Format

Send to

Choose Destination
PLoS One. 2015 Mar 4;10(3):e0118480. doi: 10.1371/journal.pone.0118480. eCollection 2015.

Reciprocal interaction of Wnt and RXR-α pathways in hepatocyte development and hepatocellular carcinoma.

Author information

1
Cancer Genome Center, Cold Spring Harbor Laboratory, Woodbury, NY 11740, United States of America.
2
Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
3
G. W. Hooper Foundation and Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143, United States of America.
4
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, United States of America.
5
Cancer Genome Center, Cold Spring Harbor Laboratory, Woodbury, NY 11740, United States of America; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, United States of America.

Abstract

Genomic analysis of human hepatocellular carcinoma (HCC) is potentially confounded by the differentiation state of the hepatic cell-of-origin. Here we integrated genomic analysis of mouse HCC (with defined cell-of-origin) along with normal development. We found a major shift in expression of Wnt and RXR-α pathway genes (up and down, respectively) coincident with the transition from hepatoblasts to hepatocytes. A combined Wnt and RXR-α gene signature categorized HCCs into two subtypes (high Wnt, low RXR-α and low Wnt, high RXR-α), which matched cell-of-origin in mouse models and the differentiation state of human HCC. Suppression of RXR-α levels in hepatocytes increased Wnt signaling and enhanced tumorigenicity, whereas ligand activation of RXR-α achieved the opposite. These results corroborate that there are two main HCC subtypes that correspond to the degree of hepatocyte differentation and that RXR-α, in part via Wnt signaling, plays a key functional role in the hepatocyte-like subtype and potentially could serve as a selective therapeutic target.

PMID:
25738607
PMCID:
PMC4349704
DOI:
10.1371/journal.pone.0118480
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center