novel differentiation products, potential effectors of epithelial-mesenchymal interactions, and candidate markers and regulators of intestinal epithelium. Transcripts that decline significantly during intestine development frequently are absent from the adult gut. We show that a significant proportion of such genes may be reactivated in human colon cancers. As an example, hepatoma-derived growth factor (HDGF) mRNA is expressed prominently in early gut tissue, with substantially reduced levels after villous epithelial differentiation. HDGF expression is dramatically increased in human colorectal cancers, especially in tumors proficient in DNA mismatch repair, and thus represents a novel marker for a distinctive tumor subtype. HDGF overexpression in fetal intestine explants inhibits maturation,suggesting a role in epithelial differentiation. To investigate the molecular basis for HDGF functions, we isolated components of a nuclear HDGF complex,including heterogeneous nuclear ribonucleoproteins implicated in processing RNA. These genes are regulated in tandem with HDGF during intestine development and one factor, TLS/Fus, is commonly overexpressed in colon cancers. Tumor expression of fetal genes may underlie similarities between developing and malignant tissues, such as self-renewal, invasion and angiogenesis. Our findings also advance understanding of HDGF functions and implicate this developmentally regulated gene in RNA metabolic pathways that may influence malignant behaviors in colorectal cancer.

TheGata5target,TGIF2, defines the pancreatic region by modulating BMP signals within the endoderm

“…This staining clearly overlaps with the domains of expression of Gata5 at similar developmental stages (Weber et al, 2000). Hepatoma derived growth factor [(HDGF); Clone 7C5] (Lepourcelet et al, 2005) showed a weak expression in endodermal cells during gastrulation (Fig. 2B), whereas Xenopus TGIF2 [(xTGIF2); clone 8B1] expression was enriched in dorsal and ventral/anterior endodermal cells at gastrula and neurula stages, respectively ( Fig.…”

What drives intense apoptosis resistance and propensity for necrosis in glioblastoma? A role for Bcl2L12 as a multifunctional cell death regulator

“…71 HMGB1-RAGE interaction induces proliferation, angiogenesis, invasion, metastasis and chemotherapy-resistance. 71 Similarly, HDGF is overexpressed in many different cancers, including gastrointestinal stromal tumors (GISTs), 72 esophageal carcinoma, 73 pancreatic cancer, 74 hepatocellular carcinoma, 75 non-small cell lung cancer, 76 colorectal cancer 77 and melanoma, 78 and has potent angiogenic, 79 invasive 80 and metastatic potential. 73 Contrasting its role under pathophysiological conditions, such as gliomagenesis, necrosis can also be beneficial for an organism as it constitutes a warning system against toxic exposure.…”

A YY1-dependent increase in aerobic metabolism is indispensable for intestinal organogenesis

“…Meanwhile, villus cells are postmitotic and express genes appropriate to their differentiated function in secretion or absorption; epithelial cells transit towards the villus tips, where they ultimately delaminate into the lumen. A number of developmental signaling molecules and transcriptional regulators have been implicated in villus development (Choi et al, 2006;Kaestner et al, 1997;Karlsson et al, 2000;Kim et al, 2007;Lepourcelet et al, 2005;Madison et al, 2005;McLin et al, 2009;Ormestad et al, 2006;Shyer et al, 2013;Spence et al, 2011;van den Brink, 2007;Walker et al, 2014;Walton et al, 2012Walton et al, , 2016; however, the role of metabolic regulators in villus development has yet to be investigated.…”