- 學位論文
B型肝炎病毒X蛋白藉由調控小泛素化蛋白酶調節B型肝炎病毒所誘發之肝癌之癌幹細胞表現
Role of HBx in SENP1 expression and stemness-related properties of HBV-related hepatocellular carcinoma
摘要
肝癌具多樣化致病因子及訊號傳遞。其中B型肝炎與肝癌的發展十分相關。但臨床上仍然缺乏針對B型肝癌病毒引起之肝癌的有效治療方法。本篇研究論文證實HBx蛋白透過小泛素化蛋白酶（SENP1）來調控PIN1及OCT4來影響細胞增生以及幹細胞特性。從臨床人類肝癌檢體組織中，我們證實B型肝癌病毒相關的肝癌中SENP1與OCT4的基因表現呈現高度的正相關。此外，肝癌組織SENP1的表現程度也和與肝癌病患的術後復發時程、肝癌分期呈現正相關 (n = 184)。同樣地，利用免疫組織染色的結果也證實SENP1、OCT4及PIN1的表現呈現正相關。我們進一步在肝癌細胞株HepG2大量表現HBx 蛋白，證實HBx蛋白的表現會促進SENP1、全能轉錄因子OCT4及細胞增生相關因子PIN1及Cyclin D1之蛋白表現量。肝癌病患檢體的臨床資料統計也支持了SENP1及PIN1在B型肝癌病毒相關的肝癌中的高度表現。藉由RNA干擾來抑制SENP1表現後，HBx所引起的細胞增生相關因子以及幹細胞特性則明顯下降。總結: 本篇論文的研究結果證實，在B型肝癌病毒相關的肝癌中，HBx蛋白會透過SENP1的調控來影響細胞增生以及幹細胞相關特性，並且和腫瘤的侵犯力及預後相關。我們的研究提供B型肝炎病毒相關的肝癌中，SENP1調控的相關路徑可作為潛在治療標的。
並列摘要
The molecular pathogenesis of hepatocellular carcinoma (HCC) is heterogeneous with diverse etiologies and complex signal activation. Chronic hepatitis B virus (HBV) hepatitis is highly associated with HCC development that continues to be a great challenge in clinical practice. However, the lacking of effective individual targeting on HBV-HCC dramatically hindered the therapeutic efficacy. Here we demonstrate that the HBx regulates the SENP1 expression by which to increase cell proliferation and stemness properties through OCT4 and PIN1 regulation. In a large cohort of frozen HCC samples, we found a significant correlation between SENP1 and OCT4 transcriptional expressions and this association preferentially occurred in HBV-related HCC (HBV-HCC) than those in non-HBV-HCC. Furthermore, The SENP1 expression levels were significantly associated with the OCT4 and PIN1 in HCC tumor tissues by immunohistochemical staining; and, were with poor disease-free survival (DFS) in the hepatectomized HCC patients using Kaplan-Meier analysis. The up-regulation of SENP1, PIN1, and OCT4 protein levels are highly associated with HBV-HCC. Furthermore, HBx overexpression in HepG2 cells significantly increased the protein levels of SENP1, pluripotent transcription factor OCT4, and the cell proliferation markers PIN1/Cyclin D1. The inhibition of the SENP1 by RNA interference significantly suppressed the HBx-induced cell proliferation stemness-related properties in vitro. In summary, in this study, we demonstrated that HBx-induced up-regulation of cell proliferation and stemness-related properties are regulated by SENP1 activation in HBV-HCC, and are associated with tumor aggressiveness and poor prognosis. Findings in this work strongly suggest that the SENP1-mediated signaling is a potential target for individualized adjuvant therapy against HBV-HCC.
參考文獻
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