CircNR3C2 promotes HRD1-mediated tumor-suppressive effect via sponging miR-513a-3p in triple-negative breast cancer

Molecular Cancer - Tập 20 Số 1
Ya Fan1, Jia Wang2, Jin Wen3, Yifei Sun4, Yuemei Xu5, Yipin Wang6, Xiubin Liang4, Dongming Su6
1Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu, China
2Department of Breast Surgery, Institute of Breast Disease, The Second Hospital of Dalian Medical University, Dalian, Liaoning, China
3State Key Laboratory of Reproductive Medicine, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu, China
4Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu, China
5Department of Pathology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
6Center of Pathology and Clinical Laboratory, Sir Run Run Hospital of Nanjing Medical University, Nanjing, Jiangsu, China

Tóm tắt

Abstract Background E3 ubiquitin ligase HRD1 (HMG-CoA reductase degradation protein 1, alias synoviolin with SYVN1 as the official gene symbol) was found downregulated and acting as a tumor suppressor in breast cancer, while the exact expression profile of HRD1 in different breast cancer subtypes remains unknown. Recent studies characterized circular RNAs (circRNAs) playing an regulatory role as miRNA sponge in tumor progression, presenting a new viewpoint for the post-transcriptional regulation of cancer-related genes. Methods Examination of the expression of HRD1 protein and mRNA was implemented using public microarray/RNA-sequencing datasets and breast cancer tissues/cell lines. Based on public RNA-sequencing results, online databases and enrichment/clustering analyses were used to predict the specific combinations of circRNA/miRNA that potentially govern HRD1 expression. Gain-of-function and rescue experiments in vitro and in vivo were executed to evaluate the suppressive effects of circNR3C2 on breast cancer progression through HRD1-mediated proteasomal degradation of Vimentin, which was identified using immunoblotting, immunoprecipitation, and in vitro ubiquitination assays. Results HRD1 is significantly underexpressed in triple-negative breast cancer (TNBC) against other subtypes and has an inverse correlation with Vimentin, inhibiting the proliferation, migration, invasion and EMT (epithelial-mesenchymal transition) process of breast cancer cells via inducing polyubiquitination-mediated proteasomal degradation of Vimentin. CircNR3C2 (hsa_circ_0071127) is also remarkably downregulated in TNBC, negatively correlated with the distant metastasis and lethality of invasive breast carcinoma. Overexpressing circNR3C2 in vitro and in vivo leads to a crucial enhancement of the tumor-suppressive effects of HRD1 through sponging miR-513a-3p. Conclusions Collectively, we elucidated a bona fide circNR3C2/miR-513a-3p/HRD1/Vimentin axis that negatively regulates the metastasis of TNBC, suggesting that circNR3C2 and HRD1 can act as potential prognostic biomarkers. Our study may facilitate the development of therapeutic agents targeting circNR3C2 and HRD1 for patients with aggressive breast cancer.

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Molecular Cancer

Tập 20 Số 1

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