ABSTRACT
Emerging numbers of endogenous circular RNAs (circRNAs) have gained much attention to serve as essential regulators in the carcinogenesis of human cancers. Unfortunately, the occurrence of paclitaxel (PTX) resistance to ovarian cancer remains to be responsible for the poor prognosis. Herein, the aim of our study is to reveal a dysregulation of a particular circRNA, circANKRD17 (has_circ_0007883), and its exact role involving in chemoresistance of ovarian cancer. Expression patterns of circANKRD17 in PTX-resistant ovarian cancer tissues and cell lines was examined using quantitative real-time PCR analysis. Role of circANKRD17 on drug resistance and cell viability was evaluated by CCK-8 assay. Colony formation was subjected to measure cell proliferation. Flow cytometry was employed to evaluate cell cycle either or cell apoptosis. Xenograft models were constructed for further in vivo confirmation. The cicrANKRD17/FUS/FOXR2 axis was demonstrated using bioinformatics analysis, RNA pull-down, as well as RNA immunoprecipitation assays. Dramatically high expressed circANKRD17 observed in ovarian cancer tissues and cells was correlated with PTX resistance, which indicated the poor prognosis. Functionally, knockdown of circANKRD17 decreased PTX resistance via inhibiting cell viability and inducing cell apoptosis. Mechanistically, circANKRD17 interacted with the RNA-binding protein, fused in sarcoma (FUS) to stabilize FOXR2. In summary, our study uncovered a novel machinery of circANKRD17/FUS/FOXR2 referring to ovarian cancer drug sensitivity and tumorigenesis, highlighting a potential strategy for circRNAs in chemoresistance.
Subject(s)
MicroRNAs , Ovarian Neoplasms , Humans , Female , Paclitaxel/pharmacology , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , RNA, Circular/genetics , Carcinogenesis , Cell Transformation, Neoplastic , Cell Proliferation , Drug Resistance, Neoplasm/genetics , Cell Line, Tumor , Forkhead Transcription Factors , RNA-Binding Protein FUSABSTRACT
More and more evidence suggests the oncogenic function of overexpressed CDC28 protein kinase regulatory subunit 2 (CKS2) in various human cancers. However, CKS2 has rarely been studied in cervical cancer. Herein, taking advantage of massive genetics data from multicenter RNA-seq and microarrays, we were the first group to perform tissue microarrays for CKS2 in cervical cancer. We were also the first to evaluate the clinical significance of CKS2 with large samples (980 cervical cancer cases and 422 noncancer cases). We further excavated the mechanism of the tumor-promoting activities of CKS2 in cervical cancer through analysis of genetic mutation profiles, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) significant enrichment of genes coexpressed with CKS2. According to the results, expression data from multilevels unanimously supported the overexpression of CKS2 in cervical cancer. Patients with cervical cancer in stage II from inhouse microarrays had significantly higher expression of CKS2, and CKS2 overexpression had an adverse impact on the disease-free survival status of cervical cancer patients in GSE44001. Both mutation types of mRNA high and mRNA low appeared in cervical cancer cases from the TCGA Firehose project. Gene coexpressed with CKS2 participated in pathways including the cell cycle, estrogen signaling pathway, and DNA replication. In summary, upregulated CKS2 is closely associated with the malignant clinical development of cervical cancer and might serve as a valuable therapeutic target in cervical cancer.
