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Oncogene. 2017 Oct 19;36(42):5874-5884. doi: 10.1038/onc.2017.193. Epub 2017 Jun 19.

MicroRNA-20a-mediated loss of autophagy contributes to breast tumorigenesis by promoting genomic damage and instability.

Liu L1,2, He J2, Wei X2, Wan G1,2, Lao Y3, Xu W1,2, Li Z4, Hu H5, Hu Z6, Luo X2, Wu J1,2, Xie W2,7, Zhang Y2,7, Xu N2,7.

Author information

1
School of Life Sciences, Tsinghua University, Beijing, China.
2
Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen, China.
3
School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
4
School of Chemical Biology and Biotechnology, Graduate School at Shenzhen, Peking University, Shenzhen, China.
5
Department of Breast Surgery, Peking University Shenzhen Hospital, Shenzhen, China.
6
Department of Clinical Oncology, Wuhan No. 1 Hospital, Wuhan, China.
7
Open FIESTA center, Tsinghua University, Shenzhen, China.

Abstract

Gene expression analysis of The Cancer Genome Atlas (TCGA) breast cancer data set show that miR-20a is upregulated in human breast cancer, especially in triple-negative subtype. Gene Set Enrichment Analysis suggests that miR-20a expression negatively correlates with the autophagy/lysosome pathway. We report here that miR-20a inhibits the basal and nutrient starvation-induced autophagic flux and lysosomal proteolytic activity, increases intracellular reactive oxygen species levels and DNA damage response by targeting several key regulators of autophagy, including BECN1, ATG16L1 and SQSTM1. Re-introduction of exogenous BECN1, ATG16L1 or SQSTM1 reverses the inhibitory effect of miR-20a on autophagy and decreases DNA damage. A negative correlation between miR-20a and its target genes is observed in breast cancer tissues. Lower levels of BECN1, ATG16L1 and SQSTM1 are more common in triple-negative cancers than in other subtypes. High levels of miR-20a also associate with higher frequency of copy-number alterations and DNA mutations in breast cancer patients. Further studies in a xenograft mouse model show that miR-20a promotes tumor initiation and tumor growth. Collectively, these findings suggest that miR-20a-mediated autophagy defect might be a new mechanism underlying the oncogenic function of miRNA during breast tumorigenesis.

PMID:
28628113
PMCID:
PMC5658668
DOI:
10.1038/onc.2017.193
[Indexed for MEDLINE]
Free PMC Article

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