High Mobility Group A1 (HMGA1): Structure, Biological Function, and Therapeutic Potential

Wang, Lu; Zhang, Ji; Xia, Min; Liu, Chang; Zu, Xuyu; Zhong, Jing

doi:10.7150/ijbs.72952

Cited by 22 publications

(12 citation statements)

References 184 publications

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“…Reports showed that in cholangiocarcinoma, HMGA1 can induce tumor cell stemness and EMT, and also participate tumor cell proliferation, differentiation, invasion and migration by promoting TRIP13 transcription [29]. In HCC, overexpressed HMGA1 can accelerate growth and migration of cancer cells by blocking the cell cycle, and can also affect in ltration of immune cells in TME and help tumor cells escape [30]. Yang et al reported that PBK can act as a key kinase, and its overexpression can activate the ETV4-uPAR signaling pathway to promote HCC invasion and metastasis [31].…”

Section: Discussionmentioning

confidence: 99%

A novel model of anoikis-related gene for predicting prognosis and assessing immune status with hepatocellular carcinoma

Zhou

et al. 2023

Preprint

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Background Hepatocellular carcinoma (HCC) is one of the highly malignant and aggressive gastrointestinal tumors. Anoikis is a specific form of cell death that is closely related to malignant aggressive behavior of tumors. The role and significance of anoikis-related genes (ANRGs) in HCC deserve to be explored. Methods Here, transcriptome profiling and relevant clinical data needed for analysis were collected from public databases. Prognostic model of ANRGs was constructed by using Lasso regression algorithm. Then, patients were given a reasonable risk grouping, and survival analysis was conducted to compare the different survival rates in each risk group. Receiver operating characteristic (ROC) curve was employed to examine the predictive accuracy of the prognostic model. The single sample gene set enrichment (ssGSEA) was carried out to investigate important disease characteristics of each risk group, such as immune status profile and tumor microenvironment differences. The gene set enrichment analysis (GSEA) method was also implemented to complete functional and pathway enrichment analysis. In addition, drug sensitivity analysis and exploration of single cell data for HCC were completed with the aid of online analytical databases. Results We successfully created a prognostic model containing 14 ANRGs, namely: ANXA5, BSG, SKP2, BAK1, PHLDA2, CDKN3, SFN, EZH2, HMGA1, PBK, NRAS, SLC2A1, MAD2L1 and CASP2, and observed a lower overall survival in high-risk group. The ROC curve confirmed good performance of this new model in predicting prognosis. The ssGSEA revealed significant differences in tumor immune microenvironment between different risk groups, with higher activity about cancer related pathways in high-risk group. The expression level of immune checkpoint and m6A genes also differed between risk subgroups. These prognostic genes were also be related to chemotherapy susceptibility. Conclusion The novel prognostic model identified with ANRGs can be applied to prediction prognostic and assessment immune status profile, tumor microenvironment differences and chemosensitivity in HCC. Rational use of the prognostic new model may provide an important reference for individualized treatment of HCC.

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Section: Discussionmentioning

confidence: 99%

A novel model of anoikis-related gene for predicting prognosis and assessing immune status with hepatocellular carcinoma

Zhou

et al. 2023

Preprint

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“…In the nucleus, HMGA1 also structurally cooperates with the specificity protein 1 (Sp1) and the activator protein 2 (AP2) ( 60 ), whose overexpression is also a hallmark of male GCTs ( 21 ). Increased expression of HMGA1 has been associated with uncontrolled cell growth and proliferation, cell invasion, resistance to chemotherapy, maintenance of stem-like properties and metastatic spread in many human cancers, including male GCTs ( 61 ). Notably, HMGA1 is a positive regulator of the IGFs system, with its own DNA binding sites within the IGFBP1 gene promoter ( 49 ), and it is also an inducer of matrix metalloproteinases and other genes involved in tumor invasion ( 50 ).…”

Section: Discussionmentioning

confidence: 99%

“…Forced expression of these miRNAs has been shown to decrease HMGA1 protein levels and reduce motility in TCam-2 cells ( 62 ), supporting the idea that HMGA1 could be relevant for determining the aggressive traits of male GTCs. Suppression of HMGA1 has been proposed as a promising strategy for treating these tumors ( 61 ); however, the currently available HMGA1 inhibitors (i.e., distamycin polyamides) lack of specificity ( 63 ), while the potential interfering RNA molecules under development have not yet reached the clinical application stage ( 64 ). Studies on Met as an anticancer agent in male GCTs may help to overcome the problems of high-costs and long implementation time, two prerogatives of new drugs.…”

Section: Discussionmentioning

confidence: 99%

The anticancer effects of Metformin in the male germ tumor SEM-1 cell line are mediated by HMGA1

et al. 2022

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IntroductionGerm cell tumors (GCTs) are the most common type of cancer in young men. These tumors usually originate from the testis, but they can occasionally develop from extragonadal sites probably due to primordial germ cells (PGCs) migration errors. Cisplatin-based chemotherapy is usually effective for male GCTs, but the risk of toxicity is high and new therapeutic strategies are needed. Although Metformin (Met) has been widely studied as a potential cancer treatment over the past decades, there is limited evidence to support its use in treating male GCTs. Additionally, the mechanism by which it acts on tumor cells is still not entirely understood.MethodsSEM-1 cells, a newly established human cell line of extragonadal origin, were treated with Met. Cell viability was studied by MTT assay, while cell migration and invasion were studied by the wound healing assay and the transwell assay, respectively. The effect of Met on 3D spheroid formation was determined by seeding SEM-1 cells in appropriate cell suspension culture conditions, and cell cycle was characterized by flow cytometry. Factors involved in PGCs migration and GCT invasion, such as IGFBP1, IGF1R, MMP-11 and c-Kit, together with cyclin D1 (a key regulator of cell cycle progression), and the upstream factor, HMGA1, were determined by immunoblots.ResultsTreatment of SEM-1 cells with Met resulted in a potent and dose-dependent reduction of cell proliferation, as evidenced by decreased nuclear abundance of cyclin D1 and cell cycle arrest in G1 phase. Also, Met prevented the formation of 3D spheroids, and blocked cell migration and invasion by reducing the expression of IGFBP1, IGF1R and MMP-11. Both, IGFBP1 and MMP-11 are under control of HMGA1, a chromatin-associated protein that is involved in the regulation of important oncogenic, metabolic and embryological processes. Intriguingly, an early reduction in the nuclear abundance of HMGA1 occurred in SEM-1 cells treated with Met.ConclusionsOur results document the antiproliferative and antimigratory effects of Met in SEM-1 cells, providing new insights into the potential treatments for male GCTs. The anticancer properties of Met in SEM-1 cells are likely related to its ability to interfere with HMGA1 and downstream targets, including cyclin D1, the IGFs system, and MMP-11.

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“…22 HMGA proteins play a role in cancer initiation and development, and they have been proposed as a suitable target to interfere with neoplastic transformation. 13,15,23 Therefore, we decided to search for new small molecules that were able to bind the minor groove of AT-rich DNA sequences that could act as HMGA competitors. To this aim, a docking-based virtual screening was carried out to evaluate the ability of a proprietary in-house natural product library to target the minor groove of AT-rich DNA sequences and to compete with HMGA for the interaction with DNA.…”

Section: ■ Introductionmentioning

confidence: 99%

“…The oncogenic role of these proteins has been demonstrated by their overexpression in vitro in cellular models and in vivo in transgenic mice. Indeed, many of their biological functions actively promote the acquisition of most cancer hallmarks and their multiple oncogenic activities have been extensively reviewed. − …”

Section: Introductionmentioning

confidence: 99%

Selection of Natural Compounds with HMGA-Interfering Activities and Cancer Cell Cytotoxicity

Mori,

Ghirga,

Amato

et al. 2023

ACS Omega

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HMGA proteins are intrinsically disordered (ID) chromatin architectural factors characterized by three DNA binding domains (AT-hooks) that allow them to bind into the DNA minor groove of AT-rich stretches. HMGA are functionally involved in regulating transcription, RNA processing, DNA repair, and chromatin remodeling and dynamics. These proteins are highly expressed and play essential functions during embryonic development. They are almost undetectable in adult tissues but are re-expressed at high levels in all cancers where they are involved in neoplastic transformation and cancer progression. We focused on identifying new small molecules capable of binding into the minor groove of AT-rich DNA sequences that could compete with HMGA for DNA binding and, thus, potentially interfere with their activities. Here, a docking-based virtual screening of a unique high diversity in-house library composed of around 1000 individual natural products identified 16 natural compounds as potential minor groove binders that could inhibit the interaction between HMGA and DNA. To verify the ability of these selected compounds to compete with HMGA proteins, we screened them using electrophoretic mobility shift assays. We identified Sorocein C, a Diels–Alder (D–A)-type adducts, isolated from Sorocea ilicifolia and Sorocea bonplandii with an HMGA/DNA-displacing activity and compared its activity with that of two structurally related compounds, Sorocein A and Sorocein B. All these compounds showed a cytotoxicity effect on cancer cells, suggesting that the Sorocein-structural family may provide new and yet unexplored chemotypes for the development of minor groove binders to be evaluated as anticancer agents.

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High Mobility Group A1 (HMGA1): Structure, Biological Function, and Therapeutic Potential

Cited by 22 publications

References 184 publications

A novel model of anoikis-related gene for predicting prognosis and assessing immune status with hepatocellular carcinoma

A novel model of anoikis-related gene for predicting prognosis and assessing immune status with hepatocellular carcinoma

The anticancer effects of Metformin in the male germ tumor SEM-1 cell line are mediated by HMGA1

Selection of Natural Compounds with HMGA-Interfering Activities and Cancer Cell Cytotoxicity

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