Skip to main content
SpringerLink
Log in

Amplified HMGA2 promotes cell growth by regulating Akt pathway in AML

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

The aim of this study was to investigate how the amplification of HMGA2 contributes to acute myeloid leukemia (AML) cell proliferation.

Methods

The amplification and expression of HMGA2 were examined by FISH, qRT-PCR and Western blot in AML cases. The effect of HMGA2 knockdown on cell proliferation was analyzed with XTT, colony-forming assays and BrdUrd incorporation assays. The effects of HMGA2 knockdown on cell cycle were studied by flow cytometry analysis. The progression of AML cells in vivo was examined by the xenografted tumor model. The interaction between Akt pathway and HMGA2 was examined by Western blot.

Results

HMGA2 is amplified in AML, and the levels of HMGA2 messenger RNA (mRNA) and protein expressed in AML cells were significantly higher than those in normal cells, which may be related to NR and prognosis of AML patients. Reduction in HMGA2 expression in AML cells inhibited cell proliferation through a decrease in the protein expression of pAkt and pmTOR, compared with control cells.

Conclusions

HMGA2 is predominantly amplified and expressed in AML cells, and that aberrant expression of HMGA2 induces AML cell proliferation through the PI3K/Akt/mTOR signaling pathway. Inhibition of HMGA2 expression represents an attractive target for AML therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Arcaro A, Guerreiro AS (2007) The phosphoinositide 3-kinase pathway in human cancer: genetic alterations and therapeutic implications. Curr Genom 8(5):271–306

    Article  CAS  Google Scholar 

  • Ayoubi TA, Jansen E, Meulemans SM, Van de Ven WJ (1999) Regulation of HMGIC expression: an architectural transcription factor involved in growth control and development. Oncogene 18(36):5076–5087

    Article  PubMed  CAS  Google Scholar 

  • Bustin M, Reeves R (1996) High-mobility-group chromosomal proteins: architectural components that facilitate chromatin function. Prog Nucleic Acid Res Mol Biol 54:35–100

    Article  PubMed  CAS  Google Scholar 

  • Di Cello F, Hillion J, Hristov A, Wood LJ, Mukherjee M, Schuldenfrei A, Kowalski J, Bhattacharya R, Ashfaq R, Resar LM (2008) HMGA2 participates in transformation in human lung cancer. Mol Cancer Res 6(5):743–750

    Article  PubMed  PubMed Central  Google Scholar 

  • Elkahloun AG, Krizman DB, Wang Z, Hofmann TA, Roe B, Meltzer PS (1997) Transcript mapping in a 46-kb sequenced region at the core of 12q13.3 amplification in human cancers. Genomics 42(2):295–301

    Article  PubMed  CAS  Google Scholar 

  • Estey E, Döhner H (2006) Acute myeloid leukaemia. Lancet 368(9550):1894–1907

    Article  PubMed  Google Scholar 

  • Fedele M, Visone R, De Martino I, Troncone G, Palmieri D, Battista S, Ciarmiello A, Pallante P, Arra C, Melillo RM, Helin K, Croce CM, Fusco A (2006) HMGA2 induces pituitary tumorigenesis by enhancing E2F1 activity. Cancer Cell 9(6):459–471

    Article  PubMed  CAS  Google Scholar 

  • Finelli P, Giardino D, Rizzi N, Buiatiotis S, Virduci T, Franzin A, Losa M, Larizza L (2000) Non random trisomies of chromosomes 5, 8 and 12 in the prolactinoma subtype of pituitary adenomas: conventional cytogenetics and interphase FISH study. Int J Cancer 86(3):344–350

    Article  PubMed  CAS  Google Scholar 

  • Fish RJ, Kruithof EK (2004) Short-term cytotoxic effects and long-term instability of RNAi delivered using lentiviral vectors. BMC Mol Biol 5:9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fusco A, Fedele M (2007) Roles of HMGA proteins in cancer. Nat Rev Cancer 7(12):899–910

    Article  PubMed  CAS  Google Scholar 

  • Kong D, Su G, Zha L, Zhang H, Xiang J, Xu W, Tang Y, Wang Z (2014) Coexpression of HMGA2 and Oct4 predicts an unfavorable prognosis in human gastric cancer. Med Oncol 31(8):130

    Article  PubMed  CAS  Google Scholar 

  • Li Z, Gilbert JA, Zhang Y, Zhang M, Qiu Q, Ramanujan K, Shavlakadze T, Eash JK, Scaramozza A, Goddeeris MM, Kirsch DG, Campbell KP, Brack AS, Glass DJ (2012) An HMGA2-IGF2BP2 axis regulates myoblast proliferation and myogenesis. Dev Cell 23(6):1176–1188

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Liu B, Pang B, Hou X, Fan H, Liang N, Zheng S, Feng B, Liu W, Guo H, Xu S, Pang Q (2014) Expression of high-mobility group AT-hook protein 2 and its prognostic significance in malignant gliomas. Hum Pathol 45(8):1752–1758

    Article  PubMed  CAS  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2−∆∆CT method. Methods 25(4):402–408

    Article  PubMed  CAS  Google Scholar 

  • Malek A, Bakhidze E, Noske A, Sers C, Aigner A, Schäfer R, Tchernitsa O (2008) HMGA2 gene is a promising target for ovarian cancer silencing therapy. Int J Cancer 123(2):348–356

    Article  PubMed  CAS  Google Scholar 

  • Mantovani F, Covaceuszach S, Rustighi A, Sgarra R, Heath C, Goodwin GH, Manfioletti G (1998) NF-kappaB mediated transcriptional activation is enhanced by the architectural factor HMGI-C. Nucleic Acids Res 26(6):1433–1439

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Martelli AM, Tazzari PL, Evangelisti C, Chiarini F, Blalock WL, Billi AM, Manzoli L, McCubrey JA, Cocco L (2007) Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin module for acute myelogenous leukemia therapy: from bench to bedside. Curr Med Chem 14(19):2009–2023

    Article  PubMed  CAS  Google Scholar 

  • Motoyama K, Inoue H, Nakamura Y, Uetake H, Sugihara K, Mori M (2008) Clinical significance of high mobility group A2 in human gastric cancer and its relationship to let-7 microRNA family. Clin Cancer Res 14(8):2334–2340

    Article  PubMed  CAS  Google Scholar 

  • Palmieri D, D’Angelo D, Valentino T, De Martino I, Ferraro A, Wierinckx A, Fedele M, Trouillas J, Fusco A (2012) Downregulation of HMGA-targeting microRNAs has a critical role in human pituitary tumorigenesis. Oncogene 31(34):3857–3865

    Article  PubMed  CAS  Google Scholar 

  • Raskin L, Fullen DR, Giordano TJ, Thomas DG, Frohm ML, Cha KB, Ahn J, Mukherjee B, Johnson TM, Gruber SB (2013) Transcriptome profiling identifies HMGA2 as a biomarker of melanoma progression and prognosis. J Invest Dermatol 133(11):2585–2592

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ravandi F, Burnett AK, Agura ED, Kantarjian HM (2007) Progress in the treatment of acute myeloid leukemia. Cancer 110(9):1900–1910

    Article  PubMed  CAS  Google Scholar 

  • Reeves R (2001) Molecular biology of HMGA proteins: hubs of nuclear function. Gene 277(1–2):63–81

    Article  PubMed  CAS  Google Scholar 

  • Reeves R, Beckerbauer L (2001) HMGI/Y proteins: flexible regulators of transcription an chromatin structure. Biochim Biophys Acta 1519(1–2):13–29

    Article  PubMed  CAS  Google Scholar 

  • Rizzi C, Cataldi P, Iop A, Isola M, Sgarra R, Manfioletti G, Giancotti V (2013) The expression of the high-mobility group A2 protein in colorectal cancer and surrounding fibroblasts is linked to tumor invasiveness. Hum Pathol 44(1):122–132

    Article  PubMed  CAS  Google Scholar 

  • Schoenmakers EF, Wanschura S, Mols R, Bullerdiek J, Van den Berghe H, Van de Ven WJ (1995) Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumours. Nat Genet 10(4):436–444

    Article  PubMed  CAS  Google Scholar 

  • Yuan TL, Cantley LC (2008) PI3K pathway alterations in cancer: variations on a theme. Oncogene 27(41):5497–5510

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 81100379 and No. 81302079), the Science and Technology Planning Project of Guangdong Province, China (No. 2013B022000102), the Medical Scientific Research Foundation of Guangdong Province, China (No. A2014292), and the Key Clinical Disciplines of Guangdong Province (No. 20111219).

Author information

Authors and Affiliations

  1. Center of Oncology and Hematology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510230, China

    Li Tan, Lixia Zheng, Jincai Zeng, Shaojiang Yang & Huo Tan

  2. Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guangdong Key Laboratory of Urology, Guangzhou, 510230, China

    Li Tan

  3. Clinical Laboratory, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China

    Xiaoping Wei

  4. Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China

    Haibo Liu

Authors
  1. Li Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoping Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lixia Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jincai Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Haibo Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shaojiang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Huo Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Li Tan.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tan, L., Wei, X., Zheng, L. et al. Amplified HMGA2 promotes cell growth by regulating Akt pathway in AML. J Cancer Res Clin Oncol 142, 389–399 (2016). https://doi.org/10.1007/s00432-015-2036-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-015-2036-9

Keywords

Search

Navigation