https://scholars.lib.ntu.edu.tw/handle/123456789/547738
標題: | RBMY, a novel inhibitor of glycogen synthase kinase 3β, increases tumor stemness and predicts poor prognosis of hepatocellular carcinoma | 作者: | Chua H.-H. Tsuei D.-J. PO-HUANG LEE YUNG-MING JENG Lu J. JIA-FENG WU Su D.-S. Chen Y.-H. Chien C.-S. Kao P.-C. CHIEN-NAN LEE REY-HENG HU YEN-HSUAN NI MEI-HWEI CHANG |
公開日期: | 2015 | 出版社: | John Wiley and Sons Inc. | 卷: | 62 | 期: | 5 | 起(迄)頁: | 1480-1496 | 來源出版物: | Hepatology | 摘要: | Male predominance of hepatocellular carcinoma (HCC) occurs particularly among young children aged 6-9 years, indicative of a possible role of the Y chromosome-encoded oncogene in addition to an androgenic effect. The discovery of oncogenic activation of RBMY (RNA-binding motif on Y chromosome), which is absent in normal hepatocytes but present in male HCC tissues, sheds light on this issue. Herein, we report on a critical hepatocarcinogenic role of RBMY and its ontogenic origin. During liver development, the Ser/Thr phosphorylated RBMY is expressed in the cytoplasm of human and rodent fetal livers. It is then silenced in mature hepatocytes and restricted to scarce expression in the bile ductular cells. Upon hepatocarcinogenesis, a noteworthy increase of cytoplasmic and nuclear RBMY is observed in HCC tissues; however, only the former is expressed dominantly in hepatic cancer stem cells and correlates significantly to a poor prognosis and decreased survival rate in HCC patients. Cytoplasmic expression of RBMY, which is mediated by binding to nuclear exporter chromosome region maintenance 1 and further enriched upon Wnt-3a stimulation, confers upon tumor cells the traits of cancer stem cell by augmenting self-renewal, chemoresistance, cell-cycle progression, proliferation, and xenograft tumor growth. This is achieved mechanistically through increasing Ser9 phosphorylation-inactivation of glycogen synthase kinase 3β by RBMY, thereby impeding the glycogen synthase kinase 3β-dependent degradation of β-catenin and eventually inducing the nuclear entry of β-catenin for the transcription of downstream oncogenes. Conclusion: RBMY is a novel oncofetal protein that plays a key role in attenuating glycogen synthase kinase 3β activity, leading to aberrant activation of Wnt/β-catenin signaling, which facilitates malignant hepatic stemness; because of its absence from normal human tissues except the testis, RBMY represents a feasible therapeutic target for the selective eradication of HCC cells in male patients. (Hepatology 2015;62:1480-1496) ? 2015 by the American Association for the Study of Liver Diseases. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84945439843&doi=10.1002%2fhep.27996&partnerID=40&md5=00cbd7e3a7cf165f88404e74a31ce0eb https://scholars.lib.ntu.edu.tw/handle/123456789/547738 |
ISSN: | 0270-9139 | DOI: | 10.1002/hep.27996 | SDG/關鍵字: | beta catenin; glycogen synthase kinase 3 inhibitor; glycogen synthase kinase 3beta; minichromosome maintenance protein 1; oncofetal antigen; RBMY protein; serine; threonine; unclassified drug; Wnt3a protein; beta catenin; glycogen synthase kinase 3; glycogen synthase kinase 3 beta; nuclear export signal; nuclear protein; RBMY1A1 protein, human; RNA binding protein; Wnt3a protein; adolescent; adult; aged; animal experiment; animal model; Article; bile duct; cancer growth; cancer patient; cancer prognosis; cancer resistance; cancer stem cell; cancer survival; cancer tissue; cell cycle progression; cell maturation; cell nucleus; cell proliferation; cell renewal; chromosome structure; controlled study; cytoplasm; enzyme activity; enzyme inactivation; enzyme phosphorylation; female; fetus; fetus liver; genetic transcription; human; human cell; human tissue; infant; liver carcinogenesis; liver cell; liver cell carcinoma; liver development; male; mouse; nonhuman; oncogene; ontogeny; priority journal; protein degradation; protein expression; protein function; protein phosphorylation; rat; RNA binding motif on the Y chromosome; survival rate; tumor xenograft; Wnt signaling pathway; Y chromosome; animal; antagonists and inhibitors; Carcinoma, Hepatocellular; Liver Neoplasms; metabolism; middle aged; mortality; nuclear export signal; pathology; phosphorylation; physiology; prognosis; protein stability; very elderly; Adult; Aged; Aged, 80 and over; Animals; beta Catenin; Carcinoma, Hepatocellular; Female; Glycogen Synthase Kinase 3; Humans; Infant; Liver Neoplasms; Male; Middle Aged; Nuclear Export Signals; Nuclear Proteins; Phosphorylation; Prognosis; Protein Stability; Rats; RNA-Binding Proteins; Wnt3A Protein |
顯示於: | 醫學系 |
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