Abstract
BackgroundAlthough both circular RNAs (circRNAs) and autophagy are associated with the function of breast cancer (BC), whether circRNAs regulate BC progression via autophagy remains unknown. In this study, we aim to explore the regulatory mechanisms and the clinical significance of autophagy-associated circRNAs in BC.MethodsAutophagy associated circRNAs were screened by circRNAs deep sequencing and validated by qRT-PCR in BC tissues with high- and low- autophagic level. The biological function of autophagy associated circRNAs were assessed by plate colony formation, cell viability, transwells, flow cytometry and orthotopic animal models. For mechanistic study, RNA immunoprecipitation, circRNAs pull-down, Dual luciferase report assay, Western Blot, Immunofluorescence and Immunohistochemical staining were performed.ResultsAn autophagy associated circRNA circCDYL was elevated by 3.2 folds in BC tissues as compared with the adjacent non-cancerous tissues, and circCDYL promoted autophagic level in BC cells via the miR-1275-ATG7/ULK1 axis; Moreover, circCDYL enhanced the malignant progression of BC cells in vitro and in vivo. Clinically, increased circCDYL in the tumor tissues and serum of BC patients was associated with higher tumor burden, shorter survival and poorer clinical response to therapy.ConclusionscircCDYL promotes BC progression via the miR-1275-ATG7/ULK1-autophagic axis and circCDYL could act as a potential prognostic and predictive molecule for breast cancer patients.
Highlights
Both circular RNAs and autophagy are associated with the function of breast cancer (BC), whether circRNAs regulate BC progression via autophagy remains unknown
Serum samples from two other cohorts of Sun Yat-sen Memorial Hospital (SYSMH) were collected for droplet digital PCR detection (Cohort 2 was a retrospective cohort collected from 1 March 2017 to 30 September 2017, containing 14 benign patients, 30 early breast cancer (EBC) patients and 18 metastatic breast cancer (MBC) patients; Cohort 3 was a prospective cohort from 1 June 2015 to 1 April 2019, in which only MBC patients at first diagnosis were enrolled)
Identification of autophagy-associated circRNAs in breast cancer In order to determine the clinical significance of autophagy in breast cancer, the expression of LC3 detected by immunohistochemical staining (IHC) in breast cancer patients was analyzed in Cohort 1
Summary
Both circular RNAs (circRNAs) and autophagy are associated with the function of breast cancer (BC), whether circRNAs regulate BC progression via autophagy remains unknown. Several studies demonstrated that circRNAs could act as miRNA sponges [7, 20,21,22,23], and circRNAs with intronic sequence could regulate transcription of parental genes by interacting with RNA polymerase II in the nucleus [24, 25], while certain circRNAs exhibited the ability to translate proteins [26,27,28]. The relationship between circRNAs and autophagy in breast cancer, as well as the role of autophagy-associated circRNAs in clinical diagnosis and treatment of breast cancer remain largely illusive
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