Noncanonical Wnt11 inhibits hepatocellular carcinoma cell proliferation and migration.
The canonical Wnt signaling is frequently activated due to overexpression and/or mutations in components of this pathway in hepatocellular carcinoma (HCC). However, the biological role of noncanonical Wnt-mediated signaling in HCC with respect to the signaling pathways involved and their physiologic function is unknown. Here, we report the role of Wnt11, a member of the noncanonical cascade, in hepatic oncogenesis. The expression levels of Wnt11 mRNA and protein were significantly downregulated in human HCC tumors compared with the adjacent uninvolved liver as measured by quantitative real-time reverse transcription-PCR and Western blot analysis. In human HCC cell lines, overexpression of Wnt11 activated protein kinase C signaling. Protein kinase C antagonized the canonical signaling through phosphorylation of beta-catenin and reduced T-cell factor-mediated transcriptional activity, resulting in a decrease of cell proliferation. Furthermore, ectopic expression of Wnt11 promotes RhoA/Rho kinase activation. We found that activated Rho kinase inhibited Rac1 to reduce cell motility and migration. These observations suggest a novel role for Wnt11 as a tumor suppressor during hepatocarcinogenesis because loss of expression promotes the malignant phenotype via both canonical and noncanonical Wnt signaling pathways.
Toyama
Takashi
T
Liver Research Center, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
Lee
Han Chu
HC
Koga
Hironori
H
Wands
Jack R
JR
Kim
Miran
M
D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D015536:Down-Regulation / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D012333:RNA, Messenger; D051820:TCF Transcription Factors; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; C540523:Wnt11 protein, human; D051176:beta Catenin; D054460:rho-Associated Kinases; D011493:Protein Kinase C; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein