Upregulation of the tumor suppressor gene menin in hepatocellular carcinomas and its significance in fibrogenesis.
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.
Zindy
Pierre J
PJ
INSERM, U620, Rennes, France.
L'Helgoualc'h
Annie
A
Bonnier
Dominique
D
Le Béchec
Antony
A
Bourd-Boitin
Katia
K
Zhang
Chang Xian
CX
Musso
Orlando
O
Glaise
Denise
D
Troadec
Marie Bérangère
MB
Loréal
Olivier
O
Turlin
Bruno
B
Léger
Jean
J
Clément
Bruno
B
Théret
Nathalie
N
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
D024042:Collagen Type I; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta