Sohlh2 suppresses epithelial to mesenchymal transition in breast cancer via downregulation of IL-8
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Shufang Ji1,*, Wenfang Zhang1,*, Xiaoli Zhang1, Chunyan Hao2, Aijun Hao1, Qing Gao1, Hongying Zhang3, Jinhao Sun4, Jing Hao1
1Key Laboratory of The Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Medicine, Shandong University, Jinan 250012, PR China
2Department of Pathology, School of Medicine, Shandong University, Jinan 250012, PR China
3Department of Biology, Jinan Vocational College of Nursing, Jinan 250000, PR China
4Department of Human Anatomy, School of Medicine, Shandong University, Jinan 250012, PR China
*These authors contributed equally to this work
Jing Hao, email: [email protected]
Keywords: Sohlh2, IL-8, EMT, metastasis, breast cancer
Abbreviations: EMT, epithelial-to-mesenchymal transition; Sohlh2, spermatogenesis- and oogenesis- specific basic helix-loop-helix transcription factor2; IL-8, interleukin 8; FBS, fetal bovine serum; ChIP, chromatin immunoprecipitation
Received: September 25, 2015 Accepted: June 16, 2016 Published: June 30, 2016
Breast cancer is one of the deadliest cancers worldwide due to its strong metastasis to other organs. Metastasis of breast cancer involves a complex set of events, including epithelial-mesenchymal transition (EMT) that increases invasiveness of the tumor cells. We previously identified sohlh2 is a tumor suppressor in the pathogenesis of ovarian cancer. However, the functions of sohlh2 in breast cancer cell migration and invasion remain unknown. Here we report a novel sohlh2/IL-8 signaling pathway in the invasive breast cancer. We observed sohlh2 expression was downregulated in the metastatic breast cancer. Ectopic sohlh2 expression in breast cancer cells reduced EMT and inhibited cell migration and invasion in vitro, and metastasis in vivo. Moreover, the depletion of sohlh2 induced the opposite effects to ectopic sohlh2 expression. RNA-Seq data from a sohlh2 knockdown breast cancer cell line showed that after sohlh2 depletion, the mRNA level of interleukin 8 (IL-8) was significantly increased in these cancer cells, which consequently increased secretion of IL-8 protein. Using chromatin immunoprecipitation and reporter assays, we demonstrated that sohlh2 bound to IL-8 promoter and repressed its activities. The enhanced migration and invasion in sohlh2 -ablated MCF-7 cells were blocked by knockdown of IL-8 expression, while exogenous IL-8 neutralized the anti-migratory and invasive activities of sohlh2 in MDA-MB-231cells. Overall, these results demonstrate that sohlh2 functions as a tumor metastasis suppressor via suppressing IL-8 expression in breast cancer.
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