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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17279
Title: | 利用小鼠動物模式探討beta-catenin於肝臟前驅細胞增殖與癌化過程之功能 A mouse model for studying the functional role of Wnt/beta-catenin in regulating the hepatic progenitor cell expansion and tumorigenesis |
Authors: | 王爾雅 Er-Yea Wang |
Advisor: | 葉秀慧 |
Keyword: | HBx 蛋白質,肝癌, Wnt/beta-catenin pathway,postnatal liver regeneration,HBx protein,liver cancer,Hepatic progenitor cell,inflammatory niche, |
Publication Year : | 2013 |
Degree: | 博士 |
Abstract: | Hepatic progenitor cells (HPCs) have long been considered as the major resource for compensatory liver regeneration in chronic hepatitis patients, in which the regeneration capability of normal hepatocytes is severely impaired. The persistent inflammation is always observed to associate with the expansion of HPCs, and ~40% of cirrhotic nodules and HCC could be derived from such HPCs by showing positive signals for CK7, CK19, OV6 and EpCAM. However, the key factor(s) and the underlying mechanisms for regulating the expansion of HPCs and subsequent tumorigenesis in the inflammatory liver are remained unclear. We first established a mouse model suitable to address by conditional beta-catenin knockout mice in hepatocytes (Alb-Cre;Ctnnb1flx/flx) where hepatocytes are gradually replaced by newly regenerated beta-catenin-positive hepatocytes from 9 months of age (over their life span). At the end of 20 month long term follow up, >90% of the hepatocytes are replaced by beta-catenin-positive cells, showing the characteristics of HPCs by expressing hepatic progenitor markers in accompanying with ductular reactions. The low albumin promoter activity of HPCs caused a lower expression of Cre and thus rendered these cells remained beta-catenin-positive. Spontaneous liver tumors are developed from the beta-catenin-positive HPCs and the tumorigenic process is accelerated by the expression of hepatitis B virus X (HBx) protein. We thus propose to identify the key factor/mechanism in regulating the expansion and carcinogenesis of HPCs by using this beta-catenin knockout mice model. We found that many inflammatory cells are recruited to the proximity of HPCs from 8 months of age, which is followed by the senescence of beta-catenin-negative hepatocytes. Furthermore, we have conducted the transplantation assay with the HPC cells isolated from 18M beta-catenin knockout mice as donor cells into the recipient WT and beta-catenin KO mice at different ages. The results showed that the inflammatory niche in the aged (10 months old) beta-catenin KO mice is critical for the proliferation of HPC cells; however the differentiation was impaired for the HPCs at the same time. Moreover, we found that the Wnt/beta-catenin pathway is activated in most HPCs by showing positive signal for glutamine synthetase, the target gene of Wnt/beta-catenin pathway in hepatocytes. Such a pattern is remained in the liver cancers either in beta-catenin knockout mice or in HBx/beta-catenin knockout mice, suggesting its involvement in the subsequent carcinogenic process. We further identified C1q as a key factor in the inflammatory niche for activating the Wnt/beta-catenin pathway in HPCs to regulate the proliferation and differentiation of HPCs and HBx induced carcinogenesis from HPCs, which can be blocked by inhibition of C1q function. These results thus indicate the novel therapeutic target of C1q in HPC derived hepatocarcinogenesis through its activation of Wnt/beta-catenin pathway in HPCs. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17279 |
DOI: | |
Fulltext Rights: | 未授權 |
Appears in Collections: | 微生物學科所 |
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ntu-101-2.pdf Restricted Access | 38.48 MB | Adobe PDF |
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