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Upregulation of the tumor suppressor gene menin in hepatocellular carcinomas and its significance in fibrogenesis
Author(s) -
Zindy Pierre J.,
L'Helgoualc'h Annie,
Bonnier Dominique,
Le Béchec Antony,
BourdBoitin Katia,
Zhang Chang Xian,
Musso Orlando,
Glaise Denise,
Bérangère Troadec Marie,
Loréal Olivier,
Turlin Bruno,
Léger Jean,
Clément Bruno,
Théret Nathalie
Publication year - 2006
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21367
Subject(s) - men1 , biology , downregulation and upregulation , cancer research , microarray analysis techniques , gene expression , cirrhosis , suppression subtractive hybridization , hepatocellular carcinoma , hepatic stellate cell , tumor progression , tumor suppressor gene , microarray , gene , medicine , endocrinology , multiple endocrine neoplasia , genetics , cdna library , carcinogenesis
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 α2(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‐β)–dependent collagen α2(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‐β response. (H EPATOLOGY 2006;44:1296–1307.)