CircZNF609 Promotes Bladder Cancer Progression and Inhibits Cisplatin Sensitivity via miR-1200/CDC25B Pathway

Circular RNAs (circRNAs) have been extensively studied in tumor development and treatment. CircZNF609 has been shown to act as an oncogene in a variety of solid tumors and may serve as a novel biomarker for tumor diagnosis and treatment. However, the underlying role and mechanism of circZNF609 in bladder cancer (BCa) development and cisplatin chemosensitivity were unknown. Quantitative real-time PCR (qRT-PCR) was applied to determine the expression of circZNF609, microRNA 1200 (miR-1200) and CDC25B in BCa cells and tissues. Western blot was used to detect the protein level of CDC25B. Functional assays in vitro and in vivo were conducted to investigate the effects of circZNF609 on tumor development and cisplatin chemosensitivity in BCa. RNA sequencing and online databases were used to predict the interactions among circZNF609, miR-1200 and CDC25B. Dual luciferase reporter assay, RNA pull-down assay and RNA fluorescence in situ hybridization (FISH) were applied to confirm the mechanism. CircZNF609 expression was significantly up-regulated in BCa cell lines and tissues. Increased expression of circZNF609 was related to a worse survival in BCa patients. In vitro and in vivo, enforced-expression of circZNF609 enhanced BCa cells proliferation, migration and cisplatin chemoresistance. Mechanistically, circZNF609 alleviated the inhibition effect on target CDC25B expression by sponging miR-1200. CircZNF609 promoted tumor growth through novel circZNF609/miR-1200/CDC25B axis, implying that circZNF609 has significant potential to serve as a new diagnostic biomarker and therapeutic target for BCa patients.

Metallothionein-3 promotes cisplatin chemoresistance remodelling in neuroblastoma

Metallothionein-3 has poorly characterized functions in neuroblastoma. Cisplatin-based chemotherapy is a major regimen to treat neuroblastoma, but its clinical efficacy is limited by chemoresistance. We investigated the impact of human metallothionein-3 (hMT3) up-regulation in neuroblastoma cells and the mechanisms underlying the cisplatin-resistance. We confirmed the cisplatin-metallothionein complex formation using mass spectrometry. Overexpression of hMT3 decreased the sensitivity of neuroblastoma UKF-NB-4 cells to cisplatin. We report, for the first time, cisplatin-sensitive human UKF-NB-4 cells remodelled into cisplatin-resistant cells via high and constitutive hMT3 expression in an in vivo model using chick chorioallantoic membrane assay. Comparative proteomic analysis demonstrated that several biological pathways related to apoptosis, transport, proteasome, and cellular stress were involved in cisplatin-resistance in hMT3 overexpressing UKF-NB-4 cells. Overall, our data confirmed that up-regulation of hMT3 positively correlated with increased cisplatin-chemoresistance in neuroblastoma, and a high level of hMT3 could be one of the causes of frequent tumour relapses.