Ke Jing, Gu Chunming, Zhang Heyan, Liu Yang, Zhang Wenhao, Rao Huiling, Li Shan, Wu Fuyun
School of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China.
J Oncol. 2021 Apr 21;2021:9992218. doi: 10.1155/2021/9992218. eCollection 2021.
Cervical cancer is the fourth most common cancer in women worldwide and is the main cause of cancer-related deaths in women. Cisplatin (DDP) is one of the major chemotherapeutic drugs for cervical cancer patients. But, drug resistance limits the effectiveness of cancer therapy. Nucleolin (NCL) is a nucleocytoplasmic multifunctional protein involved in the development of cancer. It has been reported that NCL may be a potential target for modulation of drug resistance. However, the precise molecular mechanisms are poorly understood.
Human cervical cancer Hela cells and their cisplatin-resistant cell line Hela/DDP were used in this study. The protein level of NCL in cervical cancer cells was measured by western blot analysis. Hela cells and Hela/DDP cells were transfected with NCL overexpression plasmid or NCL siRNA separately. MTT and EdU assay were performed to evaluate the cell viability and sensitivity to cisplatin. The drug efflux function of MDR1 protein was assessed by intracellular rhodamine-123 accumulation assay.The promoter activity of MDR1 was assessed by using a dual-luciferase reporter assay.
We found that the protein level of NCL was elevated in Hela/DDP cells. Overexpression of NCL increased cervical cancer cell proliferation and attenuated the sensitivity to cisplatin. Overexpression of NCL increased Multidrug resistance (MDR1) gene expression and drug efflux. Our results demonstrated that NCL was highly related with cisplatin resistance in cervical cancer. NCL played an important role in MDR1 gene transcription through regulation of the transcription factor YB1.
Our findings revealed the novel role of NCL in cisplatin-resistant cervical cancer and NCL may be a potential therapeutic target for chemoresistance.
宫颈癌是全球女性中第四大常见癌症，也是女性癌症相关死亡的主要原因。顺铂（DDP）是宫颈癌患者主要的化疗药物之一。但是，耐药性限制了癌症治疗的效果。核仁素（NCL）是一种参与癌症发展的核质多功能蛋白。据报道，NCL可能是调节耐药性的潜在靶点。然而，其确切的分子机制尚不清楚。
本研究使用人宫颈癌Hela细胞及其顺铂耐药细胞系Hela/DDP。通过蛋白质印迹分析测量宫颈癌细胞中NCL的蛋白水平。分别用NCL过表达质粒或NCL siRNA转染Hela细胞和Hela/DDP细胞。进行MTT和EdU试验以评估细胞活力和顺铂敏感性。通过细胞内罗丹明-123积累试验评估MDR1蛋白的药物外排功能。使用双荧光素酶报告基因试验评估MDR1的启动子活性。
我们发现Hela/DDP细胞中NCL的蛋白水平升高。NCL的过表达增加了宫颈癌细胞增殖并减弱了对顺铂的敏感性。NCL的过表达增加了多药耐药（MDR1）基因表达和药物外排。我们的结果表明，NCL与宫颈癌顺铂耐药高度相关。NCL通过调节转录因子YB1在MDR1基因转录中起重要作用。
我们的研究结果揭示了NCL在顺铂耐药宫颈癌中的新作用，NCL可能是化疗耐药的潜在治疗靶点。
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