The high mobility group A1 molecular switch: turning on cancer – can we turn it off?

Huso, Tait; Resar, Linda M.S.

doi:10.1517/14728222.2014.900045

Cited by 36 publications

(38 citation statements)

References 105 publications

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“…Significantly represented networks featured proteins previously implicated in ERMS biology such as Cyclin D1, IGF, AKT, SP1, and CDKN2A3536373839. Network analysis also suggested target proteins that, though not previously studied in RMS, have been implicated in other tumor types with roles in cell proliferation such as NFYB40, invasion and metastasis such as YBX141, and cellular transformation such as HMGA142. The findings of protein nodes previously implicated in ERMS biology supports the role of exosomes as mediators of such pathway alterations, while the findings of novel cancer-associated protein networks opens possibilities for investigation of such pathways in ERMS tumors.…”

Section: Discussionmentioning

confidence: 88%

Exosomes derived from embryonal and alveolar rhabdomyosarcoma carry differential miRNA cargo and promote invasion of recipient fibroblasts

Ghayad

Rammal

Ghamloush

et al. 2016

Sci Rep

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Rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue tumor, which exists in oncoprotein PAX-FOXO1 fusion positive and fusion negative subtypes, with the fusion-positive RMS being characterized by a more aggressive clinical behavior. Exosomes are small membranous vesicles secreted into body fluids by multiple cell types, including tumor cells, and have been implicated in metastatic progression through paracrine signaling. We characterized exosomes secreted by a panel of 5 RMS cell lines. Expression array analysis showed that, for both fusion-positive and fusion-negative cells, exosome miRNA clustered well together and to a higher extent than cellular miRNA. While enriched miRNA in exosomes of fusion-negative RMS cells were distinct from those of fusion-positive RMS cells, the most significant predicted disease and functions in both groups were related to processes relevant to cancer and tissue remodelling. Functionally, we found that RMS-derived exosomes exerted a positive effect on cellular proliferation of recipient RMS cells and fibroblasts, induced cellular migration and invasion of fibroblasts, and promoted angiogenesis. These findings show that RMS-derived exosomes enhance invasive properties of recipient cells, and that exosome content of fusion-positive RMS is different than that of fusion-negative RMS, possibly contributing to the different metastatic propensity of the two subtypes.

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Section: Discussionmentioning

confidence: 88%

Exosomes derived from embryonal and alveolar rhabdomyosarcoma carry differential miRNA cargo and promote invasion of recipient fibroblasts

Ghayad

Rammal

Ghamloush

et al. 2016

Sci Rep

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“…The ultimate goal of further work in this field is to identify therapeutic strategies to target HMGA1 in human cancer [reviewed in reference 282]. While many studies cited here underscore the fundamental role of HMGA1 in tumor progression, there has been relatively little work focused on targeting HMGA1 in cancer [176].…”

Section: Resultsmentioning

confidence: 99%

“…HMGA1 is also enriched in human embryonic stem cells [58, 97, 98], adult stem cells, such as hematopoietic stem cells [96, 97], intestinal stem cells [120], and high-grade or poorly differentiated tumors [27, 281, 282], suggesting that it plays a role in driving the undifferentiated, stem-like state. In addition, its high expression during embryogenesis with absent or markedly decreased levels in differentiated, adult tissues further implicates HMGA1 in enforcing a stem-like state [98].…”

Section: Areas For Future Investigationmentioning

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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“…18 Small intestinal tissue was used because we previously reported that Hmga1 transgenics develop marked proliferative changes and polyposis that involves both the small 21 intestine and colon, although polyposis was most pronounced in the small intestine. 18 We also investigated human CRC tumor and matched, adjacent non-neoplastic tissue from colonic biopsies obtained at colonoscopy.…”

Section: Samples and Metabolite Extractionmentioning

confidence: 99%

“…Gene expression profile analyses demonstrate that HMGA1 drives tumor progression and stem cell properties through transcriptional networks expressed in pluripotent stem cells and developing embryos. 18,[21][22][23] Recently, the metabolic profiles of primary CR tumors and adjacent, nonmalignant tissue have been examined using several techniques, including: magic angle spinning -nuclear magnetic resonance (MAS-NMR), gas chromatography -mass spectrometry (GC-MS), ultra-performance liquid chromatography -quadrupole time-of-flight mass spectrometry (UPLC-QToF-MS) and capillary electrophoresis -MS (CE-MS). [24][25][26][27][28][29][30][31][32][33][34] Other platforms used to investigate metabolomes from urine or serum of patients with CRC include GC-MS, UPLC-QToF-MS (MS/MS), Fourier transform ion-cyclotron-MS (FTICR-MS) and proton NMR ( 1 H-NMR).…”

Section: Introductionmentioning

confidence: 99%

HMGA1 Drives Metabolic Reprogramming of Intestinal Epithelium during Hyperproliferation, Polyposis, and Colorectal Carcinogenesis

et al. 2015

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Although significant progress has been made in the diagnosis and treatment of colorectal cancer (CRC), it remains a leading cause of cancer death worldwide. Early identification and removal of polyps that may progress to overt CRC is the cornerstone of CRC prevention. Expression of the High Mobility Group A1 (HMGA1) gene is significantly elevated in CRCs as compared with adjacent, nonmalignant tissues. We investigated metabolic aberrations induced by HMGA1 overexpression in small intestinal and colonic epithelium using traveling wave ion mobility mass spectrometry (TWIMMS) in a transgenic model in which murine Hmga1 was misexpressed in colonic epithelium. To determine if these Hmga1-induced metabolic alterations in mice were relevant to human colorectal carcinogenesis, we also investigated tumors from patients with CRC and matched, adjacent, nonmalignant tissues. Multivariate statistical methods and manual comparisons were used to identify metabolites specific to Hmga1 and CRC. Statistical modeling of data revealed distinct metabolic patterns in Hmga1 transgenics and human CRC samples as compared with the control tissues. We discovered that 13 metabolites were specific for Hmga1 in murine intestinal epithelium and also found in human CRC. Several of these metabolites function in fatty acid metabolism and membrane composition. Although further validation is needed, our results suggest that high levels of HMGA1 protein drive metabolic alterations that contribute to CRC pathogenesis through fatty acid synthesis. These metabolites could serve as potential biomarkers or therapeutic targets.

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The high mobility group A1 molecular switch: turning on cancer – can we turn it off?

Cited by 36 publications

References 105 publications

Exosomes derived from embryonal and alveolar rhabdomyosarcoma carry differential miRNA cargo and promote invasion of recipient fibroblasts

Exosomes derived from embryonal and alveolar rhabdomyosarcoma carry differential miRNA cargo and promote invasion of recipient fibroblasts

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

HMGA1 Drives Metabolic Reprogramming of Intestinal Epithelium during Hyperproliferation, Polyposis, and Colorectal Carcinogenesis

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