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標題: | 探討影響女性肝癌中成熟微型核醣核酸-18a上升之因子 Investigate the factors involved in miR-18a elevation in female HCC |
作者: | Chiao-Ling Li 李巧玲 |
指導教授: | 葉秀慧(Shiou-Hwei Yeh) |
關鍵字: | 肝癌,性別,微型核醣核酸, Hepatocellular carcinoma (HCC),gender,microRNA, |
出版年 : | 2010 |
學位: | 碩士 |
摘要: | 肝癌之發生具強烈性別特異性,男女比例約為5-7:1。流病學調查顯示此差異可能部分來自於雌激素對女性肝癌之保護作用。過去我們已發現女性肝癌中成熟微型核醣核酸-18a有顯著上升,微型核醣核酸-18a可藉負向調控雌激素受體α,進而抑制女性肝癌之發生。此研究之目的為研究女性肝癌中導致成熟微型核醣核酸-18a表現上升之機制。首先,我們於臨床女性肝癌檢體中觀察到次級微型核醣核酸-18a與成熟微型核醣核酸-18a之表現量具正相關性,但此正相關性不存在於初級微型核醣核酸-18a與成熟微型核醣核酸-18a之表現情形。此結果顯示成熟微型核醣核酸-18a之表現量上升可能源自於微型核醣核酸-18a生成過程中,由microprocessor complex進行之將初級微型核醣核酸-18a裁切成為次級核醣核酸-18a之步驟。Microprocessor complex作用之效率及專一性可受多種細胞內因子影響,其中已知p53蛋白可藉協助穩定microprocessor complex而促使微型核醣核酸-16-1、-143、-145之生成。因此,我們提出p53蛋白可能在女性肝癌中扮演促進微型核醣核酸-18a生成之角色之假說。我們使用細胞培養系統進行實驗以驗證此假說,當細胞經轉染大量表現野生型或突變型p53質體時,成熟微型核醣核酸-18a表現量上升。而當以siRNA降低p53蛋白表現量時,成熟微型核醣核酸-18a之表現量亦下降。上述結果顯示p53蛋白於成熟微型核醣核酸-18a生成路徑中具正向調控功能。此外,我們在女性肝癌臨床檢體中發現成熟微型核醣核酸-18a之表現量上升與p53蛋白之累積具正相關性亦支持此假說。本研究之新穎性在於發現p53蛋白參與女性肝癌中成熟微型核醣核酸-18a之上升,詳細之分子機制仍待進一步闡述。 Hepatocellular carcinoma (HCC) has strong gender disparity that it occurs mainly in men. The male to female ratio is 5-7 to 1. Epidemiologic data shows the differences may partly come from the protection effect of estrogen. Previously, we found that miR-18a elevates significantly in female HCC. And miR-18a can promote female HCC by downregulating its target gene, the estrogen receptor α (ER α). The goal of current research is to investigate the mechanism underlying the elevation of miR-18a in female HCC. We first identified a positive correlation between the level of pre-miR-18a and mature miR-18a in female HCC, which is not exist between the level of pri-miR-18a and mature miR-18a. It thus raised one possibility that the elevation of miR-18a in female HCC may be resulted by enhanced processing of pri-miRNA-18a to pre-miRNA-18a, a step of biogenesis conducted by a microprocessor complex. The efficiency and specificity of microprocessor complex can be regulated by many cellular factors, including p53, which can help stabilize the microprocessor complex and thus enhance the processing of a subgroup of miRNAs from pri- to pre- form. Therefore, we took p53 as a potential candidate for investigating its involvement in the elevation of miR-18a in female HCC. Using the cell culture assay system, miR-18a could be elevated by overexpression of either wild type or mutant p53 constructs. On the other hand, knocking down of p53 by siRNA decreased the miR-18a level. The results thus implicated that p53 could act as a positive regulator in miR-18a biogenesis. Such a finding was further supported by a positive correlation between miR-18a elevation and p53 accumulation preliminarily identified in clinical female HCC samples. Our study thus pointed out a novel mechanism for the involvement of p53 in accelerating the biogenesis of miR-18a in female HCC, with the detail mechanisms awaits further investigation. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/47701 |
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顯示於系所單位: | 微生物學科所 |
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