title: Upregulation of the tumor suppressor gene menin in hepatocellular carcinomas and its significance in fibrogenesis.
abstract: The molecular mechanisms underlying the progression of cirrhosis toward hepatocellular carcinoma were investigated by a combination of DNA microarray analysis and literature data mining. By using a microarray screening of suppression subtractive hybridization cDNA libraries, we first analyzed genes differentially expressed in tumor and nontumor livers with cirrhosis from 15 patients with hepatocellular carcinomas. Seventy-four genes were similarly recovered in tumor (57.8% of differentially expressed genes) and adjacent nontumor tissues (64% of differentially expressed genes) compared with histologically normal livers. Gene ontology analyses revealed that downregulated genes (n = 35) were mostly associated with hepatic functions. Upregulated genes (n = 39) included both known genes associated with extracellular matrix remodeling, cell communication, metabolism, and post-transcriptional regulation gene (e.g., ZFP36L1), as well as the tumor suppressor gene menin (multiple endocrine neoplasia type 1; MEN1). MEN1 was further identified as an important node of a regulatory network graph that integrated array data with array-independent literature mining. Upregulation of MEN1 in tumor was confirmed in an independent set of samples and associated with tumor size (P = .016). In the underlying liver with cirrhosis, increased steady-state MEN1 mRNA levels were correlated with those of collagen alpha2(I) mRNA (P < .01). In addition, MEN1 expression was associated with hepatic stellate cell activation during fibrogenesis and involved in transforming growth factor beta (TGF-beta)-dependent collagen alpha2(I) regulation. In conclusion, menin is a key regulator of gene networks that are activated in fibrogenesis associated with hepatocellular carcinoma through the modulation of TGF-beta response.
authors.affiliation: INSERM, U620, Rennes, France.
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Zindy
authors.forename: Annie
authors.initials: A
authors.lastname: L'Helgoualc'h
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonnier
authors.forename: Antony
authors.initials: A
authors.lastname: Le Béchec
authors.forename: Katia
authors.initials: K
authors.lastname: Bourd-Boitin
authors.forename: Chang Xian
authors.initials: CX
authors.lastname: Zhang
authors.forename: Orlando
authors.initials: O
authors.lastname: Musso
authors.forename: Denise
authors.initials: D
authors.lastname: Glaise
authors.forename: Marie Bérangère
authors.initials: MB
authors.lastname: Troadec
authors.forename: Olivier
authors.initials: O
authors.lastname: Loréal
authors.forename: Bruno
authors.initials: B
authors.lastname: Turlin
authors.forename: Jean
authors.initials: J
authors.lastname: Léger
authors.forename: Bruno
authors.initials: B
authors.lastname: Clément
authors.forename: Nathalie
authors.initials: N
authors.lastname: Théret
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism*; D015723:Gene Library; D016147:Genes, Tumor Suppressor; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D008103:Liver Cirrhosis / Q000150:complications / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D024042:Collagen Type I; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta