To investigate the cellular origin within periportal zone of liver tumor initiation using Mir122a-null mouse model

Autor: Wei-Ling Tu, 涂瑋玲
Rok vydání: 2018
Druh dokumentu: 學位論文 ; thesis
Popis: 107
Hepatocellular carcinoma (HCC) is the major liver malignancy with high morbidity and mortality. MicroRNA-122a (Mir122a) is a tumor suppressor miRNA and is frequently down-regulated in human HCC with a poor prognosis. In mice, Mir122a deficiency causes liver inflammation, steatosis and consequently develops HCC at around 14 months of age. In the Mir122a-deficient liver tumors, PTEN levels are drastically reduced. To further investigate the role of PTEN down-regulation in Mir122a null hepatocarcinogenesis, we generated Mir122a-null Pten heterozygous (Mir122a-/-;Pten+/- and Mir122a-/-;Alb-Cre;Ptenfx/+) mice. We found that both Mir122a-/-;Pten+/- and Mir122a-/-;Alb-Cre;Ptenfx/+ mice developed visible liver tumors at 6-9 months of age, whereas no liver tumor was detected in Mir122a-/-, Pten+/- or control mice. Histological analysis showed that expanded hepatic lesions with basophilic ductular patterns were appeared in all Mir122a-/-;Pten+/- mice at 6 months of age. Using flow cytometry, immunostaining and sphere-forming analyses, we found that hepatic progenitor cells associated with the ductular reaction were significantly increased in Mir122a-/-;Pten+/- livers compared to that in Mir122a-/- livers. Also, we found that a hybrid hepatocyte-like population expressed intermediate levels of CK8, HNF4a and Sox9 locating proximally to the oval cells in Mir122a-/-Pten+/- livers. Using cell-lineage tracing approach, we found that these periportal hybrid hepatocyte-like cells could give rise to the neoplastic cells in Mir122a-/-;Pten+/- mice. Therefore, our data suggest that downregulation of Pten levels in Mir122a-/-;Pten+/- periportal areas expands a hybrid hepatocyte-like population, which acts as the cell of origin for HCC initiation and progression
Databáze: Networked Digital Library of Theses & Dissertations
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