Abstract
BackgroundCisplatin (DDP) is a major chemotherapeutic drug which was widely used for cervical cancer (CC) patients with advanced or recurrent although its limitation in the development of resistance. LncRNA nicotinamide nucleotide transhydrogenase-antisense RNA1 (NNT-AS1) has been reported to be involved in the DDP resistance. However, the role of NNT-AS1 in DDP resistance in CC remain unknown.MethodsThe mRNA expression of NNT-AS1, microRNA-186 (miR-186) and HMGB1 was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation and apoptosis abilities were measured via MTT assay or flow cytometry, respectively. Western blot was used to measure the expression level of HMGB1, Bax, Bcl-2, Cleaved-caspase 3, N-cadherin, Vimentin and E-cadherin. Cell migration and invasion abilities were analyzed using Transwell assay. The interaction among NNT-AS1, miR-186 and HMGB1 was confirmed by luciferase reporter assay and RNA pull-down assay. Murine xenograft model was established using stably transfected SiHa/DDP cells.ResultsNNT-AS1 level was significantly elevated in CC tissues and cells, especially in DDP-resistant tumors and cell lines. Subsequently, loss-of function assays indicated that NNT-AS1 silence could attenuate DDP resistance by inhibiting proliferation, metastasis and EMT but inducing apoptosis in DDP-resistant CC cells. Besides that, knockdown of NNT-AS1 also antagonized DDP resistance in vivo. Bioinformatics predication revealed NNT-AS1 directly bound to miR-186 and HMGB1 was a target of miR-186. Additionally, NNT-AS1 could regulate HMGB1 expression via targeting miR-186. Furthermore, restoration experiments showed NNT-AS1 knockdown might improve DDP-sensitivity of CC cells via blocking HMGB1 expression by competitive interaction with miR-186.ConclusionNNT-AS1 improved chemoresistance of DDP-resistant CC cells via modulating miR-186/HMGB1 axis.
Highlights
Cisplatin (DDP) is a major chemotherapeutic drug which was widely used for cervical cancer (CC) patients with advanced or recurrent its limitation in the development of resistance
NNT‐AS1 is up‐regulated in DDP‐resistant CC tissues and cells lines and highly expressed NNT‐AS1 predicates poor prognosis To explore the role of nucleotide transhydrogenase-antisense RNA1 (NNT-AS1) in DDP-resistant CC, the expression of NNT-AS1 was detected using quantitative real-time polymerase chain reaction (qRT-PCR) in DDP-sensitive and DDP-resistant CC tissues and cells
Results showed that NNT-AS1 level was significantly elevated in CC tissues and cells, especially in DDP-resistant tumors and cell lines (HeLa/DDP and SiHa/DDP) (Fig. 1a, c)
Summary
Cisplatin (DDP) is a major chemotherapeutic drug which was widely used for cervical cancer (CC) patients with advanced or recurrent its limitation in the development of resistance. LncRNA nicotinamide nucleotide transhydrogenase-antisense RNA1 (NNT-AS1) has been reported to be involved in the DDP resistance. The role of NNT-AS1 in DDP resistance in CC remain unknown. 20–25% patients remain suffer from treatment failure because of distant metastasis and recurrence [2, 3]. Cisplatin (DDP) is a widely used chemotherapeutic drug, and is often used to combination with radiotherapy for the treatment of patients with advanced or recurrent CC [4]. The development of resistance to DDP-based chemotherapy has become a major limiting factor for its efficacy as an anticancer drug [5].
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