title: Lin-28 homologue A (LIN28A) promotes cell cycle progression via regulation of cyclin-dependent kinase 2 (CDK2), cyclin D1 (CCND1), and cell division cycle 25 homolog A (CDC25A) expression in cancer.
abstract: The RNA-binding protein LIN28A regulates the translation and stability of a large number of mRNAs as well as the biogenesis of certain miRNAs in embryonic stem cells and developing tissues. Increasing evidence indicates that LIN28A functions as an oncogene promoting cancer cell growth. However, little is known about its molecular mechanism of cell cycle regulation in cancer. Using tissue microarrays, we found that strong LIN28A expression was reactivated in about 10% (7.1-17.1%) of epithelial tumors (six tumor types, n = 369). Both in vitro and in vivo experiments demonstrate that LIN28A promotes cell cycle progression in cancer cells. Genome-wide RNA-IP-chip experiments indicate that LIN28A binds to thousands of mRNAs, including a large group of cell cycle regulatory mRNAs in cancer and embryonic stem cells. Furthermore, the ability of LIN28A to stimulate translation of LIN28A-binding mRNAs, such as CDK2, was validated in vitro and in vivo. Finally, using a combined gene expression microarray and bioinformatics approach, we found that LIN28A also regulates CCND1 and CDC25A expression and that this is mediated by inhibiting the biogenesis of let-7 miRNA. Taken together, these results demonstrate that LIN28A is reactivated in about 10% of epithelial tumors and promotes cell cycle progression by regulation of both mRNA translation (let-7-independent) and miRNA biogenesis (let-7-dependent).
authors.affiliation: Ovarian Cancer Research Center and Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Ovarian Cancer Research Center and Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Zhong
authors.affiliation: Ovarian Cancer Research Center and Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania 19104; Department of Obstetrics and Gynecology, Second West China Hospital of Sichuan University, Chengdu, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Lin
authors.affiliation: Ovarian Cancer Research Center and Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Jinyi
authors.initials: J
authors.lastname: Guo
authors.affiliation: Ovarian Cancer Research Center and Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania 19104; Department of Obstetrics and Gynecology, Second West China Hospital of Sichuan University, Chengdu, China.
authors.forename: Lian
authors.initials: L
authors.lastname: Zou
authors.affiliation: Ovarian Cancer Research Center and Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Janos L
authors.initials: JL
authors.lastname: Tanyi
authors.affiliation: Ovarian Cancer Research Center and Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Zhongjun
authors.initials: Z
authors.lastname: Shao
authors.affiliation: Ovarian Cancer Research Center and Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Shun
authors.initials: S
authors.lastname: Liang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Wang
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Hwang
authors.affiliation: Department of Obstetrics and Gynecology, University of Turin, Turin 10124, Italy.
authors.forename: Dionyssios
authors.initials: D
authors.lastname: Katsaros
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Montone
authors.affiliation: Department of Obstetrics and Gynecology, Second West China Hospital of Sichuan University, Chengdu, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Ovarian Cancer Research Center and Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania 19104. Electronic address: linzhang@mail.med.upenn.edu.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
mesh_terms: D002453:Cell Cycle; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000235:genetics; D051357:Cyclin-Dependent Kinase 2 / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D014176:Protein Biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D016601:RNA-Binding Proteins; D020687:cdc25 Phosphatases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C530104:CCND1 protein, human; D004268:DNA-Binding Proteins; C516326:LIN28B protein, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016601:RNA-Binding Proteins; C487931:mirnlet7 microRNA, human; D019938:Cyclin D1; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases