title: Integrative genomics based identification of potential human hepatocarcinogenesis-associated cell cycle regulators: RHAMM as an example.
abstract: DNA microarray has been widely used to examine gene expression profile of different human tumors. The information generated from microarray analysis usually represents the overall range of cancer-associated abnormality associated with gene regulation. In order to identify key regulatory genes involved in carcinogenesis of human cancer, hypothesis driven data mining of the microarray data plus experimental validation becomes a critical approach in the post-genome era. Here, we present an integrative genomic analysis of published microarray data and homolog gene database. Over 20,000 genes were examined to reveal 16 genes specific to vertebrates, cell cycle G2/M regulated, and overexpressed in human HCC. Using Affymetrix microarray analysis, we found that all 16 genes were up-regulated in human HCC. Among these 16 genes, we experimentally validated the up-regulation of receptor for hyaluronan-mediated motility (RHAMM) in different cell model systems. We first confirmed elevation of RHAMM in the G2/M phase of synchronized HeLa cells. We also found that RHAMM had an elevated level of expression in all the HCC samples we examined and it was induced during the G2/M phase of regenerating mouse hepatocytes after partial hepatectomy. Thus, the expression of RHAMM appears to be tightly regulated during mammalian cell cycle G2/M progression. The ectopic overexpression of RHAMM in 293T cells resulted in the accumulation of cells at G2/M phase. RHAMM-induced mitotic arrest of cells was predominantly in the prophase. Taken together, using an integrated functional genomic approach, we have uncovered a set of genes that may play specific roles in cell cycle progression and in HCC development. To elucidate the function of these genes in cell cycle regulation may shed light on the control mechanism of human HCC in the future.
authors.affiliation: Institute of Biochemistry, National Yang-Ming University, Shih-Pai, Taipei 112, Taiwan, ROC.
authors.forename: Chu-Wen
authors.initials: CW
authors.lastname: Yang
authors.forename: Jin-Yuan
authors.initials: JY
authors.lastname: Su
authors.forename: Ann-Ping
authors.initials: AP
authors.lastname: Tsou
authors.forename: Gar-Yang
authors.initials: GY
authors.lastname: Chau
authors.forename: Hui-Lin
authors.initials: HL
authors.lastname: Liu
authors.forename: Chang-Han
authors.initials: CH
authors.lastname: Chen
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Chien
authors.forename: Chen-Kung
authors.initials: CK
authors.lastname: Chou
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D017931:DNA Primers; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000502:physiology*; D023281:Genomics; D018960:Hyaluronan Receptors / Q000737:chemistry / Q000502:physiology*; D008113:Liver Neoplasms / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D017386:Sequence Homology, Amino Acid
chemical_list: D017931:DNA Primers; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; C098946:hyaluronan-mediated motility receptor