胰腺癌是一种最致命的疾病之一，具有极高的转移率和低生存率。高水平的NRF2已在许多恶性肿瘤中被检测到，包括头颈部、肺部和结直肠癌，促进肿瘤细胞的扩张和存活，提高对应激条件的化学抵抗力，影响治疗反应。为评估调控NRF2表达对治疗胰腺癌细胞的可能性，我们研究了NRF2特异性siRNA抑制NRF2基因以及与紫杉醇联合应用对胰腺癌细胞的影响。由于高表达NRF2基因，我们选择了Miapaca-2细胞系进行这项研究。然后，将不同组的Miapaca-2细胞分别处理NRF2 siRNA和紫杉醇，以及二者的联合作用。随后，通过MTT测定细胞存活率，通过Annexin V-FITC/PI染色试验诱导细胞凋亡，通过流式细胞术检测细胞周期和自噬，并通过划痕愈合实验评估细胞迁移能力。最后，通过qRT-PCR测定不同组的凋亡相关基因Bax、Caspase-3、Caspase-9以及迁移途径相关基因MMP-2和MMP-9的表达水平。NRF2特异性siRNA与紫杉醇联合应用显著降低了胰腺癌细胞中的NRF2基因表达。NRF2 siRNA转染显著降低了细胞存活率。此外，NRF2 siRNA与紫杉醇联合治疗加强了抗肿瘤效应，例如抑制细胞迁移、诱导凋亡以及自噬和G2期细胞周期阻滞。NRF2抑制增强了Bax、Caspase-3和Caspase-9基因的表达，并降低了在凋亡和细胞迁移途径中扮演重要角色的Bcl-2、MMP-2和MMP-9基因的表达。NRF2 siRNA增加了胰腺癌细胞Miapaca-2对紫杉醇的敏感性。因此，抑制NRF2并结合紫杉醇可能成为治疗胰腺癌的一种新的有效方法。©2023年作者，由Springer Science+Business Media, LLC独家许可，属于Springer Nature的一部分。

Pancreatic cancer is one of the most deadly diseases, with a very high metastasis and low survival rate. High levels of NRF2 have been detected in numerous malignancies, including head, neck, lung, and colon cancers, promoting the expansion and survival of cancer cells and chemical resistance to stressful conditions and affecting the response to treatment. To evaluate the possibility that modulation of NRF2 expression could be effective in treating pancreatic cancer cells, we explored the effect of knockdown of the NRF2 gene by NRF2-specific siRNA and its influence in combination with paclitaxel on pancreatic cancer cells. Miapaca-2 cell line, due to the high expression of the NRF2 gene, was selected for this study. Then, Miapaca-2 cells in different groups were treated with NRF2 siRNA and paclitaxel separately and in combination. After that, cell viability was measured by MTT assay and apoptosis induction by Annexin V-FITC/PI staining test. Cell cycle and autophagy were examined by flow cytometry, and cell migration was assessed by wound-healing assay. Finally, the expression of genes involved in apoptosis, Bax, Caspase-3, Caspase-9, and genes related to migration pathway, MMP-2, and MMP-9 in different groups were measured using qRT-PCR. Combined use of NRF2-specific siRNA with paclitaxel significantly reduced NRF2 gene expression in pancreatic cancer cells. NRF2 siRNA transfection significantly reduced cell viability. In addition, paclitaxel combination therapy with NRF2 siRNA strengthens the anti-tumor effects, such as inhibiting cell migration and provoking apoptosis, and autophagy and the cell cycle arrest in the G2 phase. NRF2 suppression augmented the expression of Bax, Caspase-3, and Caspase-9 genes and lowered the expression of Bcl-2, MMP-2, and MMP-9 genes, which play crucial roles in the pathways of apoptosis and cell migration, respectively. NRF2 siRNA enhances the susceptibility of Miapaca-2 cells to paclitaxel in pancreatic cancer cells. Thereby, suppressing NRF2 in combination with paclitaxel can be a new and efficacious treatment approach in treating pancreatic cancer.© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.