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The High-Mobility Group A1a/Signal Transducer and Activator of Transcription-3 Axis: An Achilles Heel for Hematopoietic Malignancies?

Hillion, Joelle, Dhara, Surajit, Sumter, Takita Felder, Mukherjee, Mita, Di Cello, Francescopaolo, Belton, Amy, Turkson, James, Jaganathan, Souyma +11 more·2008·Cancer Research
DOI 10.1158/0008-5472.can-08-2121PMC PMC2913892

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Abstract

Although HMGA1 (high-mobility group A1; formerly HMG-I/Y) is an oncogene that is widely overexpressed in aggressive cancers, the molecular mechanisms underlying transformation by HMGA1 are only beginning to emerge. HMGA1 encodes the HMGA1a and HMGA1b protein isoforms, which function in regulating gene expression. To determine how HMGA1 leads to neoplastic transformation, we looked for genes regulated by HMGA1 using gene expression profile analysis. Here, we show that the STAT3 gene, which encodes the signaling molecule signal transducer and activator of transcription 3 (STAT3), is a critical downstream target of HMGA1a. STAT3 mRNA and protein are up-regulated in fibroblasts overexpressing HMGA1a and activated STAT3 recapitulates the transforming activity of HMGA1a in fibroblasts. HMGA1a also binds directly to a conserved region of the STAT3 promoter in vivo in human leukemia cells by chromatin immunoprecipitation and activates transcription of the STAT3 promoter in transfection experiments. To determine if this pathway contributes to HMGA1-mediated transformation, we investigated STAT3 expression in our HMGA1a transgenic mice, all of which developed aggressive lymphoid malignancy. STAT3 expression was increased in the leukemia cells from our transgenics but not in control cells. Blocking STAT3 function induced apoptosis in the transgenic leukemia cells but not in controls. In primary human leukemia samples, there was a positive correlation between HMGA1a and STAT3 mRNA. Moreover, blocking STAT3 function in human leukemia or lymphoma cells led to decreased cellular motility and foci formation. Our results show that the HMGA1a–STAT3 axis is a potential Achilles heel that could be exploited therapeutically in hematopoietic and other malignancies overexpressing HMGA1a. [Cancer Res 2008;68(24):10121–7]

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  • HMGA1 activation of STAT3, which results in an increase of miR-181 expression, could represent an important feedback loop to regulate expression of HMGA1 in adult tissues.

    “HMGA1 activation of STAT3, which results in an increase of miR-181 expression, could represent an important feedback loop to regulate expression of HMGA1 in adult tissues (Hillion et al., 2008).”

    From Evidence for miR‐181 involvement in neuroinflammatory responses of astrocytes (2013) · cites this paper as Hillion et al., 2008

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Research works printed but not linked: 22

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Authors
Hillion, J., Dhara, S., Sumter, T. F., Mukherjee, M., Di Cello, F., Belton, A., Turkson, J., Jaganathan, S., Cheng, L., Ye, Z., Jove, R., Aplan, P., Lin, Y.-W., Wertzler, K., Reeves, R., Elbahlouh, O., Kowalski, J., Bhattacharya, R., & Resar, L. M. S.
Affiliations
  • 1Hematology Division and
  • 6BioMolecular Science Center and
  • 4Oncology, and
  • 8Experimental Therapeutics Program, City of Hope Comprehensive Cancer Center and
  • 10National Cancer Institute, Center for Cancer Research, Genetics Branch, Bethesda, Maryland; and
  • 11Washington State University, Pullman, Washington
  • 5Biostatistics, The Johns Hopkins University School of Medicine, Baltimore, Maryland;
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2008-12-15
Volume
68
Issue
24
Pages
10121-10127
ISSN
  • 0008-5472
  • 1538-7445
DOI
10.1158/0008-5472.can-08-2121
PMC
PMC2913892
Cited by
89
References
0
Language
en

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