Reciprocal interaction of Wnt and RXR-α pathways in hepatocyte development and hepatocellular carcinoma.
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.
Cancer Genome Center, Cold Spring Harbor Laboratory, Woodbury, NY 11740, United States of America.
Jinyu
J
Li
Cancer Genome Center, Cold Spring Harbor Laboratory, Woodbury, NY 11740, United States of America.
Maia
M
Chanrion
Cancer Genome Center, Cold Spring Harbor Laboratory, Woodbury, NY 11740, United States of America.
Eric
E
Sawey
Cancer Genome Center, Cold Spring Harbor Laboratory, Woodbury, NY 11740, United States of America.
Tim
T
Wang
Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
Edward
E
Chow
G. W. Hooper Foundation and Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143, United States of America.
Aaron
A
Tward
Cancer Genome Center, Cold Spring Harbor Laboratory, Woodbury, NY 11740, United States of America.
Yi
Y
Su
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, United States of America.
Wen
W
Xue
Cancer Genome Center, Cold Spring Harbor Laboratory, Woodbury, NY 11740, United States of America.
Robert
R
Lucito
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, United States of America.
Lars
L
Zender
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, United States of America.
Scott W
SW
Lowe
G. W. Hooper Foundation and Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143, United States of America.
J Michael
JM
Bishop
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.
Scott
S
Powers
D000818:Animals; D063646:Carcinogenesis; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D005260:Female; D023281:Genomics; D022781:Hepatocytes / Q000473:pathology*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D011485:Protein Binding; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
D047490:Retinoid X Receptor alpha; D051153:Wnt Proteins; D051176:beta Catenin