Frequent Overexpression of <i>HMGA2</i> in Human Atypical Teratoid/Rhabdoid Tumor and Its Correlation with <i>let-7a3/let-7b</i> miRNA

Zhang, Keqiang; Gao, Hanlin; Wu, Xiwei; Wang, Jinhui; Zhou, Wendi; Sun, Guihua; Wang, Jinghan; Wang, Yafan; Mu, Bing; Kim, Charles; Ho, Donald Ming Tak; Ann, David K.; Wong, Tai-Tong; Yen, Yun

doi:10.1158/1078-0432.ccr-13-1452

Cited by 36 publications

(42 citation statements)

References 39 publications

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“…The High Mobility Group AT-hook 2 (HMGA2) protein upregulates a pro-invasive program in diverse cancer types [7, 10, 12, 18-23, 34, 36]. We found increased expression of HMGA2 protein in the majority of GBM tumors by western blot analysis and immunohistochemistry using a cohort of 80 pediatric and adult GBM samples.…”

Section: Discussionmentioning

confidence: 90%

The transcriptional modulator HMGA2 promotes stemness and tumorigenicity in glioblastoma

et al. 2016

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Glioblastoma (GBM) contains a population of stem-like cells that promote tumor invasion and resistance to therapy. Identifying and targeting stem cell factors in GBM may lead to the development of more effective therapies. High Mobility Group AT-hook 2 (HMGA2) is a transcriptional modulator that mediates motility and self-renewal in normal and cancer stem cells. We identified increased expression of HMGA2 in the majority of primary human GBM tumors and cell lines compared to normal brain. Additionally, HMGA2 expression was increased in CD133+ GBM neurosphere cells compared to CD133- cells. Targeting HMGA2 with lentiviral short hairpin RNA (shRNA) led to decreased GBM stemness, invasion, and tumorigenicity. Ectopic expression of HMGA2 in GBM cell lines promoted stemness, invasion, and tumorigenicity. Our data suggests that targeting HMGA2 in GBM may be therapeutically beneficial.

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Section: Discussionmentioning

confidence: 90%

The transcriptional modulator HMGA2 promotes stemness and tumorigenicity in glioblastoma

et al. 2016

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“…Patients with HMGA1-negative tumors have a better prognosis with longer median survival (Liau et al, 2008). Several transcription factors (e.g., Sp1, Sp3, AP-1, and E2F1), microRNAs (e.g., let-7, miR-196a-2, and microRNA-296) and signals (e.g., Wnt/β-catenin signaling) contribute aberrantly to HMGA expression in tumors (De Martino et al, 2009; Ferguson et al, 2003; Motoyama et al, 2008; Wend et al, 2013; Zhang et al, 2014b). In addition, oncogenic genes such as K-RAS, N-RAS, and c-Myc can induce HMGA1 overexpression during cell transformation (Li et al, 2013i).…”

Section: Introduction and Historical Backgroundmentioning

confidence: 99%

HMGB1 in health and disease

Kang

Chen

Zhang

et al. 2014

Molecular Aspects of Medicine

822

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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“…AT/RTs express multiple stem cell factors, including SOX2, NANOG, KLF4, and high mobility group A2 (HMGA2) (10, 11). HMGA2 is a chromatin-architectural protein that is highly expressed during embryogenesis with little to no expression in normal adult tissues (12–16).…”

Section: Introductionmentioning

confidence: 99%

“…HMGA2 is a chromatin-architectural protein that is highly expressed during embryogenesis with little to no expression in normal adult tissues (12–16). Increased expression of HMGA2 is associated with a poor prognosis in multiple adult cancer types, including lung, gastric, pancreatic and ovarian carcinomas, and leukemia (11, 17–26). HMGA2 promotes tumor cell growth, invasion and clonogenic potential in cancer cells (13, 14, 17–21, 27–33).…”

Section: Introductionmentioning

confidence: 99%

“…HMGA2 promotes tumor cell growth, invasion and clonogenic potential in cancer cells (13, 14, 17–21, 27–33). Reduction of HMGA2 in a kidney rhabdoid tumor cell line decreased proliferation and colony formation (11) but the functional significance of HMGA2 in central nervous system (CNS) AT/RTs and the role of HMGA2 in CNS AT/RT tumor formation in vivo are unknown.…”

Section: Introductionmentioning

confidence: 99%

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The Chromatin-Modifying Protein HMGA2 Promotes Atypical Teratoid/Rhabdoid Cell Tumorigenicity

Kaur

Hütt-Cabezas

Weingart

et al. 2015

J Neuropathol Exp Neurol

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Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive pediatric central nervous system tumor. The poor prognosis of AT/RT warrants identification of novel therapeutic targets and strategies. High mobility group A2 (HMGA2) is a developmentally important chromatin modifying protein that positively regulates tumor growth, self-renewal and invasion in other cancer types. HMGA2 was recently identified as being upregulated in AT/RT tissue, but the role of HMGA2 in brain tumors remains unknown. We used lentiviral short hairpin RNA to suppress HMGA2 in AT/RT cell lines and found that loss of HMGA2 led to decreased cell growth, proliferation, colony formation and increased apoptosis. We also found that suppression of HMGA2 negatively affected in vivo orthotopic xenograft tumor growth, more than doubling median survival of the mice from 58 days to 153 days. Our results indicate a role for HMGA2 in AT/RT in vitro and in vivo and demonstrate that HMGA2 is a potential therapeutic target in these lethal pediatric tumors.

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Frequent Overexpression of HMGA2 in Human Atypical Teratoid/Rhabdoid Tumor and Its Correlation with let-7a3/let-7b miRNA

Cited by 36 publications

References 39 publications

The transcriptional modulator HMGA2 promotes stemness and tumorigenicity in glioblastoma

The transcriptional modulator HMGA2 promotes stemness and tumorigenicity in glioblastoma

HMGB1 in health and disease

The Chromatin-Modifying Protein HMGA2 Promotes Atypical Teratoid/Rhabdoid Cell Tumorigenicity

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