title: IL-8 induces miR-424-5p expression and modulates SOCS2/STAT5 signaling pathway in oral squamous cell carcinoma.
abstract: Suppressor of cytokine signaling (SOCS) proteins are negative feedback regulators of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Dysregulation of SOCS protein expression in cancers can be one of the mechanisms that maintain STAT activation, but this mechanism is still poorly understood in oral squamous cell carcinoma (OSCC). Here, we report that SOCS2 protein is significantly downregulated in OSCC patients and its levels are inversely correlated with miR-424-5p expression. We identified the SOCS2 protein, which modulates STAT5 activity, as a direct target of miR-424-5p. The miR-424-5p-induced STAT5 phosphorylation, matrix metalloproteinases (MMPs) expression, and cell migration and invasion were blocked by SOCS2 restoration, suggesting that miR-424-5p exhibits its oncogenic activity through negatively regulating SOCS2 levels. Furthermore, miR-424-5p expression could be induced by the cytokine IL-8 primarily through enhancing STAT5 transcriptional activity rather than NF-κB signaling. Antagomir-mediated inactivation of miR-424-5p prevented the IL-8-induced cell migration and invasion, indicating that miR-424-5p is required for IL-8-induced cellular invasiveness. Taken together, these data indicate that STAT5-dependent expression of miR-424-5p plays an important role in mediating IL-8/STAT5/SOCS2 feedback loop, and scavenging miR-424-5p function using antagomir may have therapeutic potential for the treatment of OSCC.
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan; Department of Life Sciences, National Central University, Taoyuan, Taiwan.
authors.forename: Hsuan-Yu
authors.initials: HY
authors.lastname: Peng
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Shih-Sheng
authors.initials: SS
authors.lastname: Jiang
authors.affiliation: Department of Otolaryngology, Head and Neck Collaborative Oncology Group, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Jenn-Ren
authors.initials: JR
authors.lastname: Hsiao
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Yuan-Ming
authors.initials: YM
authors.lastname: Hsu
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Guan-Hsun
authors.initials: GH
authors.lastname: Wu
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan; Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Chang
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan; Department of Internal Medicine, Division of Hematology and Oncology, National Cheng Kung University Hospital, College of Medical, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Jang-Yang
authors.initials: JY
authors.lastname: Chang
authors.affiliation: Department of Life Sciences, National Central University, Taoyuan, Taiwan.
authors.forename: Shiow-Lian Catherine
authors.initials: SL
authors.lastname: Jin
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. Electronic address: davidssg@nhri.org.tw.
authors.forename: Shine-Gwo
authors.initials: SG
authors.lastname: Shiah
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009055:Mouth / Q000378:metabolism / Q000473:pathology*; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016209:Interleukin-8; C554214:MIRN424 microrna, human; D035683:MicroRNAs; C106643:SOCS2 protein, human; D050799:STAT5 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins
keywords: IL-8; Invasion; Oral squamous cell carcinoma; SOCS2; microRNA