title: A regulatory BMI1/let-7i/ERK3 pathway controls the motility of head and neck cancer cells.
abstract: Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase (MAPK), whose biological activity is tightly regulated by its cellular abundance. Recent studies have revealed that ERK3 is upregulated in multiple cancers and promotes cancer cell migration/invasion and drug resistance. Little is known, however, about how ERK3 expression level is upregulated in cancers. Here, we have identified the oncogenic polycomb group protein BMI1 as a positive regulator of ERK3 level in head and neck cancer cells. Mechanistically, BMI1 upregulates ERK3 expression by suppressing the tumor suppressive microRNA (miRNA) let-7i, which directly targets ERK3 mRNA. ERK3 then acts as an important downstream mediator of BMI1 in promoting cancer cell migration. Importantly, ERK3 protein level is positively correlated with BMI1 level in head and neck tumor specimens of human patients. Taken together, our study revealed a molecular pathway consisting of BMI1, miRNA let-7i, and ERK3, which controls the migration of head and neck cancer cells, and suggests that ERK3 kinase is a potential new therapeutic target in head and neck cancers, particularly those with BMI1 overexpression.
authors.affiliation: Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA.
authors.forename: Lobna
authors.initials: L
authors.lastname: Elkhadragy
authors.affiliation: Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA.
authors.forename: Minyi
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Pathology, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA.
authors.forename: Kennon
authors.initials: K
authors.lastname: Miller
authors.affiliation: Institute of Clinic Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Muh-Hwa
authors.initials: MH
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA.
authors.forename: Weiwen
authors.identifier: 0000-0002-4792-242X
authors.initials: W
authors.lastname: Long
mesh_terms: D002465:Cell Movement; D006367:HeLa Cells; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D048053:Mitogen-Activated Protein Kinase 6 / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D063150:Polycomb Repressive Complex 1 / Q000096:biosynthesis* / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C069077:BMI1 protein, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; C487931:mirnlet7 microRNA, human; D063150:Polycomb Repressive Complex 1; D048053:Mitogen-Activated Protein Kinase 6
keywords: BMI1; ERK3; cell migration; head and neck cancer; let-7i