High mobility group A1 expression correlates with the histological grade of human glial tumors

Donato, Giuseppe; Hoyos, Josefina Martinez; Amorosi, Andrea; Maltese, Lorenza; Lavano, Angelo; Volpentesta, Giorgio; Signorelli, Francesco; Pentimalli, Francesca; Pallante, Pierlorenzo; Ferraro, Giuseppe; Tucci, Luigi; Signorelli, C D; Viglietto, Giuseppe

doi:10.3892/or.11.6.1209

Cited by 20 publications

(17 citation statements)

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“…For brain cancers, the expression of HMGA1 remains controversial in glioblastoma. Donato et al [14] found all 15 glioblastoma expressed high level of HMGA1, whereas only 1 out of 8 showed the expression in Akai's study [4]. Currently, no data are yet available for MB.…”

Section: Discussionmentioning

confidence: 92%

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

et al. 2012

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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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Section: Discussionmentioning

confidence: 92%

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

et al. 2012

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“…HMGA1 is typically restricted to embryonic tissues and is frequently observed in both benign and malignant tumors (see Cleynen et al, 2008 for a review). HMGA1 is a transcription factor that binds to AT-rich regions of the genome, and increased HMGA1 expression is typically observed in glioblastoma with its expression level being greater in more severe tumors (Donato et al, 2004;Fan et al, 2011;Pang et al, 2012). It has previously been demonstrated that HMGA1 and HMGA2 are subject to repressive regulation through elements in the 3 0 UTR by an as yet unknown mechanism (Borrmann et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Evidence for miR‐181 involvement in neuroinflammatory responses of astrocytes

Hutchison

Kawamoto

Taub

et al. 2013

Glia

218

185

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Inflammation is a common component of acute injuries of the central nervous system (CNS) and degenerative disorders such as Alzheimer’s disease. Glial cells play important roles in local CNS inflammation, and an understanding of the roles for microRNAs in glial reactivity in injury and disease settings may therefore enable novel therapeutic interventions. Here we show that the miR-181 family is developmentally regulated and present in high amounts in astrocytes compared to neurons. Over-expression of miR-181c in cultured astrocytes results in increased cell death when exposed to lipopolysaccharide (LPS). We show that miR-181 expression is altered in brain cells in vivo in response to LPS, a model of inflammation, in both wild-type mice and transgenic mice lacking both receptors for the inflammatory cytokine TNF-α. Knockdown of miR-181 enhanced LPS-induced production of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-8) and HMGB1, while over-expression of miR-181 resulted in a significant increase in the expression of the anti-inflammatory cytokine IL-10. To assess the effects of miR-181 on the astrocyte transcriptome, we performed gene array and pathway analysis on astrocytes with reduced levels of miR-181b/c. To examine the pool of potential miR-181 targets, we employed a biotin pull-down of miR-181c and microarray analysis. We validated both MeCP2 and XIAP mRNAs as targets of miR-181. These findings suggest that miR-181 plays important roles in the response of astrocytes to inflammatory settings. Further understanding of the role of miR-181 in inflammatory events and CNS injury could lead to novel therapies for CNS disorders with an inflammatory component.

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“…Furthermore, its expression is more frequently associated to advanced, metastatic stages, and to poorer prognosis. Even in tumors of the nervous system, HMGA1 expression is deregulated and associated with more aggressive/advanced stages and/or treatment failure [37–41].…”

Section: Introductionmentioning

confidence: 99%

The HMGA1 protoncogene frequently deregulated in cancer is a transcriptional target of E2F1

Massimi¹,

Guerrieri²,

Petroni³

et al. 2012

Molecular Carcinogenesis

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Reactivation of the HMGA1 protoncogene is very frequent in human cancer, but still very little is known on the molecular mechanisms leading to this event. Prompted by the finding of putative E2F binding sites in the human HMGA1 promoter and by the frequent deregulation of the RB/E2F1 pathway in human carcinogenesis, we investigated whether E2F1 might contribute to the regulation of HMGA1 gene expression. Here we report that E2F1 induces HMGA1 by interacting with a 193 bp region of the HMGA1 promoter containing an E2F binding site surrounded by three putative Sp1 binding sites. Both gain and loss of function experiments indicate that Sp1 functionally interacts with E2F1 to promote HMGA1 expression. However, while Sp1 constitutively binds HMGA1 promoter, it is the balance between different E2F family members that tunes the levels of HMGA1 expression between quiescence and proliferation. Finally, we found increased HMGA1 expression in pituitary and thyroid tumors developed in Rb(+/-) mice, supporting the hypothesis that E2F1 is a novel important regulator of HMGA1 expression and that deregulation of the RB/E2F1 path might significantly contribute to HMGA1 deregulation in cancer.

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High mobility group A1 expression correlates with the histological grade of human glial tumors

Cited by 20 publications

References 0 publications

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

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

Evidence for miR‐181 involvement in neuroinflammatory responses of astrocytes

The HMGA1 protoncogene frequently deregulated in cancer is a transcriptional target of E2F1

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