title: Molecular characterization of the microRNA-138-Fos-like antigen 1 (FOSL1) regulatory module in squamous cell carcinoma.
abstract: MicroRNA-138 is one of the most frequently down-regulated microRNAs in cancer. We recently identified 51 candidate targets of microRNA-138 (Jiang, L., Dai, Y., Liu, X., Wang, C., Wang, A., Chen, Z., Heidbreder, C. E., Kolokythas, A., and Zhou, X. (2011) Hum. Genet. 129, 189-197). Among these candidates, Fos-like antigen 1 (FOSL1) is a member of Fos gene family and is a known proto-oncogene. In this study, we first confirmed the microRNA-138-mediated down-regulation of FOSL1 in squamous cell carcinoma cell lines. We then demonstrated the effect of this microRNA-138-FOSL1 regulatory module on downstream genes (homolog of Snail 2 (Snai2) expression and the Snai2-mediated repression of E-cadherin expression), as well as its contributions to tumorigenesis. The microRNA-138-directed recruitment of FOSL1 mRNA to the RNAi-induced silencing complex was confirmed by a ribonucleoprotein-immunoprecipitation assay. Three canonical and three high affinity non-canonical microRNA-138 (miR-138) targeting sites were identified on the FOSL1 mRNA: one in the 5'-UTR, three overlapping sites in the coding sequences, and two overlapping sites in the 3'-UTR. The direct targeting of miR-138 to these sites was confirmed using luciferase reporter gene assays. In summary, we describe an important microRNA regulatory module, which may play an important role in cancer initiation and progression. Our results also provide evidence that microRNAs target both canonical and non-canonical targeting sites located in all areas of the mRNA molecule (e.g. 5'-UTR, coding sequences, and 3'-UTR).
authors.affiliation: Center for Molecular Biology of Oral Diseases, College of Dentistry, University of Illinois, Chicago, Illinois 60612, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jin
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.forename: Xiqiang
authors.initials: X
authors.lastname: Liu
authors.forename: Wenbo
authors.initials: W
authors.lastname: Mu
authors.forename: Zujian
authors.initials: Z
authors.lastname: Chen
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Yu
authors.forename: Anxun
authors.initials: A
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Dai
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zhou
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099169:Fos-Related Antigen 1
chemical_list: D035683:MicroRNAs; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D000099169:Fos-Related Antigen 1; C000715470:MAS1 protein, human; C546110:MIRN138 microRNA, human; C000604407:SNAI1 protein, human; C000604408:SNAI2 protein, human