Nrf2 induced cisplatin resistance in ovarian cancer by promoting CD99 expression

Abstract

Cisplatin resistance is a vital obstacle for the prognosis of ovarian cancer. However, the mechanism of cisplatin resistance is still unknown. This research was performed to explore the role of Nrf2 (nuclear factor, erythroid 2 like 2) and CD99 (CD99 molecule) in cisplatin resistance in ovarian cancer. QRT-PCR and Western blot were used to detect the expression of CD99 in ovarian cancer cells and tissues with different cisplatin sensitivities. Cell viability was analyzed by the Cell Counting Kit-8 (CCK8). The relationship of Nrf2 and CD99 was assessed by dual-luciferase reporter gene assay and chromatin immunoprecipitation (ChIP). Bioinformatics analysis was performed to search for the downstream gene of CD99. In this study, it was revealed that CD99 was highly expressed in cisplatin-resistant ovarian cancer cells and tissues, while lower CD99 expression was found in cisplatin-sensitive ovarian cancer cells and tissues. In addition, the overexpression of CD99 resulted in cisplatin resistance; on the other hand, knockdown of CD99 sensitized ovarian cancer to cisplatin. Furthermore, survival analysis indicated that overall survival (OS) and progression-free survival (PFS) of patients with higher CD99 expression were shorter than those with lower CD99 expression. It was also found that when Nrf2 was upregulated in cisplatin-sensitive ovarian cells, CD99 expression and cell viability increased after cisplatin treatment. Knockdown of CD99 could reverse cisplatin resistance induced by Nrf2. Conversely, when Nrf2 was knocked down in cisplatin-resistant ovarian cancer cells, CD99 expression and cell viability with cisplatin treatment decreased, while simultaneously upregulating CD99 reactivated cisplatin resistance in ovarian cancer cells. The dual-luciferase reporter gene assay and ChIP analysis suggested CD99 was a downstream gene of Nrf2, and Nrf2 positively regulated the expression of CD99 at the transcriptional level. In conclusion, Nrf2 induced cisplatin resistance in ovarian cancer cells by promoting CD99 expression. Targeted CD99 might be an effective way to reverse cisplatin resistance in ovarian cancer.