Upregulation of the tumor suppressor gene menin in hepatocellular carcinomas and its significance in fibrogenesis.

Pierre J. Zindy (1, 2) , Annie L'Helgoualc'H (1, 2) , Dominique Bonnier (1, 2) , Antony Le Béchec (1, 2) , Katia Bourd-Boitin (1, 2) , Chang Xian Zhang (3) , Orlando Musso (2, 4) , Denise Glaise (5) , Marie-Bérengère Troadec (5) , Olivier Loréal (5, 4) , Bruno Turlin (5) , Jean Léger (6) , Bruno Clément (2, 4) , Nathalie Théret (1, 2)

1 SeRAIC - Signalisation et Réponses aux Agents Infectieux et Chimiques
2 Détoxication et réparation tissulaire
3 GMSC - Génétique moléculaire, signalisation et cancer
4 Foie, métabolismes et cancer
5 Régulations des équilibres fonctionnels du foie normal et pathologique
6 Physiopathologie et pharmacologie cellulaires et moléculaires

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.

Mots clés: HCC; hepatocellular carcinoma; SSH; suppression subtractive hybridization; HSC; hepatic stellate cell; TGF-β; transforming growth factor beta; PCR; polymerase chain reaction; RT-qPCR; reverse transcription quantitative polymerase chain reaction; NT; nontumor; AS; antisense; MEN1; multiple endocrine neoplasia type 1; NF-κB; nuclear factor-kappaB

Domaines: Biologie cellulaire

Pierre J. Zindy, Annie L'Helgoualc'H, Dominique Bonnier, Antony Le Béchec, Katia Bourd-Boitin, et al.. Upregulation of the tumor suppressor gene menin in hepatocellular carcinomas and its significance in fibrogenesis.. Hepatology, 2006, 44 (5), pp.1296-307. ⟨10.1002/hep.21367⟩. ⟨hal-00702090⟩