【摘要】 背景与目的：胰腺癌对白蛋白结合型紫杉醇耐药会影响疗效及患者预后，信号转导及转录激活因子3(signal transducer and activator of transcription 3,STAT3)是调控癌细胞化疗敏感性的重要分子之一，针对STAT3 mRNA反义寡核苷酸的中性脂质体BP1003能够抑制STAT3表达并增加化疗敏感性。但BP1003对胰腺癌细胞白蛋白结合型紫杉醇敏感性的影响尚不清楚。本研究旨在研究脂质体结合的反义寡核苷酸BP1003通过抑制STAT3对胰腺癌细胞白蛋白结合型紫杉醇敏感性的影响。方法：培养胰腺癌细胞株PANC-1及ASPC-1，分为对照组（不含药物）、BP1003组（200μg/mL BP1003干预）、不同浓度白蛋白结合型紫杉醇组（5、10、20 nmol/L白蛋白结合型紫杉醇干预）、BP1003+不同浓度白蛋白结合型紫杉醇组（200μg/mL BP1003联合5、10、20 nmol/L白蛋白结合型紫杉醇干预）。检测细胞增殖活力、凋亡率及STAT3、STAT4、STAT6、Bcl-2、Bax、c-Myc的蛋白表达水平。BALC/c裸小鼠皮下注射PANC-1、ASPC-1细胞悬液，建立移植瘤模型，分为对照组（生理盐水干预）、BP1003组（25 mg/kg BP1003干预，每2周1次）、白蛋白结合型紫杉醇组（10 mg/kg白蛋白结合型紫杉醇，每周1次）、BP1003+白蛋白结合型紫杉醇组（25 mg/kg BP1003干预，每2周1次联合10 mg/kg白蛋白结合型紫杉醇，每周1次）。4周后测量移植瘤体积及质量，检测STAT3、Bcl-2、Bax、c-Myc的蛋白表达水平。结果：BP1003组及不同浓度白蛋白结合型紫杉醇组PANC-1及ASPC-1细胞的凋亡率、Bax的蛋白表达水平均高于对照组，细胞增殖活力及STAT3、Bcl-2、c-Myc的蛋白表达水平低于对照组（P<0.05）。BP1003组PANC-1及ASPC-1细胞的STAT4、STAT6蛋白表达水平与对照组相比差异无统计学意义（P>0.05）。BP1003+不同浓度白蛋白结合型紫杉醇组PANC-1及ASPC-1细胞的凋亡率、Bax的蛋白表达水平均高于对应浓度白蛋白结合型紫杉醇组，细胞增殖活力及STAT3、Bcl-2、c-Myc的蛋白表达水平均低于对应浓度白蛋白结合型紫杉醇组（P <0.05）。BP1003组、白蛋白结合型紫杉醇组、BP1003+白蛋白结合型紫杉醇组裸鼠移植瘤的体积、质量及STAT3、Bcl-2、c-Myc的蛋白表达水平均低于对照组，Bax的蛋白表达水平高于对照组（P<0.05）且BP1003+白蛋白结合型紫杉醇组的上述变化较BP1003组、白蛋白结合型紫杉醇组更为显著。结论：BP1003通过抑制STAT3表达增加胰腺癌细胞对白蛋白结合型紫杉醇的敏感性。更多还原

【Abstract】 Background and purpose: The resistance of pancreatic cancer to albumin-bound paclitaxel affects the therapeutic effect and prognosis. Signal transducer and activator of transcription 3(STAT3) is one of the important molecules regulating the chemotherapy sensitivity of cancer cells. The liposome BP1003 targeting the antisense oligonucleotide of STAT3 mRNA can inhibit the expression of STAT3 and increase the chemotherapy sensitivity. However, the effect of BP1003 on the sensitivity of pancreatic cancer cells to albumin-bound paclitaxel remains unclear. The purpose of this study was to investigate the effects of liposome binding antisense oligonucleotide BP1003 on albumin-bound paclitaxel sensitivity in pancreatic cancer cells by inhibiting STAT3. Methods: Pancreatic cancer cell lines PANC-1 and ASPC-1 were cultured. They were divided into control group(without drugs), BP1003 group(200 μg/mL BP1003 intervention), different concentrations of albumin-bound paclitaxel group(5, 10, 20 nmol/L albumin-bound paclitaxel intervention), BP1003+different concentrations of albumin-bound paclitaxel group(200 μg/mL BP1003 combined with 5, 10, 20 nmol/L albumin-bound paclitaxel intervention). The proliferation viability, apoptotic rate and the protein expression levels of STAT3, STAT4, STAT6, Bcl-2, Bax and c-Myc were detected. The transplanted tumor model was established by subcutaneous injection of PANC-1 and ASPC-1 cell suspension in nude mice, which were divided into control group(normal saline intervention),BP1003 group(25 mg/kg BP1003 intervention, once every 2 weeks) and albumin-bound paclitaxel group(10 mg/kg albumin-bound paclitaxel, once a week), BP1003+albumin-bound paclitaxel group(25 mg/kg BP1003 intervention, once every 2 weeks combined with 10 mg/kg albumin-bound paclitaxel, once a week). Four weeks later, the graft volume and mass were measured, and the protein expression levels of STAT3, Bcl-2, Bax and c-Myc were detected. Results: The apoptotic rate and the protein expression levels of Bax of PANC-1 and ASPC-1 cells in BP1003 group and albumin-bound paclitaxel group were higher than those in the control group,while the proliferation viability and protein expression levels of STAT3, Bcl-2 and c-Myc were lower than those in control group(P<0.05). There was no significant difference in the expression levels of STAT4 and STAT6 in PANC-1 and ASPC-1 cells between BP1003 group and the control group(P>0.05). The apoptotic rate and the protein expression levels of Bax of PANC-1 and ASPC-1 cells in BP1003+different concentrations of albumin-bound paclitaxel groups were higher than those in different concentrations of albumin-bound paclitaxel groups, and the proliferation viability and protein expression levels of STAT3, Bcl-2 and c-Myc were lower than those in different concentrations of albumin-bound paclitaxel groups(P <0.05). The volume and mass of transplanted tumor and the protein expression levels of STAT3, Bcl-2 and c-Myc of nude mice in BP1003 group, albumin-bound paclitaxel group and BP1003+albumin-bound paclitaxel group were all lower compared with the control group, the protein expression level of Bax was higher compared with the control group(P<0.05), and the above changes in BP1003+albumin-bound paclitaxel group were more significant compared with BP1003 and albumin-bound paclitaxel group. Conclusion: BP1003 increases the sensitivity of pancreatic cancer cells to albumin-bound paclitaxel by inhibiting the expression of STAT3.更多还原