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Candidate tumor suppressor gene IRF6 is involved in human breast cancer pathogenesis via modulating PI3K-regulatory subunit PIK3R2 expression

Authors Xu HF, Huang TJ, Yang Q, Xu L, Lin F, Lang YH, Hu H, Peng LX, Meng DF, Xie YJ, Tan L, Qian CN, Huang BJ

Received 26 January 2019

Accepted for publication 13 May 2019

Published 21 June 2019 Volume 2019:11 Pages 5557—5572


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Editor who approved publication: Dr Chien-Feng Li

Hong-Fa Xu,1,2,* Tie-Jun Huang,3,* Qin Yang,1 Liang Xu,1 Fen Lin,1 Yan-Hong Lang,1 Hao Hu,4 Li-Xia Peng,1 Dong-Fang Meng,1 Yu-Jie Xie,1 Li Tan,5 Chao-Nan Qian,1 Bi-Jun Huang1

1Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, People’s Republic of China; 2Zhuhai Precision Medical Center, Zhuhai People’s Hospital Affiliated to Jinan University, Zhuhai 519000, People’s Republic of China; 3Department of Nuclear Medicine, The Second People’s Hospital of Shenzhen, Shenzhen 518035, People’s Republic of China; 4Department of Traditional Chinese Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510060, People’s Republic of China; 5Center of Hematology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510230, People’s Republic of China

*These authors contributed equally to this work

Background/Aims: The tumor-suppressive functions of interferon regulatory factor 6 (IRF6) in some tumors have been preliminarily established, but its pathogenesis and underlying molecular mechanisms in breast cancer, the most common malignancy in women, remains poorly understood.
Methods: Pairs of typical breast cancer cell lines (high- and low-aggressive) in addition to 27 breast cancer tissue samples and 31 non-cancerous breast tissues were used to investigate the expression level of IRF6 and Lentivirus-mediated gain-of-function studies, short hairpin RNA-mediated loss-of-function studies in vivo and in vitro were used to validate the role of IRF6 in breast cancer. Next, we performed RNA-Seq analysis to identify the molecular mechanisms of IRF6 involved in breast cancer progression.
Results: Our findings showed that IRF6 was downregulated in highly invasive breast cancer cell lines but upregulated in poorly aggressive ones. Functional assays revealed that elevated IRF6 expression could suppress cell proliferation and tumorigenicity, and enhanced cellular chemotherapeutic sensitivity. To identify the molecular mechanisms involved, we performed a genome-wide and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis in breast cancer cells using RNA sequencing of gene expression profiles following the overexpression of IRF6. Genome-wide and KEGG analyses showed that IRF6 might mediate the PI3K-regulatory subunit PIK3R2, which in turn modulated the PI3K/AKT pathway to control breast cancer pathogenesis.
Conclusion: We provide the first evidence of the involvement of IRF6 in breast cancer pathogenesis, which was found to modulate the PI3K/AKT pathway via mediating PIK3R2; indicating that IRF6 can be targeted as a potential therapeutic treatment of breast cancer.

Keywords: breast cancer, IRF6, proliferation, RNA sequencing, PIK3R2, PI3K/AKT

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