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Overexpression of HMGA1 deregulates tumor growth via cdc25A and alters migration/invasion through a cdc25A-independent pathway in medulloblastoma

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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.

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Acknowledgments

This work was supported by Hong Kong Research Grant Council General Research Funds 469211 to KML and 472307 to HKN.

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Authors and Affiliations

  1. Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Room 38018, 1/F, Clinical Sciences Building, Shatin, New Territories, Hong Kong

    Kin-Mang Lau, Queeny Kwan Yi Chan, Jesse C. S. Pang, Fanny Man-Ting Ma, Kay K. W. Li, Walter Wai Yeung, Nellie Y. F. Chung, Hiu-Ming Li & Ho-Keung Ng

  2. State Key Laboratory of Southern China in Oncology, The Chinese University of Hong Kong, New Territories, Hong Kong

    Kin-Mang Lau, Jesse C. S. Pang & Ho-Keung Ng

  3. Institute of Digestive Disease, The Chinese University of Hong Kong, New Territories, Hong Kong

    Alfred S. L. Cheng & Hai Feng

  4. Department of Neurosurgery, HuaShan Hospital, Fudan University, Shanghai, China

    Liangfu Zhou & Ying Mao

  5. Department of Neuropathology, HuaShan Hospital, Fudan University, Shanghai, China

    Yin Wang

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  1. Kin-Mang Lau
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Correspondence to Kin-Mang Lau.

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K.-M. Lau and Q. K. Y. Chan equally contributed to the work.

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Lau, KM., Chan, Q.K.Y., Pang, J.C.S. et al. Overexpression of HMGA1 deregulates tumor growth via cdc25A and alters migration/invasion through a cdc25A-independent pathway in medulloblastoma. Acta Neuropathol 123, 553–571 (2012). https://doi.org/10.1007/s00401-011-0934-8

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