乙型肝炎病毒 (HBV) 是造成急性和慢性肝炎、肝硬化以及肝細胞癌 (HCC) 的主要病原體。然而，目前臨床上主要用在 HBV 的藥物並不能有效地清除 HBV 的感染。在先前的研究中認為，HBV 病毒基因的複製很可能跟拓樸異構酶 (TOPs) 以及細胞內 DNA 修復途徑，例如 DNA 同源性重組修復路徑 (HR) 或是核苷酸切除修復路徑 (NER) 有關。然而，HBV 病毒基因複製的分子機制目前仍所知甚少。在本實驗室先前的研究結果中，我們使用了幾種 DNA 修復途徑的抑制劑進行篩選，發現了 Chk1 以及拓樸異構酶 (TOPs) 的抑制劑，能夠有效減少抑制 HBV 的複製。Chk1 能藉由磷酸化 RAD51 蛋白，以調控 DNA 同源性重組修復路徑 (HR) 。因此在本研究中，我們想去探討同源性重組修復路徑以及拓樸異構酶是否會影響 HBV 病毒基因複製的過程。我們首先生產了包含有能抑制 rad51、top1 或 top2α 基因表達的短髮夾型 RNA (shRNA) 的重組慢病毒 (Recombinant Lentivirus)。再利用慢病毒 (Lentivirus) 感染的方式，建立了能穩定且低度表現 rad51、top1 或 top2α 基因的 HepAD38 細胞株。HepAD38 是一株在沒有加入四環黴素 (Tetracyclin) 的時候，能穩定產生 HBV 病毒顆粒的細胞株。用嘌呤黴素 (Puromycin) 篩選出成功感染的細胞後，我們再以反轉錄聚合酶連鎖反應 (RT-PCR) 確認目標基因的表現量是否減少。根據實驗結果，我們分別挑出了 shRAD51-353568、shTOP1-3990 以及 shTOP2α-49279 這幾株特定基因穩定低度表現的 HepAD38 細胞。我們接下來便在這些挑出的細胞株內偵測多項 HBV 指標，以分析 HBV 複製的情形。我們利用即時定量偵測反轉錄聚合酶連鎖反應 (qRT-PCR) 去檢測 HBV 前基因型 RNA (pgRNA) 的含量是否有改變。根據其實驗結果，我們發現在 top1 或 top2α 基因穩定低度表現的 HepAD38 細胞中，HBV pgRNA 的含量有明顯的減少。而在血清學的 HBV 指標方面，西方墨點法 (Western Blot) 的結果顯示，雖然 HBV 的表面抗原 (LHBs) 的表現量在 top1 或 top2α 基因穩定低度表現的 HepAD38 細胞中有明顯的減少，但是 HBV 的核抗原 (HBcAg) 以及代表 HBV 複製活躍度的 e 抗原 (HBeAg) 卻只有在 top2α 基因穩定低度表現的 HepAD38 細胞中有明顯的減少。同時在即時定量偵測聚合酶連鎖反應 (qPCR) 的結果中，我們發現 HBV 總 DNA 含量 (HBV total DNA) 在只有在 top2α 基因穩定低度表現的 HepAD38 細胞中有明顯的減少。綜合以上結果，我們發現當細胞內 top2α 基因表現量降低時，能夠有效減少 HBV 的複製，此外，當 top1 基因表現量降低時，也會稍微影響 HBV 複製的情形。而當 DNA 同源性重組修復路徑 (HR) 抑制後則沒有減少 HBV 複製。因此，本研究證明了 top2α 基因在 HBV 病毒基因複製可能扮演著一個重要的角色，同時在未來 HBV 治療上，top2α 基因也可做為一個治療的目標。此外，拓樸異構酶對於 DNA 拓樸學的調控上也是佔有一席之地，因此我們推測 TOP2 可能會結合在 HBV 的 DNA 上且在 HBV 複製的過程中是需要的。另一方面，我們也發現細胞中的 HR 機制也包含在 HBV 複製的過程中，而根據實驗結果，我們推測細胞中 HR 途徑可能本身對於 HBV 複製就有抑制的功能。在未來的研究中， top2α 基因調控 HBV 基因複製的機制以及 HR 途徑對於 HBV 複製的影響仍可再深入探討。

Hepatitis B virus (HBV) is a major pathogen for acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC). However, the current therapeutic agents are ineffective to eliminate HBV. Previous studies suggested that HBV replication may correlate to topoisomerases and cellular DNA repair pathways, such as homologous recombination (HR) or nucleotide excision repair (NER) pathway, but the mechanism remains unclear. In our preliminary data, we screened some DNA repair inhibitors and found the chk1 inhibitor targeting RAD51, a HR protein, and topoisomerase inhibitors significantly suppressed HBV replication. In this study, we aimed to investigate the potential roles of DNA HR pathway and topoisomerases in HBV replication. The recombinant lentiviruses carrying the shRNAs of rad51, top1, and top2α were first produced to infect HepAD38 cells, which stably express HBV virion under the control of tet-off system. The target gene expressions were then checked by RT-PCR to select the HepAD38 cells with stable knockdown of RAD51, topoisomerase I (TOP1) and topoisomerase IIα (TOP2α). According to the results, the HepAD38 cells introduced with shRAD51-353568, shTOP1-3990, and shTOP2α-49279 showed the most significant and stablest knockdown efficiencies than the others. We next detected multiple HBV markers to measure the HBV replication efficiency in these clones. The HBV pre-genomic RNA (pgRNA) levels were measured by real-time RT-PCR (qRT-PCR) in these HepAD38 cells with target gene stable knockdown. We found that the HBV pgRNA levels were decreased significantly in the HepAD38 cells with gene silencing of top1 and top2α, instead of the knockdown of rad51. For serological markers, the results of western blot revealed that the expressions of LHBs were decreased significantly in the cells with silencing of top1 and top2α. However, only the top2α knockdown stable clones showed decreased HBcAg and HBeAg expressions, as well as the HBV total DNA levels in the results of real-time PCR (qPCR). Taken together, these results demonstrated that the HBV replication was significantly decreased in the cells with top2α knockdown and minor suppressed by top1 knockdown. However, the deficiency of HR pathway did not appear to suppress the HBV replication process. In conclusion, this study indicated that TOP2α may play an important role in HBV replication and serve as a potential therapeutic target. Topoisomerases are important for regulating DNA topology. We supposed that TOP2α may be associated with viral DNA and required for HBV replication. In contrast, we also indicated that HR pathway is involved in HBV replication, although the knockdown of HR pathway facilitated HBV production. We supposed that the cellular HR pathway may be a suppressive pathway for HBV replication. Therefore, the mechanisms of TOP2α or HR pathway mediated HBV replication are needed to be further investigated in the future.

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