Molecular Liver Cancer Prevention in Cirrhosis by Organ Transcriptome Analysis and Lysophosphatidic Acid Pathway Inhibition

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...

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Published in:Cancer cell 2016-12, Vol.30 (6), p.879-890
Main Authors: Nakagawa, Shigeki, Wei, Lan, Song, Won Min, Higashi, Takaaki, Ghoshal, Sarani, Kim, Rosa S., Bian, C. Billie, Yamada, Suguru, Sun, Xiaochen, Venkatesh, Anu, Goossens, Nicolas, Bain, Gretchen, Lauwers, Gregory Y., Koh, Anna P., El-Abtah, Mohamed, Ahmad, Noor B., Hoshida, Hiroki, Erstad, Derek J., Gunasekaran, Ganesh, Lee, Youngmin, Yu, Ming-Lung, Chuang, Wan-Long, Dai, Chia-Yen, Kobayashi, Masahiro, Kumada, Hiromitsu, Beppu, Toru, Baba, Hideo, Mahajan, Milind, Nair, Venugopalan D., Lanuti, Michael, Villanueva, Augusto, Sangiovanni, Angelo, Iavarone, Massimo, Colombo, Massimo, Llovet, Josep M., Subramanian, Aravind, Tager, Andrew M., Friedman, Scott L., Baumert, Thomas F., Schwarz, Myron E., Chung, Raymond T., Tanabe, Kenneth K., Zhang, Bin, Fuchs, Bryan C., Hoshida, Yujin
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
cancer chemoprevention
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - prevention & control
Cell Line, Tumor
Cirrosi hepàtica
Càncer de fetge
Gene Expression Profiling - methods
Gene Regulatory Networks
gene signature
Genetic Predisposition to Disease
Hepatic cirrhosis
Hepatitis B virus
hepatocellular carcinoma
Human health and pathology
Humans
Hépatology and Gastroenterology
Life Sciences
Liver cancer
Liver Cirrhosis - complications
Liver Cirrhosis - genetics
Liver Neoplasms - genetics
Liver Neoplasms - prevention & control
Lysophospholipids - biosynthesis
prognostic prediction
Rats
Risk Factors
Signal Transduction - drug effects
transcriptome
Xenograft Model Antitumor Assays
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Summary: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. [Display omitted] •Clinically applicable pan-etiology HCC risk biomarker was established•Global transcriptome map of cirrhosis identified HCC chemoprevention targets•Global transcriptome map of cirrhosis identified clinically relevant animal models•LPA pathway inhibitors were verified as HCC chemopreventive and anti-fibrotic drugs Nakagawa et al. establish a hepatocellular carcinoma (HCC) risk gene signature applicable to all major HCC etiologies and identify the lysophosphatidic acid pathway as a central chemoprevention target, pharmacological inhibition of which reduces tumors and reverses the gene signature in preclinical models.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccell.2016.11.004