title: IL-17/miR-192/IL-17Rs regulatory feedback loop facilitates multiple myeloma progression.
abstract: Multiple myeloma (MM) is a clonal plasma cell disorder which constitutes the second most common hematological malignancy, and remains an incurable tumor with poor survival. Recently, interleukin-17 (IL-17), produced locally in the tumor microenvironment, has been reported to play a crucial role in tumor immunity. In this study, we determined that exposure of MM cells to IL-17 had various promotive influences on different aspects of tumor progression. IL-17 significantly induced cell proliferation, inhibited cellular apoptosis, repressed cell adhesion to fibronectin and collagen I, and facilitated cell migration. Exposure to IL-17 also resulted in epithelial-mesenchymal transition (EMT), as evidenced by repression of the epithelial marker E-cadherin, and induction of the mesenchymal marker Vimentin, and EMT transcription factors Snail and Slug. Further experiments showed that IL-17 activated the oncogenic p65 transcription factor, which directly repressed the miR-192 gene via binding to the miR-192 promoter. Loss of miR-192 in MM cells can mimic the effects of IL-17, and was required for the above oncogenic effects of IL-17 on MM. Furthermore, we found that miR-192, and its homologous miR-215 directly targeted the 3'-untranslated regions of IL-17Rs, including IL-17RA and RE mRNA. By examining bone marrow specimens derived from MM patients, a negative correlation between miR-192 expression and IL-17 or IL-17RA expression was observed. Also, IL-17 was negatively correlated with E-cadherin and positively with Vimentin. Taken together, our study provides evidence that the IL-17/miR-192/IL-17Rs regulatory feedback loop is manifest in MM and might represent a promising and efficient prognostic marker and therapeutic target for MM.
authors.affiliation: Department of Hematology, the First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Hematology, the First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Pan
authors.affiliation: Department of Hematology, the First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning, China.
authors.forename: Shudan
authors.initials: S
authors.lastname: Mao
authors.affiliation: Department of Hematology, the First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning, China.
authors.forename: Jieping
authors.initials: J
authors.lastname: Jin
mesh_terms: D017209:Apoptosis; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D025461:Feedback, Physiological; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D051996:Transcription Factor RelA / Q000378:metabolism; D059016:Tumor Microenvironment; D014746:Vimentin / Q000378:metabolism
chemical_list: D020381:Interleukin-17; C546783:MIRN192 microRNA, human; C553667:MIRN215 microRNA, human; D035683:MicroRNAs; D051996:Transcription Factor RelA; D014746:Vimentin