title: Overexpression of HMGA1 deregulates tumor growth via cdc25A and alters migration/invasion through a cdc25A-independent pathway in medulloblastoma.
abstract: Overexpression of high mobility group AT-hook 1 (HMGA1) is common in human cancers. Little is known about the mechanisms underlying its deregulation and downstream targets, and information about its clinical and biological significance in medulloblastoma (MB) is lacking. Here, we demonstrated frequent genomic gain at 6p21.33-6p21.31 with copy number increase leading to overexpression of HMGA1 in MB. The overexpression correlated with a high proliferation index and poor prognosis. Moreover, we found that hsa-miR-124a targeted 3'UTR of HMGA1 and negatively modulated the expression in MB cells, indicating that loss/downregulation of hsa-miR-124a reported in our previous study could contribute to the overexpression. Regarding the biological significance of HMGA1, siRNA knockdown and ectopic expression studies revealed the crucial roles of HMGA1 in controlling MB cell growth and migration/invasion through modulation of apoptosis and formation of filopodia and stress fibers, respectively. Furthermore, we identified cdc25A as a target of HMGA1 and showed that physical interaction between HMGA1 and the cdc25A promoter is required for transcriptional upregulation. In clinical samples, HMGA1 and cdc25A were concordantly overexpressed. Functionally, cdc25A is involved in the HMGA1-mediated control of MB cell growth. Finally, netropsin, which competes with HMGA1 in DNA binding, reduced the expression of cdc25A by suppression of its promoter activity and inhibited in vitro and in vivo intracranial MB cell growth. In conclusion, our results delineate the mechanisms underlying the deregulation and reveal the functional significance of HMGA1 in controlling MB cell growth and migration/invasion. Importantly, the results highlight the therapeutic potential of targeting HMGA1 in MB patients.
authors.affiliation: Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong. kmlau@cuhk.edu.hk
authors.forename: Kin-Mang
authors.initials: KM
authors.lastname: Lau
authors.forename: Queeny Kwan Yi
authors.initials: QK
authors.lastname: Chan
authors.forename: Jesse C S
authors.initials: JC
authors.lastname: Pang
authors.forename: Fanny Man-Ting
authors.initials: FM
authors.lastname: Ma
authors.forename: Kay K W
authors.initials: KK
authors.lastname: Li
authors.forename: Walter Wai
authors.initials: WW
authors.lastname: Yeung
authors.forename: Alfred S L
authors.initials: AS
authors.lastname: Cheng
authors.forename: Hai
authors.initials: H
authors.lastname: Feng
authors.forename: Nellie Y F
authors.initials: NY
authors.lastname: Chung
authors.forename: Hiu-Ming
authors.initials: HM
authors.lastname: Li
authors.forename: Liangfu
authors.initials: L
authors.lastname: Zhou
authors.forename: Yin
authors.initials: Y
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Mao
authors.forename: Ho-Keung
authors.initials: HK
authors.lastname: Ng
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D002869:Chromosome Aberrations; D002886:Chromosomes, Human, Pair 17; D002896:Chromosomes, Human, Pair 6; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D055786:Gene Knockout Techniques; D025741:HMGA1a Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D009429:Netropsin / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016019:Survival Analysis; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D025741:HMGA1a Protein; D009429:Netropsin; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases