关键词: 核呼吸因子(NRF1), ATP结合盒转运蛋白C1(ABCC1), 肺腺癌, 上皮细胞-间充质转化, 化学治疗抵抗

Abstract: Objective To explore the effect of nuclear respiratory factor 1(NRF1) activation of ATP binding cassette transporter C1(ABCC1) transcription on cisplatin resistance in lung adenocarcinoma cells and its potential mechanisms. Methods The expression levels of ABCC1 in lung adenocarcinoma tumor tissues were analyzed by oncogenomic datasets. Cells were grouped into: sh-NC, sh-ABCC1, sh-NC+oe-NC, sh-NRF1+oe-NC and sh-NRF1+oe-ABCC1. Real-time polymerase chain reaction (RT-qPCR) was used to detect the expression of ABCC1 in lung adenocarcinoma cells. Cisplatin-resistant lung adenocarcinoma cell strains were constructed to detect the expression level of ABCC1. Cell proliferation, migration and invasion were assessed by colony formation and Transwell assay. The IC₅₀ values of drug-resistant lung adenocarcinoma cells treated with different doses(0, 0.001, 0.002,0.004, 0.008,0.016 and 0.032 mg/mL) of cisplatin were detected by CCK-8 assay. Western blot was used to detect the protein expression of epithelial-mesenchymal transition markers (E-cadherin, N-cadherin). Dual luciferase and ChIP assays were performed to verify the binding relationship between NRF1 and ABCC1. Results ABCC1 was highly expressed in lung adenocarcinoma tumor tissues and cells. Compared with cisplatin-sensitive lung adenocarcinoma cells, ABCC1 was highly expressed in cisplatin-resistant lung adenocarcinoma cells, and knockdown of ABCC1 significantly inhibited cell proliferation, migration and invasion, and increased the expression of E-cadherin (P＜0.05) and decreased the expression of N-cadherin (P＜0.05). Knockdown of ABCC1 significantly increased the sensitivity of lung adenocarcinoma cells to cisplatin (P＜0.05). In addition, dual luciferase and ChIP experiments confirmed the binding relationship between NRF1 and ABCC1 promoter de-binding, and NRF1 could activate the transcription of ABCC1. Knockdown of NRF1 attenuated the inhibitory effect of over-expressed ABCC1 on the proliferation, migration, invasion and cisplatin-resistance of lung adenocarcinoma cells(P＜0.05). Conclusions This study revealed the effect of the NRF1/ABCC1 axis enhancement is a potential strategy to overcome the barrier of cisplatin-resistance in chemotherapy of lung adenocarcinoma.

Key words: nuclear respiratory factor 1(NRF1), ATP binding cassette transporter C1(ABCC1), lung adenocarcinoma, epithelial-mesenchymal transition, chemotherapy resistance