التفاصيل البيبلوغرافية
| العنوان: |
GATA4 loss of function in liver cancer impedes precursor to hepatocyte transition. |
| المؤلفون: |
Enane, Francis O.1, Wai Ho Shuen2, Xiaorong Gu1, Quteba, Ebrahem1, Przychodzen, Bartlomiej1, Hideki Makishima1, Bodo, Juraj1, Ng, Joanna2, Chit Lai Chee2, Ba, Rebecca2, Lip Seng Koh2, Lim, Janice2, Cheong, Rachael2, Teo, Marissa2, Zhenbo Hu1, Kwok Peng Ng1, Maciejewski, Jaroslaw1, Radivoyevitch, Tomas3, Chung, Alexander4, Ooi, London Lucien4 |
| المصدر: |
Journal of Clinical Investigation. Sep2017, Vol. 127 Issue 9, p3527-3542. 16p. 1 Diagram, 8 Graphs. |
| مصطلحات موضوعية: |
*LIVER cancer, *TUMOR suppressor genes, *MOLECULAR genetics, *TRANSCRIPTION factors, *GENE expression |
| مستخلص: |
The most frequent chromosomal structural loss in hepatocellular carcinoma (HCC) is of the short arm of chromosome 8 (8p). Genes on the remaining homologous chromosome, however, are not recurrently mutated, and the identity of key 8p tumor-suppressor genes (TSG) is unknown. In this work, analysis of minimal commonly deleted 8p segments to identify candidate TSG implicated GATA4, a master transcription factor driver of hepatocyte epithelial lineage fate. In a murine model, liver-conditional deletion of 1 Gata4 allele to model the haploinsufficiency seen in HCC produced enlarged livers with a gene expression profile of persistent precursor proliferation and failed hepatocyte epithelial differentiation. HCC mimicked this gene expression profile, even in cases that were morphologically classified as well differentiated. HCC with intact chromosome 8p also featured GATA4 loss of function via GATA4 germline mutations that abrogated GATA4 interactions with a coactivator, MED12, or by inactivating mutations directly in GATA4 coactivators, including ARID1A. GATA4 reintroduction into GATA4-haploinsufficient HCC cells or ARID1A reintroduction into ARID1A-mutant/GATA4-intact HCC cells activated hundreds of hepatocyte genes and quenched the proliferative precursor program. Thus, disruption of GATA4-mediated transactivation in HCC suppresses hepatocyte epithelial differentiation to sustain replicative precursor phenotype. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
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