Full metadata record
DC FieldValueLanguage
dc.contributor.authorLEE WU YAN-HWAen_US
dc.description.abstract肝癌為一具高侵襲力且難以治療的常見腫瘤。研究指出腫瘤組織中之「癌源幹 細胞」可導致腫瘤生成,並為可能的癌症治療標的。這些細胞具有高度侵襲能力、抗 藥性及自我更新與分化能力等特徵,並存在於不同腫瘤組織中。目前數種肝癌癌源幹 細胞可藉由其特有表型(如:CD133 之表現)而被分離,且其可能源自基因變異之 肝臟細胞或肝臟前驅細胞。雖然特定miRNA 的不正常表現可導致癌源特徵的表現, 然而目前對於肝癌癌源幹細胞產生之分子機制仍未明瞭。RNA 解螺旋酶DDX3 參與 核酸代謝且調控細胞功能。我們先前研究指出DDX3 對肝癌具有抑制腫瘤生成之功 能。初步結果更發現降低肝癌細胞株中DDX3 表現可增加CD133+細胞數量比例,並 伴隨幹細胞相關轉錄因子的表現上升;而DDX3 大量表現可抑制癌源細胞特徵。微 陣列晶片分析顯示DDX3 可調控一群預測或證明可抑制癌源特徵基因表現的 miRNA。以上結果暗示DDX3 可藉由透過調節miRNA 生合成,進而調控肝癌源細胞 之產生。因此,本計畫將分析DDX3 調控幹細胞特性之功能角色及其對肝癌發生之 影響。我們將利用肝癌細胞株與臨床檢體研究DDX3 對肝癌癌源幹細胞產生及相關 特徵的影響,分析其與病人預後的相關性。並於小鼠肝臟再生模式中,探討Ddx3x 於肝臟細胞/肝臟前驅細胞所導致肝癌發生的功能角色。此外,藉由分析DDX3 影響 miRNA 生合成進而調控癌源特徵的機制,闡明DDX3 抑制肝癌癌源幹細胞生成的功 能性角色。本研究成果將有助於釐清癌源幹細胞的致病機轉,並提供肝癌研究之基礎 資訊,以期有利於未來治療策略的研發。zh_TW
dc.description.abstractHepatocellular carcinoma (HCC) is an aggressive malignancy with poor prognosis. Growing evidence support that cancer-initiating stem cells (CISCs), a small portion of cells responsible for tumorigenesis, could be a therapeutic target. In addition to self-renewal and differentiation capacity, CISCs exhibit features of enhanced invasiveness and chemoresistance. To date, the existence of CISCs has been proven in many malignancies, including HCC. Recently, several hepatic CISC populations have been identified by their specific phenotype, such as the expression of CD133 surface marker. Characterization of the source of hepatic CISCs suggests that they could originate from hepatic progenitor cells or hepatocytes with genetic alteration. Although aberrant expression of certain miRNA could result in CISC-associated features in HCC, the molecular details about the regulation of hepatic CISC generation remains elusive. The DEAD-box RNA helicase DDX3 plays important roles in various cellular function via its engagement in RNA metabolism. Our previous studies suggest a tumor suppressor role of DDX3 in HCC. Recently, our preliminary data revealed reduction of DDX3 expression in CD133+ hepatic CISC cells. Moreover, DDX3 knockdown led to generation of CD133+ cells along with up-regulation of stem cell-related transcription factors. On the contrary, DDX3 overexpression suppressed certain CISC-associated features. Most interestingly, according to our miRNA microarray analysis, DDX3 could regulate the expression of a group of miRNAs predicted or proved to suppress CISC-associated genes. These evidences strongly suggest that DDX3 may regulate hepatic CISC generation by modulating miRNA biogenesis. Thus, in this proposal, efforts will be made to elaborate the functional role of DDX3 on regulating cell stemness and its impact on HCC tumorigenesis. In the first part of this proposal, we will clarify the regulatory role of DDX3 on generation of CISCs in HCC. The expression levels of DDX3 in defined hepatic CISC populations will be delineated. Moreover, effect of DDX3 on CISC features and CISC generation will also be examined in vitro, validated in clinical samples and correlated to patients’ clinical outcome. Secondly, the functional role of Ddx3x on hepatocytic- and hepatic progenitor cells-mediated hepatocarcinogenesis will be investigated in mouse liver regeneration model. Finally, the DDX3-mediated regulation of miRNAs targeting CISC-associated genes will be addressed. We will validate the effect of DDX3 on the expression of miRNAs predicted to suppress CISC-associated genes. Additionally, the targeting effect of these miRNA candidates will be certified. Furthermore, we will explore the functional role of DDX3 on miRNA biogenesis. The interplay among DDX3 and miRNA processing complexes will also be investigated. Collectively, the approaches outlined above will allow envisaging DDX3-mediated regulation on CISC-associated gene and hepatic CISC generation, which may be informative for the future research on HCC carcinogenesis and ultimate development of diagnostic or therapeutic strategies for hepatic malignancy.en_US
dc.subjectRNA 解螺旋酶 DDX3zh_TW
dc.subjectRNA helicase DDX3en_US
dc.subjectcancer-initiating stem cells (CISCs)en_US
dc.subjectliver regenerationen_US
dc.subjectmiRNA biogenesisen_US
dc.subjecthepatocellular carcinoma (HCC)en_US
dc.titleFunctional Roles of DDX3 on Regulating Cell Stemness and Its Impact on Hepatic Tumorigenesisen_US
Appears in Collections:Research Plans