High Mobility Group A (HMGA) proteins: Molecular instigators of breast cancer onset and progression

Sgarra, Riccardo; Pegoraro, Silvia; Ros, Gloria; Penzo, Carlotta; Chiefari, Eusebio; Foti, Daniela; Brunetti, Antonio; Manfioletti, Guidalberto

doi:10.1016/j.bbcan.2018.03.001

Cited by 70 publications

(75 citation statements)

References 136 publications

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“…In these circumstances, INSR can exert its oncogenic potential, by directly affecting cell metabolism and/or by synergizing with other oncogenes, with adverse impact on tumor growth and differentiation [169]. The high-mobility group A1 protein (HMGA1) is as a crucial regulator of INSR gene transcription, which directs the assembly of a transcriptionally active multiprotein-DNA complex on the INSR gene promoter [169,170]. As demonstrated by our group [169], the physical and functional cooperation between the transcription factor AP2 and HMGA1 is a fundamental prerequisite for INSR overexpression in neoplastic breast tissues.…”

Section: Meddiet and Nutrient-gene Interactions In The Modulation Of mentioning

confidence: 99%

“…In addition, breast cancer growth can take advantage of systemic metabolic effects linked to HMGA1-regulated genes in organs distant from the tumor site, reinforcing the close relationship between cancer and abnormal glucose metabolism. HMGA1 regulates both insulin transcription in pancreatic β-cells and expression levels of IGF1-binding proteins involved in glucose disposal in peripheral tissues [170,171], other than a variety of adipokines related to IR and genes relevant for cholesterol biosynthesis [171,172]. Although no data are currently available regarding a potential overlap between cancer and T2D [172], HMGA proteins are also implicated in the multistep processes of tumorigenesis and are susceptible of microRNAs-dependent suppression in normal tissues [173].…”

Section: Meddiet and Nutrient-gene Interactions In The Modulation Of mentioning

confidence: 99%

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Mediterranean Diet Nutrients to Turn the Tide against Insulin Resistance and Related Diseases

et al. 2020

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Insulin resistance (IR), defined as an attenuated biological response to circulating insulin, is a fundamental defect in obesity and type 2 diabetes (T2D), and is also linked to a wide spectrum of pathological conditions, such as non-alcoholic fatty liver disease (NAFLD), cognitive impairment, endothelial dysfunction, chronic kidney disease (CKD), polycystic ovary syndrome (PCOS), and some endocrine tumors, including breast cancer. In obesity, the unbalanced production of pro- and anti-inflammatory adipocytokines can lead to the development of IR and its related metabolic complications, which are potentially reversible through weight-loss programs. The Mediterranean diet (MedDiet), characterized by high consumption of extra-virgin olive oil (EVOO), nuts, red wine, vegetables and other polyphenol-rich elements, has proved to be associated with greater improvement of IR in obese individuals, when compared to other nutritional interventions. Also, recent studies in either experimental animal models or in humans, have shown encouraging results for insulin-sensitizing nutritional supplements derived from MedDiet food sources in the modulation of pathognomonic traits of certain IR-related conditions, including polyunsaturated fatty acids from olive oil and seeds, anthocyanins from purple vegetables and fruits, resveratrol from grapes, and the EVOO-derived, oleacein. Although the pharmacological properties and clinical uses of these functional nutrients are still under investigation, the molecular mechanism(s) underlying the metabolic benefits appear to be compound-specific and, in some cases, point to a role in gene expression through an involvement of the nuclear high-mobility group A1 (HMGA1) protein.

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Section: Meddiet and Nutrient-gene Interactions In The Modulation Of mentioning

confidence: 99%

Section: Meddiet and Nutrient-gene Interactions In The Modulation Of mentioning

confidence: 99%

Mediterranean Diet Nutrients to Turn the Tide against Insulin Resistance and Related Diseases

et al. 2020

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“…This admixture signal at 12q14 seems to be explained by the two SNPs (rs9739580 and rs10878313) identified by us in the present work. This region includes the HMGA2 gene, which belongs to the High Mobility Group A (HMGA) chromatin architectural factors that are highly expressed during development of the embryo (Sgarra et al 2018). HMGA2 carries GWAS-identified SNPs associated with phenotypes from different stages of life such as birth weight (Horikoshi et al 2016; Horikoshi et al 2013), birth and infant length (van der Valk et al 2015), childhood height (Weedon et al 2007), and type 2 diabetes (Mahajan et al 2014; Morris et al 2012; Ng et al 2014; Voight et al 2010; Zhao et al 2017) and anthropometric traits (Carty et al 2012; He et al 2015; Justice et al 2017; N’Diaye et al 2011; Shungin et al 2015; Soranzo et al 2009; Weedon et al 2007) in adulthood.…”

Section: Discussionmentioning

confidence: 99%

Admixture mapping and fine-mapping of birth weight loci in the Black Women’s Health Study

et al. 2018

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Several genome-wide association studies (GWAS) have identified genetic variants associated with birth weight. To date, however, most GWAS of birth weight have focused primarily on European ancestry samples even though prevalence of low birth weight is higher among African-Americans. We conducted admixture mapping using 2918 ancestral informative markers in 2596 participants of the Black Women's Health Study, with the goal of identifying novel genomic regions where local African ancestry is associated with birth weight. In addition, we performed a replication analysis of 11 previously identified index single nucleotide polymorphisms (SNPs), and fine-mapped those genetic loci to identify better or new genetic variants associated with birth weight in African-Americans. We found that high African ancestry at 12q14 was associated with low birth weight, and we identified multiple independent birth weight-lowering variants in this genomic region. We replicated the association of a previous GWAS SNP in ADRB1 and our fine-mapping efforts suggested the presence of new birth weight-associated variants in ADRB1, HMGA2, and SLC2A4. Further studies are needed to determine whether birth weight-associated loci can in part explain race-associated birth weight disparities.

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“…In adult tissues these proteins are almost undetectable except in cancer cells, where HMGA are over-expressed and crucial for tumor onset and progression (19,20). In fact, HMGA drive tumor progression through the modulation of several hallmarks of cancer, such as cell proliferation, metastatic processes, drug resistance and stem cell properties (21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Human HMGA proteins are encoded by two distinct paralogous genes: HMGA1, that extends for 10 kb on chromosome 6 (6p21) and HMGA2 that is a 160 kb long gene located on chromosome 12 (12q14-15) (20).…”

Section: Introductionmentioning

confidence: 99%

HMGA2 Antisense Long Non-coding RNAs as New Players in the Regulation of HMGA2 Expression and Pancreatic Cancer Promotion

et al. 2020

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Background: Natural antisense long non-coding RNAs (lncRNAs) are regulatory RNAs transcribed from the opposite strand of either protein coding or non-coding genes, able to modulate their own sense gene expression. Hence, their dysregulation can lead to pathologic processes. Cancer is a complex class of diseases determined by the aberrant expression of a variety of factors, among them, the oncofetal chromatin architectural proteins High Mobility Group A (HMGA) modulate several cancer hallmarks. Thus, we decided to investigate the presence of natural antisense lncRNAs in HMGA1 and HMGA2 loci, and their possible involvement in gene expression regulation. Methods: We used FANTOM5 data resources, FANTOM-CAT genome browser and Zenbu visualization tool, which employ 1,829 human CAGE and RNA-sequencing libraries, to determine expression, ontology enrichment, and dynamic regulation of natural antisense lncRNAs in HMGA1 and HMGA2 loci. We then performed qRT-PCR in different cancer cell lines to validate the existence of HMGA2-AS1 transcripts. We depleted HMGA2-AS1 transcripts with siRNAs and investigated HMGA2 expression by qRT-PCR and western blot analyses. Moreover, we evaluated cell viability and migration by MTS and transwell assays, and EMT markers by qRT-PCR and immunofluorescence. Furthermore, we used bioinformatics approaches to evaluate HMGA2 and HMGA2-AS1 correlation and overall survival in tumor patients. Results: We found the presence of a promoter-associated lncRNA (CATG00000088127.1) in the HMGA1 gene and three antisense genes (RPSAP52, HMGA2-AS1, and RP11-366L20.3) in the HMGA2 gene. We studied the uncharacterized HMGA2-AS1 transcripts, validating their existence in cancer cell lines and observing a positive correlation between HMGA2 and HMGA2-AS1 expression in a cancer-derived patient dataset. We showed that HMGA2-AS1 transcripts positively modulate HMGA2 expression and migration properties of PANC1 cells through HMGA2. In addition, Kaplan-Meier analysis showed that high level of HMGA2-AS1 is a negative prognostic factor in pancreatic cancer patients. Ros et al. HMGA2 Regulation by HMGA2-AS1 Conclusions: Our results describe novel antisense lncRNAs associated with HMGA1 and HMGA2 genes. In particular, we demonstrate that HMGA2-AS1 is involved in the regulation of its own sense gene expression, mediating tumorigenesis. Thus, we highlight a new layer of complexity in the regulation of HMGA2 expression, providing new potential targets for cancer therapy.

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High Mobility Group A (HMGA) proteins: Molecular instigators of breast cancer onset and progression

Cited by 70 publications

References 136 publications

Mediterranean Diet Nutrients to Turn the Tide against Insulin Resistance and Related Diseases

Mediterranean Diet Nutrients to Turn the Tide against Insulin Resistance and Related Diseases

Admixture mapping and fine-mapping of birth weight loci in the Black Women’s Health Study

HMGA2 Antisense Long Non-coding RNAs as New Players in the Regulation of HMGA2 Expression and Pancreatic Cancer Promotion

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