HAND1 gene expression is negatively regulated by the High Mobility Group A1 proteins and is drastically reduced in human thyroid carcinomas

Hoyos, Josefina Martinez; Ferraro, Angelo; Sacchetti, Silvana; Keller, Simona; Martino, Ivana De; Borbone, Eleonora; Pallante, P; Fedele, Monica; Montanaro, Donatella; Esposito, Francesco; Cserjesi, Peter; Chiariotti, Lorenzo; Troncone, Giancarlo

doi:10.1038/onc.2008.438

Cited by 13 publications

(10 citation statements)

References 19 publications

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“…HMGA1 downregulation by siRNA enhanced transcriptional activity of p53, and increased thyroid cancer apoptosis (37). It was also reported that HMGA1 proteins can inhibit Hand1 promoter activity, and HMGA1 overexpression exerts an important role on HAND1 silencing in differentiated thyroid carcinomas (38). In addition, HMGA1 silencing decreased the expression of vimentin and Snail, increased the expression of E-cadherin in triple-negative breast cancer MDA-MB-231 cells (4).…”

Section: Discussionmentioning

confidence: 99%

TGF-β1 induces HMGA1 expression: The role of HMGA1 in thyroid cancer proliferation and invasion

Zhong¹,

Liu²,

Zhang³

et al. 2017

International Journal of Oncology

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The role of transforming growth factor-β1 (TGF-β1) is complicated and plays a different role in the development of cancer. High mobility group A (HMGA1) participates in multiple cellular biology processes, and exerts important roles in the epithelial-mesenchymal transition (EMT). However, the correlation of TGF-β1 and HMGA1 in cancer cells is not yet fully understood. In this study, we determined the effects of TGF-β1 on HMGA1 expression in thyroid cancer cells and examined the role of HMGA1 in thyroid cancer progression. With real-time PCR and immunofluorescence staining, our study demonstrated that TGF-β1 induced the expression of HMGA1 through phosphoinositide 3-kinase (PI3K) and the extracellular signal-related kinase (ERK) signaling in thyroid cancer cells. With luciferase reported assay, the HMGA1 promoter activity was activated by TGF-β1 in the SW579 cells. Furthermore, lentivirus mediated HMGA1 knockdown inhibits cellular oncogenic properties of thyroid cancer cells. Clinically, tissue microarray revealed that HMGA1 was expressed in thyroid carcinoma more than that in normal thyroid tissues (P<0.001); expression of HMGA1 and MMP-2 was identified to be positively correlated (P=0.017). The present study established the first link between HMGA1 and TGF-β1 in the regulation of thyroid cancer proliferation and invasion, and provided evidence for the pivotal role of HMGA1 in the progression of thyroid cancer, indicating HMGA1 to be potential biological marker for the diagnosis of thyroid cancer.

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Section: Discussionmentioning

confidence: 99%

TGF-β1 induces HMGA1 expression: The role of HMGA1 in thyroid cancer proliferation and invasion

Zhong¹,

Liu²,

Zhang³

et al. 2017

International Journal of Oncology

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“…To illustrate, HMGA1 was reported to repress HAND1 (Heart and Neural Crest Derivatives expressed 1) , a member of the Twist subfamily of basic helix-loop-helix (bHLH) transcription factors [215]. Studies in Hand1 null mice indicate that it plays a critical role in placenta formation and cardiac morphogenesis in the ventricular chambers [215] Hand1 expression was reported to be enhanced in Hmga1 null mice and HMGA1 binds to the Hand1 promoter, both in vitro and in vivo , as demonstrated by in gel shift analysis and chromatin immunoprecipitation. Transfection experiments showed that HMGA1 represses HAND1 promoter expression.…”

Section: Hmga1 Transcriptional Targetsmentioning

confidence: 99%

“…Moreover , HMGA1 overexpression was reported to be associated with DNA methylation of the HAND1 promoter in anaplastic thyroid carcinomas in advanced tumors. HAND1 is also silenced in gastric, colorectal, and pancreatic cancers [215–218]. …”

Section: Hmga1 Transcriptional Targetsmentioning

confidence: 99%

The High Mobility Group A1 (HMGA1) Transcriptome in Cancer and Development

Sumter¹,

Xian²,

Huso³

et al. 2016

CMM

103

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Background & Objectives Chromatin structure is the single most important feature that distinguishes a cancer cell from a normal cell histologically. Chromatin remodeling proteins regulate chromatin structure and high mobility group A (HMGA1) proteins are among the most abundant, nonhistone chromatin remodeling proteins found in cancer cells. These proteins include HMGA1a/HMGA1b isoforms, which result from alternatively spliced mRNA. The HMGA1 gene is overexpressed in cancer and high levels portend a poor prognosis in diverse tumors. HMGA1 is also highly expressed during embryogenesis and postnatally in adult stem cells. Overexpression of HMGA1 drives neoplastic transformation in cultured cells, while inhibiting HMGA1 blocks oncogenic and cancer stem cell properties. Hmga1 transgenic mice succumb to aggressive tumors, demonstrating that dysregulated expression of HMGA1 causes cancer in vivo. HMGA1 is also required for reprogramming somatic cells into induced pluripotent stem cells. HMGA1 proteins function as ancillary transcription factors that bend chromatin and recruit other transcription factors to DNA. They induce oncogenic transformation by activating or repressing specific genes involved in this process and an HMGA1 “transcriptome” is emerging. Although prior studies reveal potent oncogenic properties of HMGA1, we are only beginning to understand the molecular mechanisms through which HMGA1 functions. In this review, we summarize the list of putative downstream transcriptional targets regulated by HMGA1. We also briefly discuss studies linking HMGA1 to Alzheimer’s disease and type-2 diabetes. Conclusion Further elucidation of HMGA1 function should lead to novel therapeutic strategies for cancer and possibly for other diseases associated with aberrant HMGA1 expression.

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“…Multiple molecular mechanisms contribute to the oncogenic activities of HMGAs. These mechanisms include uncontrolled cell cycling (Tessari et al, 2003), enhancement of transcription factor DNA-binding activity (Vallone et al, 1997), inhibition of apoptosis activity (Esposito et al, 2012), impairment of the DNA damage response (Pentimalli et al, 2008), promotion of inflammatory mediator production (Hillion et al, 2008; Perrella et al, 1999), regulation of cancer stem cells (Yanagisawa and Resar, 2013), downregulation of potential tumor-suppressor genes (Martinez Hoyos et al, 2009), upregulation of epithelial-mesenchymal transition (Morishita et al, 2013; Thuault et al, 2006), functioning as a competing endogenous RNA for microRNA (e.g., let-7 and MicroRNA-137) (Kumar et al, 2014; Liang et al, 2013a), and enhancement of autophagy-mediated aerobic glycolysis (Ha et al, 2012a). However, HMGAs also exerts anti-proliferative properties in some cells (Fedele et al, 2006), calling for further study of HMGA1 as potential therapeutic agent in cancer treatment.…”

Section: Introduction and Historical Backgroundmentioning

confidence: 99%

HMGB1 in health and disease

Kang

Chen

Zhang

et al. 2014

Molecular Aspects of Medicine

795

828

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Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed High-Mobility Group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo. These include antibodies, peptide inhbitiors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localizationtion, structure, post-translational modification, and identifccation of additional partners will undoubtedly uncover additional secrets regarding HMGB1’s multiple functions.

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HAND1 gene expression is negatively regulated by the High Mobility Group A1 proteins and is drastically reduced in human thyroid carcinomas

Cited by 13 publications

References 19 publications

TGF-β1 induces HMGA1 expression: The role of HMGA1 in thyroid cancer proliferation and invasion

TGF-β1 induces HMGA1 expression: The role of HMGA1 in thyroid cancer proliferation and invasion

The High Mobility Group A1 (HMGA1) Transcriptome in Cancer and Development

HMGB1 in health and disease

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