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    請使用永久網址來引用或連結此文件: http://libir.tmu.edu.tw/handle/987654321/61421


    題名: 探討 POLQ 與 IMPA2 分別在促進去勢抗性攝護腺癌之治療抗 性和亮細胞腎細胞癌之轉移進程所扮演的功能性角色
    Studying on the functional role of POLQ and IMPA2 in promoting the therapeutic resistance and metastatic progression respectively in castration-resistant prostate cancer and clear-cell renal cell carcinoma
    作者: 歸家豪
    Kuei, Chia-Hao
    貢獻者: 臨床醫學研究所博士班
    林源峰
    陳冠州
    關鍵詞: 去勢抗性攝護腺癌;亮細胞腎細胞癌
    castration-resistant prostate cancer;clear-cell renal cell carcinoma
    日期: 2021-07-01
    上傳時間: 2022-03-05 22:56:32 (UTC+8)
    摘要: 歐洲紫杉醇目前仍然是轉移性去勢抗性型前列腺癌 (mCRPC) 的主要治療方法；然而，在一些 mCRPC 患者當中，發現了歐洲紫杉醇抗藥性。因此，我們迫切需要一種有效的生物標誌，用來預測歐洲紫杉醇對 mCRPC 患者的治療效果。另一方面，與其他 RCC 類型相比，透明細胞腎細胞癌 (ccRCC) 具有高度的轉移性。然而，造成ccRCC轉移的分子機轉目前仍不清楚。
    我們的研究結果顯示，在CRPC 組織中的 DNA 聚合酶 theta (POLQ) mRNA 數量，明顯高於非 CRPC 前列腺組織中，其他 DNA 聚合酶的數量。在 mCRPC組織當中，我們發現 POLQ 表現增加，並且與患者預後不良有著顯著的正相關。此外，在進行細胞毒性的試驗當中，弱化了POLQ的表現量，會進而增強了歐洲紫杉醇的藥物敏感性，並提高了歐洲紫杉醇對異種植入動物模型中，轉移型 PC-3M 腫瘤生長細胞株的治療效果。 更進一步，利用計算軟體GSEA的模擬模型顯示，POLQ 高表現與 E2F/G2M 檢查點之間相關的途徑，有著顯著的關係 。因此，在熒光素酶基因報告和 RT-PCR 分析中顯示，弱化POLQ的表現量，會降低E2F的轉錄調節活性，並且會抑制mCRPC細胞中 E2F/G2M 途徑的檢查調節點 CDK1。
    在以前的研究當中，肌醇單磷酸酶 2 (IMPA2) 的低表現與 ccRCC 的癌細胞轉移能力增加以及 ccRCC 患者的預後較差都有關聯。在這裡，我們進一步發現 ，IMPA2 表現量與 Akt/mTOR 途徑的活化呈現負相關，而與 ccRCC的自噬作用活化呈現正相關。在弱化了IMPA2的A498 ccRCC癌細胞中，使用雷帕黴素(一種mTOR 活性抑制劑)會促進癌細胞自噬作用，並進而抑制了癌細胞轉移的能力，而加入3-甲基腺嘌呤抑制劑，則是可以挽救了過度表現 IMPA2 的 ACHN 癌細胞的轉移能力。
    這些結果發現顯示，POLQ 可以作為預測歐洲紫杉醇對轉移型 CRPC 患者治療效果的生物標誌物。而臨床上使用的標靶藥物替西羅莫司(一種mTOR 抑制劑)，可能有助於治療具有 IMPA2 低表現的轉移性的ccRCC。
    Docetaxel remains a main treatment for metastatic castration-resistant prostate cancer (mCRPC); however, the development of docetaxel resistance has been found in some mCRPC patients. As a result, identifying an effective biomarker to predict the therapeutic effectiveness of docetaxel in mCRPC patients is urgently needed. On the other hand, clear cell renal cell carcinoma (ccRCC) compared to other RCC types has been known to be highly metastatic. However, the molecular mechanism underlying ccRCC metastasis remains unclear.
    Our results showed that DNA polymerase theta (POLQ) mRNA levels in CRPC tissues are significantly higher than those of other DNA polymerases in non-CRPC prostate tissues. POLQ upregulation was extensively detected in mCRPC and strongly predicted a poor prognosis. POLQ knockdown enhanced docetaxel sensitivity in a cell-based cytotoxicity assay and promoted the therapeutic effectiveness of docetaxel on the tumor growth of metastatic PC-3M cells in xenograft models. The computational simulation by GSEA software significantly predicted an association between POLQ upregulation and the activation of E2F/G2M checkpoint-related pathways. Moreover, luciferase reporter and RT-PCR assays demonstrated that POLQ knockdown downregulated the transcriptional regulatory activity of E2F and repressed E2F/G2M checkpoint-regulated CDK1 in mCRPC cells.
    Previously, it has been found that downregulation of inositol-monophosphatase 2 (IMPA2) was correlated with an increased metastatic potential of ccRCC and a poorer prognosis in ccRCC patients. Here we further found that IMPA2 expression negatively correlates with the activity of Akt/mTOR pathway but positively associates with the formation of autophagy in ccRCC. The pharmaceutical inhibition of mTOR activity by rapamycin promoted the autophagy formation and ultimately suppressed the metastatic potentials of IMPA2-silencing A498 cells, whereas the inhibition of autophagy assembly by 3-methyladenine rescued the metastatic potentials of IMPA2-overexpressing ACHN cells in vitro and in vivo.
    These findings suggest that POLQ could serve as a biomarker for predicting the therapeutic effectiveness of docetaxel in patients with metastatic CRPC. Moreover, targeting mTOR activity by temsirolimus, a clinically used mTOR inhibitor, might be useful for treating the metastatic ccRCC with IMPA2 downregulation.
    描述: 博士
    指導教授：林源峰
    指導教授：陳冠州
    委員：廖俊厚
    委員：梁博煌
    委員：林秋烽
    資料類型: thesis
    顯示於類別:[臨床醫學研究所] 博碩士論文

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