title: microRNAs with AAGUGC seed motif constitute an integral part of an oncogenic signaling network.
abstract: microRNA (miRNA) dysregulation is a common feature of cancer cells, but the complex roles of miRNAs in cancer are not fully elucidated. Here, we used functional genomics to identify oncogenic miRNAs in non-small cell lung cancer and evaluate their impact on response to epidermal growth factor (EGFR)-targeting therapy. Our data demonstrate that miRNAs with an AAGUGC motif in their seed sequence increase both cancer cell proliferation and sensitivity to EGFR inhibitors. Global transcriptomics, proteomics and target prediction resulted in the identification of several tumor suppressors involved in the G1/S transition as AAGUGC-miRNA targets. The clinical implications of our findings were evaluated by analysis of AAGUGC-miRNA expression in multiple cancer types, supporting the link between this miRNA seed family, their tumor suppressor targets and cancer cell proliferation. In conclusion, we propose the AAGUGC seed motif as an oncomotif and that oncomotif-miRNAs promote cancer cell proliferation. These findings have potential therapeutic implications, especially in selecting patients for EGFR-targeting therapy.
authors.affiliation: Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
authors.forename: O
authors.initials: O
authors.lastname: Frings
authors.affiliation: Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
authors.forename: R M
authors.initials: RM
authors.lastname: Branca
authors.affiliation: Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.|Bioinformatics Infrastructure for Life Sciences (BILS), Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Boekel
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: le Sage
authors.affiliation: Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Fredlund
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Agami
authors.affiliation: Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
authors.forename: L M
authors.initials: LM
authors.lastname: Orre
mesh_terms: D001483:Base Sequence; D063646:Carcinogenesis / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D059372:Nucleotide Motifs; D015398:Signal Transduction
chemical_list: D035683:MicroRNAs