多型性腦膠質母細胞瘤 (Glioblastoma multiforme) 是大腦中的惡性腦腫瘤。目前的治療方式為手術切除，並配合放射性治療及化學治療，患者的存活期可延長至18個月。然而，因腫瘤細胞具有抗藥性，化療效果仍不理想。實驗室之前DNA microarray 分析發現大鼠膠質瘤細胞C6具有高量的BRCC3基因表現。BRCC3是 BRCA1-BRCA2 containing complex的子單元，具有去泛素化之酵素活性， BRCC3與DNA修復蛋白複合體會參與DNA受損後修復過程。先前之報告指出，BRCC3在乳癌細胞中具有高度表現，被認爲可能是乳癌治療重要的一環，且參與細胞的HR-dependent DNA repair。目前尚無BRCC3分子參與腦膠質瘤細胞生長和抗藥性的相關性研究成果。因此本研究使用三種人類惡性腦膠質瘤瘤細胞株 (U87，U251，A172 malignant gliomas) 探討BRCC3與腦膠質瘤DNA 修復系統的關係。實驗結果顯示， BRCC3基因表現在A172細胞最高，並且對TMZ有抗藥性；U251細胞內BRCC3基因表現比U87細胞高，且對TMZ反應也較不敏感。此三種膠質瘤細胞此以TMZ處理 48小時後，BRCC3基因在U251與A172細胞中的表現也有顯著上升，而BRCA1，BRCA2，RAD51 和FANCD2 （DNA 修復基因）也隨之提高。進一步發現，降低BRCC3基因表現後，U251與A172細胞的增生速度減低，而且細胞群落形成，遷移與侵入之能力被抑制。 抑制BRCC3基因表現增加TMZ對U251 與A172 細胞毒性作用。並且，BRCC3基因表現降低的U251 與A172 細胞在TMZ處理120小時之後仍有大量 DNA 損傷標誌 H2AX的聚集；DNA 修補相關基因也顯著減低。這些實驗結果顯示BRCC3基因表現的降低導致DNA修復的效果下降。總結目前研究結果，BRCC3扮演調控腦膠質瘤細胞生長和其抗藥性的角色。

Glioblastoma multiforme (GBM) is the most aggressive form of brain tumors. Although the median survival of patients with GBM has been raised up to 18 months by the current glioma treatment using surgery combined with chemotherapy and radiation therapy. Yet, drug-resistance induced in glioma cells is a critical issue in chemotherapeutic efficiency. Previous observations in our laboratory showed that the expression of BRCA1-BRCA2-containing complex subunit 3 (BRCC3) was highly abundant in rat C6 glioma cells. BRCC3, a deubiquitinating enzyme which is encoded by the BRCC3 gene in human. This molecule has been known as one of the component of DNA repair complex to execute DNA repair in response to DNA damage. Previous studies have indicated that BRCC3 acts as a potential target for treatment of breast cancer. However, the roles of BRCC3 in glioma cells still remain elusive. Here, we used three human malignant glioma cell lines including U87, U251 and A172 to determine the role of BRCC3 in glioma growth. Among the three glioma cell lines, A172 cells expressed the highest level of BRCC3 mRNA and exhibited the greatest resistance to temozolomide (TMZ), the alkylating chemotherapeutic agent for glioma treatment. When compared to U87 cells, U251 cells had a higher BRCC3 mRNA expression and less sensitivity to TMZ. Moreover, exposure to TMZ resulted in upregulation of BRCC3 mRNA expression in U251 and A172 cells. Interestingly, the expression of the other genes commonly associated with HR-dependent DNA repair, i.e. BRCA1, BRCA2, RAD51 and FANCD2 were increased in TMZ-treated U251 and A172 cells. Apart from that, inhibition of BRCC3 using lentivirus-mediated shRNA targeting system was conducted. The results showed that depletion of BRCC3 expression significantly suppressed cell growth, migration and invasion in U251 and A172 cells. In addition, BRCC3 gene knockdown improved sensitization of U251 and A172 cells to TMZ. Persistent accumulation of intense H2AX foci (DNA damage marker) was observed at the later time points post TMZ treatment in U251 and A172 cells with BRCC3 knockdown. Further, expression of DNA repair genes as indicated above was also downregulated in TMZ-treated U251 and A172 cells when BRCC3 gene expression was inhibited. These results indicated that ablation of BRCC3 expression resulted in impairment of DNA repair in TMZ-treated U251 and A172. Collectively, our data provides important evidence to show that BRCC3 is critical for glioma cell growth and its upregluation is the responsive factor to induce resistance in human glioma cells to alkylating agents.

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