Genome-Wide Detection of Putative Oncofetal Genes in Human Hepatocellular Carcinoma by Splicing Pattern Comparison

ncofetal genes are those genes that express themselves similarly in fetal and tumorous adult tissues but differently or below detectable levels in normal adult tissues. These genes are thought to play important roles in cell proliferation, differentiation and carcinogenesis. They have recently been used as biomarkers of cancer. For example, the alpha-fetoprotein (AFP) is one of the most commonly used diagnostic markers for hepatocellular carcinoma (HCC). In this paper, we present a computational method that compares the distributions of co-expression splicing patterns to detect potential biomarker genes in HCC, according to the cDNA/EST data. Using this method, we successfully identified 84 putative oncofetal genes (POFG) in HCC. We also found that the fetal and tumorous isoforms of POFG tended to be longer than their normal counterparts. Our preliminary screening of domain compositions of those long fetal/tumorous isoforms re-discovered a pleckstrin homology (PH) domain on AKT2, which is known to be cancer-related.

[1]  Jon W. Huss,et al.  BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources , 2009, Genome Biology.

[2]  J. Marrero,et al.  Newer markers for hepatocellular carcinoma. , 2004, Gastroenterology.

[3]  Christopher J. Lee,et al.  A genomic view of alternative splicing , 2002, Nature Genetics.

[4]  Xiang Ding,et al.  Determination of High Mobility Group A1 (HMGA1) Expression in Hepatocellular Carcinoma: A Potential Prognostic Marker , 2005, Digestive Diseases and Sciences.

[5]  David Martin,et al.  GOToolBox: functional analysis of gene datasets based on Gene Ontology , 2004, Genome Biology.

[6]  Wei Cheng,et al.  Cloning and expression of a developmentally regulated transcript MXR7 in hepatocellular carcinoma: biological significance and temporospatial distribution. , 1997, Cancer research.

[7]  Thangavel Alphonse Thanaraj,et al.  ASD: a bioinformatics resource on alternative splicing , 2005, Nucleic Acids Res..

[8]  Chia-Hung Liu,et al.  Detection of the inferred interaction network in hepatocellular carcinoma from EHCO (Encyclopedia of Hepatocellular Carcinoma genes Online) , 2007, BMC Bioinformatics.

[9]  A M Martelli,et al.  Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia , 2006, Leukemia.

[10]  S. Cheung,et al.  Quantitative correlation of serum levels and tumor expression of vascular endothelial growth factor in patients with hepatocellular carcinoma. , 2003, Cancer research.

[11]  Xianjin Zhou,et al.  Mutation responsible for the mouse pygmy phenotype in the developmentally regulated factor HMGI-C , 1995, Nature.

[12]  P. Schirmacher,et al.  Dysregulation of growth factor signaling in human hepatocellular carcinoma , 2006, Oncogene.

[13]  T. Kamataki,et al.  Novel Transcriptional Regulation of the Human CYP3A7Gene by Sp1 and Sp3 through Nuclear Factor κB-like Element , 2001 .

[14]  David Haussler,et al.  Unusual Intron Conservation near Tissue-Regulated Exons Found by Splicing Microarrays , 2005, PLoS Comput. Biol..

[15]  Rong Zeng,et al.  Sys-BodyFluid: a systematical database for human body fluid proteome research , 2008, Nucleic Acids Res..

[16]  Robert D. Finn,et al.  New developments in the InterPro database , 2007, Nucleic Acids Res..

[17]  Neil A. Thacker,et al.  The Bhattacharyya metric as an absolute similarity measure for frequency coded data , 1998, Kybernetika.

[18]  M. Monden,et al.  Akt2 expression correlates with prognosis of human hepatocellular carcinoma. , 2004, Oncology reports.

[19]  C. V. Jongeneel,et al.  eVOC: a controlled vocabulary for unifying gene expression data. , 2003, Genome research.

[20]  Xin Wei Wang,et al.  Gene Expression Profiling Reveals Potential Biomarkers of Human Hepatocellular Carcinoma , 2007, Clinical Cancer Research.

[21]  Eric T. Wang,et al.  Alternative Isoform Regulation in Human Tissue Transcriptomes , 2008, Nature.

[22]  Abelev Gi.  Alpha-Fetoprotein in Ontogenesis and its Association with Malignant Tumors , 1971 .

[23]  P. Sharp,et al.  Proliferating Cells Express mRNAs with Shortened 3' Untranslated Regions and Fewer MicroRNA Target Sites , 2008, Science.

[24]  H. Aburatani,et al.  Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. , 2005, Genomics.

[25]  Christopher J. Lee,et al.  Evidence that public database records for many cancer-associated genes reflect a splice form found in tumors and lack normal splice forms , 2005, Nucleic acids research.

[26]  S. Fan,et al.  Comparative proteomic analysis of mouse livers from embryo to adult reveals an association with progression of hepatocellular carcinoma , 2008, Proteomics.

[27]  S. Thorgeirsson,et al.  Molecular pathogenesis of human hepatocellular carcinoma , 2002, Nature Genetics.

[28]  T. Hashimoto,et al.  A new inhibitor of mitochondrial fatty acid oxidation. , 1996, Journal of biochemistry.

[29]  Peer Bork,et al.  SMART 5: domains in the context of genomes and networks , 2005, Nucleic Acids Res..

[30]  M. Ingelman-Sundberg,et al.  A Novel Polymorphic Cytochrome P450 Formed by Splicing of CYP3A7 and the Pseudogene CYP3AP1* , 2005, Journal of Biological Chemistry.

[31]  C. Townsend,et al.  Fatty acid synthase inhibition triggers apoptosis during S phase in human cancer cells. , 2003, Cancer research.

[32]  G. Fu,et al.  Insight into hepatocellular carcinogenesis at transcriptome level by comparing gene expression profiles of hepatocellular carcinoma with those of corresponding noncancerous liver , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[33]  J. Castle,et al.  Genome-Wide Survey of Human Alternative Pre-mRNA Splicing with Exon Junction Microarrays , 2003, Science.

[34]  G. Salles,et al.  Identification of an alternative CD20 transcript variant in B-cell malignancies coding for a novel protein associated to rituximab resistance. , 2010, Blood.

[35]  L. Holm,et al.  The Pfam protein families database , 2005, Nucleic Acids Res..

[36]  G. Michalopoulos,et al.  Beta-catenin antisense studies in embryonic liver cultures: role in proliferation, apoptosis, and lineage specification. , 2003, Gastroenterology.

[37]  Sherif Abou Elela,et al.  Identification of alternative splicing markers for breast cancer. , 2008, Cancer research.

[38]  S. Hirohashi,et al.  Involvement of splicing factor-1 in beta-catenin/T-cell factor-4-mediated gene transactivation and pre-mRNA splicing. , 2007, Gastroenterology.

[39]  Chia-Hung Liu,et al.  Gene Name Service: No-Nonsense Alias Resolution Service for Homo Sapiens Genes , 2007, 2007 IEEE/WIC/ACM International Conferences on Web Intelligence and Intelligent Agent Technology - Workshops.

[40]  E. Birney,et al.  The International Protein Index: An integrated database for proteomics experiments , 2004, Proteomics.

[41]  R. Sorek,et al.  A novel algorithm for computational identification of contaminated EST libraries. , 2003, Nucleic acids research.