title: A regulatory loop involving miR-22, Sp1, and c-Myc modulates CD147 expression in breast cancer invasion and metastasis.
abstract: Breast cancer is the most common cancer in women for which the metastatic process is still poorly understood. CD147 is upregulated in breast cancer and has been associated with tumor progression, but little is known about its regulatory mechanisms. In this study, we demonstrated that CD147 was overexpressed in breast cancer tissues and cell lines, and the high expression correlated with tumor invasion and metastasis. We also found that the transcription factors Sp1 and c-Myc could bind to the CD147 promoter and enhance its expression. The CD147 mRNA has a 748-bp 3'-untranslated region (UTR) with many miRNA target sites, suggesting possible regulation by miRNAs. We discovered that miR-22 repressed CD147 expression by directly targeting the CD147 3'UTR. We also determined that miR-22 could indirectly participate in CD147 modulation by downregulating Sp1 expression. miR-22 could form an autoregulatory loop with Sp1, which repressed miR-22 transcription by binding to the miR-22 promoter. Together with the c-Myc-mediated inhibition of miR-22 expression, our investigation identified a miR-22/Sp1/c-Myc network that regulates CD147 gene transcription. In addition, miR-22 overexpression suppressed breast cancer cell invasion, metastasis, and proliferation by targeting CD147 in vitro and in vivo. Furthermore, we found that miR-22 was significantly downregulated in breast cancer tissues and that its expression was inversely correlated with the tumor-node-metastasis stage and lymphatic metastasis in patients. Our study provides the first evidence that an miR-22/Sp1/c-Myc network regulates CD147 upregulation in breast cancer and that miR-22 represses breast cancer invasive and metastatic capacities.
authors.affiliation: Authors' Affiliations: Cell Engineering Research Center and Department of Cell Biology, Fourth Military Medical University, Xi'an;
authors.forename: Ling-Min
authors.initials: LM
authors.lastname: Kong
authors.affiliation: Department of Oncology, Urumqi General Hospital of Lanzhou Military Command of PLA, Urumqi; and Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Cheng-Gong
authors.initials: CG
authors.lastname: Liao
authors.affiliation: Authors' Affiliations: Cell Engineering Research Center and Department of Cell Biology, Fourth Military Medical University, Xi'an;
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Authors' Affiliations: Cell Engineering Research Center and Department of Cell Biology, Fourth Military Medical University, Xi'an;
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Authors' Affiliations: Cell Engineering Research Center and Department of Cell Biology, Fourth Military Medical University, Xi'an;
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Authors' Affiliations: Cell Engineering Research Center and Department of Cell Biology, Fourth Military Medical University, Xi'an;
authors.forename: Wan
authors.initials: W
authors.lastname: Huang
authors.affiliation: Authors' Affiliations: Cell Engineering Research Center and Department of Cell Biology, Fourth Military Medical University, Xi'an;
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Authors' Affiliations: Cell Engineering Research Center and Department of Cell Biology, Fourth Military Medical University, Xi'an; zhinanchen@fmmu.edu.cn hjbian@fmmu.edu.cn.
authors.forename: Huijie
authors.initials: H
authors.lastname: Bian
authors.affiliation: Authors' Affiliations: Cell Engineering Research Center and Department of Cell Biology, Fourth Military Medical University, Xi'an; zhinanchen@fmmu.edu.cn hjbian@fmmu.edu.cn.
authors.forename: Zhi-Nan
authors.initials: ZN
authors.lastname: Chen
mesh_terms: D020413:3' Untranslated Regions; D020029:Base Pairing; D001483:Base Sequence; D051926:Basigin / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D034622:RNA Interference; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D047368:Tumor Burden
chemical_list: D020413:3' Untranslated Regions; C548375:MIRN22 microRNA, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D016329:Sp1 Transcription Factor; D051926:Basigin