title: Interleukin-8 upregulates integrin β3 expression and promotes estrogen receptor-negative breast cancer cell invasion by activating the PI3K/Akt/NF-κB pathway.
abstract: Interleukin-8 (IL-8) possesses tumorigenic and proangiogenic properties and is overexpressed in many human cancers. The integrin family regulates a diverse array of cellular functions crucial to the initiation, progression and metastasis of solid tumors. However, the mechanisms of action of IL-8 and integrin in estrogen receptor-negative breast cancer are largely unknown. In this study, IL-8 and integrin β3 expression in human breast cancer cells and tissues was examined by real-time PCR, Western blot and immunochemistry analysis. Integrin β3 expression, invasive ability and the activation of PI3K/Akt and NF-κB pathways in IL-8 knockdown breast cancer cells were evaluated. In addition, reporter assay and ChIP were performed to assess integrin β3 promoter activity in IL-8 knockdown cells. We observed a positive correlation between integrin β3 and IL-8 expression, which was inversely correlated with ER status in breast cancer cell lines and tissues. IL-8 siRNA decreased the invasion and integrin β3 expression in human breast cancer cells. Moreover, IL-8 siRNA attenuated the phosphorylation of PI3K and Akt and inhibited NF-κB activity and binding on integrin β3 promoter. IL-8 siRNA diminished NF-κB nuclear translocation via blocking IκB phosphorylation in the cytoplasm. In conclusion, IL-8 activates the PI3K/Akt pathway, which in turn activates NF-κB, resulting in the upregulation of integrin β3 expression and increased invasion of estrogen receptor-negative breast cancer cells. IL-8/PI3K/Akt/NF-κB/integrin β3 axis may be exploited for therapeutic intervention to breast cancer metastasis.
authors.affiliation: Breast Disease Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Shao
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors.forename: Zhenhai
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Breast Disease Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Yunjian
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Breast Disease Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Mian
authors.initials: M
authors.lastname: Wang
authors.affiliation: Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Breast Disease Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Ziye
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Breast Disease Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China. Electronic address: shenmingwang@hotmail.com.
authors.forename: Shenming
authors.initials: S
authors.lastname: Wang
authors.affiliation: Breast Disease Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China. Electronic address: frostlin@hotmail.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Lin
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D039661:Integrin beta3 / Q000096:biosynthesis*; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D039661:Integrin beta3; D016209:Interleukin-8; D016328:NF-kappa B; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Breast cancer; IL-8; Integrin β3; NF-κB; PI3K/Akt