Molecular Liver Cancer Prevention in Cirrhosis by Organ Transcriptome Analysis and Lysophosphatidic Acid Pathway Inhibition.
Fiche publication
Date publication
décembre 2016
Journal
Cancer cell
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BAUMERT Thomas
Tous les auteurs :
Nakagawa S, Wei L, Song WM, Higashi T, Ghoshal S, Kim RS, Bian CB, Yamada S, Sun X, Venkatesh A, Goossens N, Bain G, Lauwers GY, Koh AP, El-Abtah M, Ahmad NB, Hoshida H, Erstad DJ, Gunasekaran G, Lee Y, Yu ML, Chuang WL, Dai CY, Kobayashi M, Kumada H, Beppu T, Baba H, Mahajan M, Nair VD, Lanuti M, Villanueva A, Sangiovanni A, Iavarone M, Colombo M, Llovet JM, Subramanian A, Tager AM, Friedman SL, Baumert TF, Schwarz ME, Chung RT, Tanabe KK, Zhang B, Fuchs BC, Hoshida Y,
Lien Pubmed
Résumé
Cirrhosis is a milieu that develops hepatocellular carcinoma (HCC), the second most lethal cancer worldwide. HCC prediction and prevention in cirrhosis are key unmet medical needs. Here we have established an HCC risk gene signature applicable to all major HCC etiologies: hepatitis B/C, alcohol, and non-alcoholic steatohepatitis. A transcriptome meta-analysis of >500 human cirrhotics revealed global regulatory gene modules driving HCC risk and the lysophosphatidic acid pathway as a central chemoprevention target. Pharmacological inhibition of the pathway in vivo reduced tumors and reversed the gene signature, which was verified in organotypic ex vivo culture of patient-derived fibrotic liver tissues. These results demonstrate the utility of clinical organ transcriptome to enable a strategy, namely, reverse-engineering precision cancer prevention.
Mots clés
Animals, Antineoplastic Agents, pharmacology, Carcinoma, Hepatocellular, genetics, Cell Line, Tumor, Gene Expression Profiling, methods, Gene Regulatory Networks, Genetic Predisposition to Disease, Humans, Liver Cirrhosis, complications, Liver Neoplasms, genetics, Lysophospholipids, biosynthesis, Rats, Risk Factors, Signal Transduction, drug effects, Xenograft Model Antitumor Assays
Référence
Cancer Cell. 2016 Dec 12;30(6):879-890