YAP Subcellular Localization and Hippo Pathway Transcriptome Analysis in Pediatric Hepatocellular Carcinoma.
Pediatric hepatocellular carcinoma (HCC) is a rare tumor which is associated with an extremely high mortality rate due to lack of effective chemotherapy. Recently, the Hippo pathway and its transcriptional co-activator Yes-associated protein (YAP) have been shown to play a role in hepatocyte proliferation and development of HCC in animal models. Therefore, we sought to examine the activity of YAP and the expression of Hippo pathway components in tumor and non-neoplastic liver tissue from 7 pediatric patients with moderately differentiated HCC. None of the patients had underlying cirrhosis or viral hepatitis, which is commonly seen in adults with HCC. This highlights a major difference in the pathogenesis of HCC between children and adults. We found a statistically significant increase in YAP nuclear localization in 100% of tumors. YAP target gene (CCNE1, CTGF, Cyr61) mRNA expression was also increased in the tumors that had the most significant increase in YAP nuclear localization. Based on Ki67 co-localization studies YAP nuclear localization was not simply a marker of proliferation. Our results demonstrate a clear increase in YAP activity in moderately differentiated pediatric HCC, providing evidence that it may play an important role in tumor survival and propagation.
Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115 USA.
Michael J
MJ
LaQuaglia
Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115 USA.
James L
JL
Grijalva
MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129-4404 USA.
Kaly A
KA
Mueller
Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115 USA.
Antonio R
AR
Perez-Atayde
Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115 USA.
Heung Bae
HB
Kim
MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129-4404 USA.
Ghazaleh
G
Sadri-Vakili
Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115 USA.
Khashayar
K
Vakili
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D002648:Child; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D000090683:Hippo Signaling Pathway; D006801:Humans; D007223:Infant; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D008297:Male; D060787:Neoplasm Grading; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors; D059467:Transcriptome; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; C501848:CCN1 protein, human; C526317:CCN2 protein, human; C475820:CCNE1 protein, human; D019927:Cyclin E; D055515:Cysteine-Rich Protein 61; D019394:Ki-67 Antigen; D015513:Oncogene Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D055513:Connective Tissue Growth Factor; D017346:Protein Serine-Threonine Kinases