Search Results (42)

Urothelial carcinoma (UC) of the bladder exhibits low- and high-grade papillary forms with distinct prognoses. High mobility group proteins (HMGA1, HMGA2, HMGB1) and miR-106a-5p are involved in tumor progression, but their interplay in UC remains incompletely understood. The aim of this study was to compare the expression of these parameters in low- and high-grade papillary UC. Tissue samples from 80 patients (40 low-grade and 40 high-grade) undergoing transurethral resection or cystectomy were analyzed, with control samples consisting of tumor-adjacent tissues without histopathological alterations obtained from the same patients. HMGA1, HMGA2, and HMGB1 protein expression was assessed immunohistochemically. Gene expression was quantified by real-time PCR, and miR-106a-5p levels were measured by droplet digital PCR. Statistical analysis was conducted using Statistica 13.3, applying one-way ANOVA with Tukey’s post hoc test and correlation analysis, with p < 0.05 considered significant. Expression of HMGA1 and HMGB1 was reduced in low-grade papillary urothelial carcinoma compared to control tissues, whereas both proteins were significantly increased in high-grade lesions. HMGA2 expression was minimal in low-grade tumors but partially restored in high-grade tumors. Analysis revealed the highest levels of miR-106a-5p in normal urothelium, slightly decreased in low-grade tumors, and significantly reduced in high-grade cancers. HMG proteins and miR-106a-5p demonstrate distinct expression patterns in low- versus high-grade papillary UC, which correlates with tumor aggressiveness. These molecules may serve as diagnostic and prognostic biomarkers. Their potential as therapeutic targets requires further mechanistic and translational investigation. Full article

RNA In Situ Hybridization (RISH) is a powerful tool for spatial gene expression analysis, yet its quantitative use remains limited by the high cost and inaccessibility of commercial software, particularly in under-resourced settings. This study developed an Artificial Intelligence/Machine Learning (AI/ML)-assisted RISH quantification pipeline to evaluate expression patterns of High Mobility Group AT Hook-2 (HMGA2) in prostate cancer (PCa), focusing on racial disparities. We created a machine learning model capable of analyzing RISH images. Expressions of full-length (wild-type) and truncated HMGA2 isoforms were assessed in tissues from 85 men of African descent, European American, and Asian descent. A training dataset was generated for supervised learning analysis of the full cohort. RISH findings revealed that the wild-type HMGA2 isoform was significantly more abundant in tumors from men of African descent and positively correlated with increasing Gleason grade. The truncated isoform was less abundant and did not display a consistent expression pattern across racial groups. These results demonstrate the feasibility of AI/ML-based RISH quantification and suggest that elevated wild-type HMGA2 expression may represent a biomarker linked to prostate cancer aggressiveness and racial disparities. These findings highlight the importance of interdisciplinary collaboration and equitable computational tools in advancing biomarker discovery and addressing cancer health inequities. Full article

High mobility group A1 (HMGA1) is a chromatin-associated protein that regulates transcription and drives cancer progression. In this pan-cancer study, we analyzed multi-omics data to comprehensively characterize HMGA1’s expression patterns, prognostic significance, epigenetic regulation, and immunotherapy roles. We found that HMGA1 was markedly upregulated in most cancers, mainly driven by promoter hypomethylation and copy number alterations. Elevated HMGA1 expression was consistently associated with unfavorable patient survival, stemness features, and the activation of oncogenic signaling pathways. Crucially, HMGA1 expression correlated with an immune-excluded tumor microenvironment, characterized by suppressed stromal and immune scores. Even in tumors with immune infiltration, high HMGA1 predicted poor prognosis, likely mediated by enhanced regulatory T-cell (Treg) recruitment and impaired effector immune function. Moreover, HMGA1 levels were positively correlated with tumor mutational burden (TMB), and microsatellite instability (MSI), and immunotherapy-related checkpoints including PD-1, CTLA-4, and TIGIT. Drug sensitivity analysis further revealed that HMGA1 predicted resistance to AKT inhibitors, which was experimentally validated in breast cancer cells treated with Capivasertib. Collectively, our findings establish HMGA1 as a pivotal oncogenic regulator and a promising biomarker for prognosis and for guiding strategies in immunotherapy and overcoming targeted therapy resistance. Full article

Background and Objectives: Aging-related bone loss still lacks interventions. As bone marrow-derived mesenchymal stem cells (BMSCs) undergo aging, R-loop-induced DNA replication stress impairs the osteogenic ability of BMSCs. High-mobility group A-2 (Hmga2) acts as a DNA-binding protein, and the understanding of its underlying mechanisms is crucial for developing effective preventive and therapeutic strategies. Materials and Methods: Aging mice were used as the experimental model, and mouse BMSCs were isolated from their femurs. Hmga2 was achieved through specific gene delivery methods. R-loop formation was detected using dot blotting, chromatin immunoprecipitation (ChIP), and DNA–RNA immunoprecipitation (DRIP) assays. Osteogenic differentiation was evaluated. Results: R-loops were highly accumulated in aging BMSCs. Notably, the key regulator Hmga2 reversed the accumulation of R-loops in aging BMSCs. Hmga2 overexpression significantly decreased the senescence and improved the osteogenic differentiation of aging mBMSCs. Mechanistically, R-loop-forming sequence (RLFS) regions were confirmed in key osteogenesis-related genes, including runt-related transcription factor 2 (Runx2). Hmga2 bound to the RLFS region of Runx2 and promoted its expression by reducing the R-loop level. More, Hmga2 treatment delivered via the AAV system effectively decreased bone loss in aging mice and increased the serum bone turnover biomarkers and collagen remodeling. Conclusions: Our study demonstrates that Hmga2 acts as an activator of aging BMSCs, significantly promoting their osteogenic ability by eliminating the aging-induced DNA replication stress caused by R-loops. Our findings provide new insights into the mechanisms of aging-related bone loss, suggesting that Hmga2 may be a new strategy for alleviating the bone loss phenotype in aging individuals. Full article

Patients with chronic, indolent myeloproliferative neoplasms (MPNs) are at risk for transformation to highly lethal leukemia, although targetable mechanisms driving progression remain elusive. We discovered that the High Mobility Group A1 (HMGA1) gene is up-regulated with MPN progression in patients and required for evolution into myelofibrosis (MF) or acute myeloid leukemia (AML) in preclinical models. HMGA1 encodes the HMGA1 epigenetic regulators that modulate the chromatin state during embryogenesis and tissue regeneration. While HMGA1 is silenced in most differentiated cells, it becomes aberrantly re-expressed in JAK2 mutant (JAK2-V617F) MPN, with the highest levels after transformation to secondary MF or AML. Here, we review recent work highlighting HMGA1 function in MPN progression. Though underlying mechanisms continue to emerge, increasing evidence suggests that HMGA1 functions as a “chromatin key” required to “unlock” regions of the genome involved in clonal expansion and progression in MPN. Together, these findings illuminate HMGA1 as a driver of MPN progression and a promising therapeutic target. Full article

Artificial insemination (AI), as an efficient assisted reproduction technology, can help the livestock industry to improve livestock and poultry breeds, optimize production performance and improve reproductive efficiency. AI technology has been widely used in pig production in China, but boar fertility affects the effectiveness of AI, and more and more studies have shown that there are significant differences in the fertility of boars with similar semen quality indicators. Therefore, this study aimed to identify biomarker molecules that indicate the level of boar fertility, which is important for improving the efficiency of AI. In this study, we collected 40 mL of ejaculates per boar used for extracellular vesicle (EV) characterization in 20 boars and identified 53 differentially expressed miRNAs by small RNA sequencing, of which 44 miRNAs were up-regulated in the high-fertility seminal EVs compared with low-fertility seminal EVs, and nine miRNAs were down-regulated. miR-26a was most significantly down-regulated in the high-fertility group compared to the low-fertility group, and it was hypothesized that this miRNA could be used as a biomolecular marker of semen reproductive performance. To further determine the effect of miR-26a on sperm function, we successfully established a miR-26a overexpression model and found that miR-26a reduced sperm viability, motility, acrosome integrity, plasma membrane integrity and ATP levels. Bioinformatics analysis and dual luciferase reporter analysis revealed that miR-26a directly targets High mobility group A1 (HMGA1). In conclusion, miR-26a can be used as a biomarker to identify high and low fertility in boar semen. Full article

Metastatic prostate cancer (mPCa) is a leading cause of mortality, partly due to its resistance to anti-androgens like enzalutamide. Snail can promote this resistance by increasing full-length AR and AR-V7. High Mobility Group AT-hook 2 (HMGA2), a DNA-binding protein upstream of Snail, is crucial in proliferation and epithelial–mesenchymal transition (EMT). This study examines HMGA2’s role in enzalutamide resistance. LNCaP and 22Rv1 cells overexpressing wild-type HMGA2, but not truncated HMGA2, showed EMT. Both variants led to a decreased sensitivity to enzalutamide but not alisertib compared to Neo control cells. The overexpression of HMGA2 did not alter AR expression. Enzalutamide-resistant C4-2B cells (C4-2B MDVR) had higher HMGA2 and AR/AR variant expression than enzalutamide-sensitive C4-2B cells but remained sensitive to alisertib. The HMGA2 knockdown in C4-2B MDVR cells increased sensitivity to both enzalutamide and alisertib without changing AR expression. A clinical analysis via cBioPortal revealed HMGA2 alterations in 3% and AR alterations in 59% of patients. The HMGA2 changes were linked to treatments like enzalutamide, abiraterone, or alisertib, with amplifications more prevalent in bone, lymph node, and liver metastases. Conclusively, HMGA2 is a potential biomarker for enzalutamide resistance in mPCa, independent of Snail and AR signaling, and alisertib may be an effective treatment for mPCa that expresses HMGA2. Full article

Survival of Medulloblastoma (MB) depends on various factors, including the gene expression profiles of MB tumor tissues. In this study, we identified 967 MB survival-related genes (SRGs) using a gene expression dataset and the Cox proportional hazards regression model. Notably, the SRGs were over-represented on chromosomes 6 and 17, known for the abnormalities monosomy 6 and isochromosome 17 in MB. The most significant SRG was HMGA1 (high mobility group AT-hook 1) on chromosome 6, which is a known oncogene and a histone H1 competitor. High expression of HMGA1 was associated with worse survival, primarily in the Group 3γ subtype. The high expression of HMGA1 was unrelated to any known somatic copy number alteration. Most SRGs on chromosome 17p were associated with low expression in Group 4β, the MB subtype, with 93% deletion of 17p and 98% copy gain of 17q. GO enrichment analysis showed that both chromosomes 6 and 17 included SRGs related to telomere maintenance and provided a rationale for testing telomerase inhibitors in Group 3 MBs. We conclude that HMGA1, along with other SRGs on chromosomes 6 and 17, warrant further investigation as potential therapeutic targets in selected subgroups or subtypes of MB. Full article

The high-mobility group AT-hook 2(HMGA2) gene has been widely studied in the context of cancer and animal growth. However, recently, several studies have uncovered its critical role in cell proliferation. A genome-wide association study (GWAS) further suggests that the HMGA2 gene is a candidate gene in fertility, indicating its connection not only to growth traits but also to reproduction, specifically ovarian traits. Thus, this study aimed to analyze the distribution of the HMGA2 gene in 54 bovine breeds worldwide, identify important short fragment variants (indels), and investigate the relationship between HMGA2 and ovarian development. The dataset included genotypic information from a bovine population of 634 individuals (n = 634). After genotyping and analyzing four selected loci, we found that one out of four loci, rs133750033 (P4-D_22-bp), was polymorphic. Our results also reveal that this indel of HMGA2 is significantly associated with certain ovarian traits (p < 0.05). Specifically, it has connection with ovarian length (p = 0.004) and ovarian height (p = 0.026) during diestrus. Additionally, we discovered a higher expression of the HMGA2 gene in Asian cattle breeds. In summary, this study suggests that HMGA2 has the potential to serve as an animal fertility testing marker gene. Moreover, these findings contribute to a more promising outlook for the bovine industry. Full article

Colorectal cancer (CRC) is one of the most lethal cancers worldwide, accounting for nearly ~10% of all cancer diagnoses and deaths. Current therapeutic approaches have considerably increased survival for patients diagnosed at early stages; however, ~20% of CRC patients are diagnosed with late-stage, metastatic CRC, where 5-year survival rates drop to 6–13% and treatment options are limited. Genome instability is an enabling hallmark of cancer that confers increased acquisition of genetic alterations, mutations, copy number variations and chromosomal rearrangements. In that regard, research has shown a clear association between genome instability and CRC, as the accumulation of aberrations in cancer-related genes provides subpopulations of cells with several advantages, such as increased proliferation rates, metastatic potential and therapeutic resistance. Although numerous genes have been associated with CRC, few have been validated as predictive biomarkers of metastasis or therapeutic resistance. A growing body of evidence suggests a member of the High-Mobility Group A (HMGA) gene family, HMGA2, is a potential biomarker of metastatic spread and therapeutic resistance. HMGA2 is expressed in embryonic tissues and is frequently upregulated in aggressively growing cancers, including CRC. As an architectural, non-histone chromatin binding factor, it initiates chromatin decompaction to facilitate transcriptional regulation. HMGA2 maintains the capacity for stem cell renewal in embryonic and cancer tissues and is a known promoter of epithelial-to-mesenchymal transition in tumor cells. This review will focus on the known molecular mechanisms by which HMGA2 exerts genome protective functions that contribute to cancer cell survival and chemoresistance in CRC. Full article

The non-histone chromatin binding protein High Mobility Group AT-hook protein 2 (HMGA2) has important functions in chromatin remodeling, and genome maintenance and protection. Expression of HMGA2 is highest in embryonic stem cells, declines during cell differentiation and cell aging, but it is re-expressed in some cancers, where high HMGA2 expression frequently coincides with a poor prognosis. The nuclear functions of HMGA2 cannot be explained by binding to chromatin alone but involve complex interactions with other proteins that are incompletely understood. The present study used biotin proximity labeling, followed by proteomic analysis, to identify the nuclear interaction partners of HMGA2. We tested two different biotin ligase HMGA2 constructs (BioID2 and miniTurbo) with similar results, and identified known and new HMGA2 interaction partners, with functionalities mainly in chromatin biology. These HMGA2 biotin ligase fusion constructs offer exciting new possibilities for interactome discovery research, enabling the monitoring of nuclear HMGA2 interactomes during drug treatments. Full article

Breast cancer (BC) is the primary cause of cancer mortality in women and the triple-negative breast cancer (TNBC) is the most aggressive subtype characterized by poor differentiation and high proliferative properties. High mobility group A1 (HMGA1) is an oncogenic factor involved in the onset and progression of the neoplastic transformation in BC. Here, we unraveled that the replication-dependent-histone (RD-HIST) gene expression is enriched in BC tissues and correlates with HMGA1 expression. We explored the role of HMGA1 in modulating the RD-HIST genes expression in TNBC cells and show that MDA-MB-231 cells, depleted of HMGA1, express low levels of core histones. We show that HMGA1 participates in the activation of the HIST1H4H promoter and that it interacts with the nuclear protein of the ataxia-telangiectasia mutated locus (NPAT), the coordinator of the transcription of the RD-HIST genes. Moreover, we demonstrate that HMGA1 silencing increases the percentage of cells in G0/G1 phase both in TNBC and epirubicin resistant TNBC cells. Moreover, HMGA1 silencing causes an increase in epirubicin IC₅₀ both in parental and epirubicin resistant cells thus suggesting that targeting HMGA1 could affect the efficacy of epirubicin treatment. Full article

Organ culture allows for the understanding of normal and tumor cell biology, and tissues generally remain viable for 5–7 days. Strikingly, we determined that myometrial and MED12 mutant leiomyoma cells repopulated cell-depleted tissue slices after 20 days of culture. Using immunofluorescence and quantitative PCR of stem cell and undifferentiated cell markers, we observed clusters of CD49b⁺ cells in tumor slices. CD49b⁺ cells, however, were sparsely detected in the myometrial slices. Almost all LM cells strongly expressed Ki67, while only a few myometrial cells were stained for this proliferation marker. The CD73 marker was expressed only in tumor cells, whereas the mesenchymal stem cell receptor KIT was detected only in normal cells. HMGA2 and CD24 showed broader expression patterns and higher signal intensity in leiomyoma than in myometrial cells. In this study, we propose that activating CD49b⁺ stem cells in myometrium leads to asymmetrical division, giving rise to transit-amplifying KIT⁺ cells that differentiate to smooth muscle cells. On the contrary, activated leiomyoma CD49b⁺ cells symmetrically divide to form clusters of stem cells that divide and differentiate to smooth muscle cells without losing proliferation ability. In conclusion, normal and mutant stem cells can proliferate and differentiate in long-term organ culture, constituting a helpful platform for novel therapeutic discovery. Full article

High-mobility group protein 1 (HMGA1) participates in the processes of DNA transcription, replication, recombination, and repair. The HMGA1 gene is expressed abundantly during embryogenesis and is reactivated during carcinogenesis. HMGA1 gene expression has been associated with a high degree of malignancy, metastatic tendency, and poor survival in breast, colon, ovary, and pancreatic cancers. However, its prognostic significance in lung cancer remains unclear. Using publicly available data, HMGA1 was shown to be overexpressed in both small and non-small lung tumors, with higher expression compared to both the adjacent non-malignant lung tissues and non-tumor lung tissues of healthy individuals. Elevated HMGA1 expression could result from lowered HMGA1 methylation and was connected with some clinicopathological features like sex, age, and stage of the disease. The high HMGA1 expression level was connected with shorter overall and first progression survival time among lung adenocarcinoma patients, but not lung squamous cell carcinoma patients. HMGA1 could interact with proteins involved in cellular senescence and cell cycle control (TP53, RB1, RPS6KB1, and CDK1), transcription regulation (EP400 and HMGA2), chromatin assembly and remodeling (LMNB1), and cholesterol and isoprene biosynthesis (HMGCR and INSIG1). Taken together, HMGA1 overexpression could be an essential element of lung carcinogenesis and a prognostic feature in lung cancer. Full article

The prognosis of advanced gastric cancer remains poor. Overexpression of high mobility group A 1 (HMGA1) in breast cancer and neuroblastoma indicates a poor prognosis. However, the relationship between HMGA1 expression and gastric cancer development remains unclear. Treatment strategies can be developed by identifying potential markers associated with gastric cancer. We used a constructed tissue array and performed hematoxylin and eosin and immunohistochemical staining. We quantified the staining results and performed statistical analysis to evaluate the relationship between HMGA1 expression and prognosis. HMGA1 expression was related to the expression of Ki-67, caspase3, CD31, N-cadherin, fibronectin, pAkt, and pErk. In the Kaplan–Meier graph, higher HMGA1 expression levels were associated with a relatively poor survival rate (p = 0.04). High expression of HMGA1 leads to a low survival rate, which is associated with HMGA1, proliferation, apoptosis, angiogenesis, epithelial-mesenchymal transition, and tyrosine kinase. Full article