Farzaneh Darbeheshti1,2, Elham Zokaei3, Yaser Mansoori4,5, Sima Emadi Allahyari1, Zeeba Kamaliyan6, Sepideh Kadkhoda1, Javad Tavakkoly Bazzaz1, Nima Rezaei7,8,9, Abbas Shakoori10,11. 1. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. 2. Medical Genetics Network (MeGeNe), Universal Scientific Education and Research Network (USERN), Tehran, Iran. 3. Department of Biology, Faculty of Sciences, Shahid Bahonar University of Kerman, Kerman, Iran. 4. Noncommunicable Disease Research Center, Fasa University of Medical Sciences, Fasa, Iran. 5. Department of Medical Genetics, Fasa University of Medical Sciences, Fasa, Iran. 6. Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 7. Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, Tehran, Iran. rezaei_nima@tums.ac.ir. 8. Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. rezaei_nima@tums.ac.ir. 9. Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran. rezaei_nima@tums.ac.ir. 10. Medical Genetic Ward, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, Tehran, Iran. shakooria@sina.tums.ac.ir. 11. Breast Disease Research Center (BDRC), Tehran University of Medical Sciences, Tehran, Iran. shakooria@sina.tums.ac.ir.
Abstract
BACKGROUND: Circular RNAs (circRNAs) have been implicated in the initiation and development of breast cancer as functional non-coding RNAs (ncRNA). The roles of circRNAs as the competing endogenous RNAs (ceRNAs) to sponge microRNAs (miRNAs) have also been indicated. However, the functions of circRNAs in breast cancer have not been totally elucidated. This study aimed to explore the clinical implications and possible roles of circ_0044234 in carcinogenesis of the most problematic BC subtype, triple negative breast cancer (TNBC), which are in desperate need of biomarkers and targeted therapies. METHODS: The importance of circ_0044234 as one of the most dysregulated circRNAs in TNBC was discovered through microarray expression profile analysis. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to confirm the downregulation of circ_0044234 in triple negative tumors and cell lines versus non-triple negative ones. The bioinformatics prediction revealed that circ_0044234 could act as an upstream sponge in the miR-135b/GATA3 axis, two of the most dysregulated transcripts in TNBC. RESULTS: Our experimental investigation of circ_0044234 expressions in various BC subtypes as well as cell lines reveals that TNBC expresses circ_0044234 at a substantially lower level than non-TNBC. The ROC curve analysis indicates that it could be applied as a discriminative biomarker to identify TNBC from other BC subtypes. Moreover, circ_0044234 expression could be an independent prognostic biomarker in BC. Interestingly, a substantial inverse expression correlation was detected between circ_0044234 and miR-135b-5p as well as between miR-135b-5p and GATA3 in breast tumors. CONCLUSIONS: The possible clinical usefulness of circ_0044234 as a promising distinct biomarker and upcoming therapeutic target for TNBC have been indicated in this research. Our comprehensive approach revealed the potential circ_0044234/miR135b-5p/GATA3 ceRNA axis in TNBC.
BACKGROUND: Circular RNAs (circRNAs) have been implicated in the initiation and development of breast cancer as functional non-coding RNAs (ncRNA). The roles of circRNAs as the competing endogenous RNAs (ceRNAs) to sponge microRNAs (miRNAs) have also been indicated. However, the functions of circRNAs in breast cancer have not been totally elucidated. This study aimed to explore the clinical implications and possible roles of circ_0044234 in carcinogenesis of the most problematic BC subtype, triple negative breast cancer (TNBC), which are in desperate need of biomarkers and targeted therapies. METHODS: The importance of circ_0044234 as one of the most dysregulated circRNAs in TNBC was discovered through microarray expression profile analysis. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to confirm the downregulation of circ_0044234 in triple negative tumors and cell lines versus non-triple negative ones. The bioinformatics prediction revealed that circ_0044234 could act as an upstream sponge in the miR-135b/GATA3 axis, two of the most dysregulated transcripts in TNBC. RESULTS: Our experimental investigation of circ_0044234 expressions in various BC subtypes as well as cell lines reveals that TNBC expresses circ_0044234 at a substantially lower level than non-TNBC. The ROC curve analysis indicates that it could be applied as a discriminative biomarker to identify TNBC from other BC subtypes. Moreover, circ_0044234 expression could be an independent prognostic biomarker in BC. Interestingly, a substantial inverse expression correlation was detected between circ_0044234 and miR-135b-5p as well as between miR-135b-5p and GATA3 in breast tumors. CONCLUSIONS: The possible clinical usefulness of circ_0044234 as a promising distinct biomarker and upcoming therapeutic target for TNBC have been indicated in this research. Our comprehensive approach revealed the potential circ_0044234/miR135b-5p/GATA3 ceRNA axis in TNBC.
Entities:
Keywords:
Bioinformatics; GATA3; Triple negative breast cancer; ceRNA; circ_0044234; miR135b-5p
Authors: Fatima Domenica Elisa De Palma; Francesco Salvatore; Jonathan G Pol; Guido Kroemer; Maria Chiara Maiuri Journal: Biomedicines Date: 2022-03-21