Ming Luo1,2, Ling Ding1,2, Qingjian Li1,2, Herui Yao3,4,5. 1. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China. 2. Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, Guangdong, China. 3. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China. yaoherui@163.com. 4. Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, Guangdong, China. yaoherui@163.com. 5. Breast Tumor Center, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China. yaoherui@163.com.
Abstract
BACKGROUND: A large proportion of breast cancer patients are resistant to radiotherapy, which is a mainstay treatment for this malignancy, but the mechanisms of radioresistance remain unclear. METHODS AND MATERIALS: To evaluate the role of miRNAs in radioresistance, we established two radioresistant breast cancer cell lines MCF-7R and T-47DR derived from parental MCF-7 and T-47D. Moreover, miRNA microarray, quantitative RT-PCR analysis, luciferase reporter assay and western blotting were used. RESULTS: We found that miR-668 was most abundantly expressed in radioresistant cells MCF-7R and T-47DR. miR-668 knockdown reversed radioresistance of MCF-7R and T-47DR, miR-668 overexpression enhanced radioresistance of MCF-7 and T-47D cells. Mechanically, bioinformatics analysis combined with experimental analysis demonstrated IκBα, a tumor-suppressor as well as an NF-κB inhibitor, was a direct target of miR-668. Further, miR-668 overexpression inhibited IκBα expression, activated NF-κB, thus, increased radioresistance of MCF-7 and T-47D cells. Conversely, miR-668 knockdown restored IκBα expression, suppressed NF-κB, increased radiosensitivity of MCF-7R and T-47DR cells. CONCLUSION: Our findings suggest miR-668 is involved in the radioresistance of breast cancer cells and miR-668-IκBα-NF-κB axis may be a novel candidate for developing rational therapeutic strategies for human breast cancer treatment.
BACKGROUND: A large proportion of breast cancerpatients are resistant to radiotherapy, which is a mainstay treatment for this malignancy, but the mechanisms of radioresistance remain unclear. METHODS AND MATERIALS: To evaluate the role of miRNAs in radioresistance, we established two radioresistant breast cancer cell lines MCF-7R and T-47DR derived from parental MCF-7 and T-47D. Moreover, miRNA microarray, quantitative RT-PCR analysis, luciferase reporter assay and western blotting were used. RESULTS: We found that miR-668 was most abundantly expressed in radioresistant cells MCF-7R and T-47DR. miR-668 knockdown reversed radioresistance of MCF-7R and T-47DR, miR-668 overexpression enhanced radioresistance of MCF-7 and T-47D cells. Mechanically, bioinformatics analysis combined with experimental analysis demonstrated IκBα, a tumor-suppressor as well as an NF-κB inhibitor, was a direct target of miR-668. Further, miR-668 overexpression inhibited IκBα expression, activated NF-κB, thus, increased radioresistance of MCF-7 and T-47D cells. Conversely, miR-668 knockdown restored IκBα expression, suppressed NF-κB, increased radiosensitivity of MCF-7R and T-47DR cells. CONCLUSION: Our findings suggest miR-668 is involved in the radioresistance of breast cancer cells and miR-668-IκBα-NF-κB axis may be a novel candidate for developing rational therapeutic strategies for humanbreast cancer treatment.
Entities:
Keywords:
Breast cancer; IκBα; NF-κB; Radioresistance; miR-668
Authors: J L Hu; G Y He; X L Lan; Z C Zeng; J Guan; Y Ding; X L Qian; W T Liao; Y Q Ding; L Liang Journal: Oncogenesis Date: 2018-02-20 Impact factor: 7.485