Search Results (124)

The strategy of active surveillance for papillary thyroid microcarcinoma (PTMC) is becoming increasingly popular within the global medical community. A key criterion for selecting this strategy is the absence of any signs of lymphogenic or distant metastases. The present study assessed the diagnostic accuracy of molecular genetic markers for predicting the metastatic potential of patients with PTMC. We evaluated the expression levels of 33 molecular genetic markers in cytology samples from 92 patients with PTMC and confirmed histological diagnosis. Among these patients, 32 had metastases to regional cervical lymph nodes. Our findings revealed the upregulated expression of the HMGA2, TIMP1, and FN1 genes, as well as microRNA-146b, in patients with metastatic PTMC. Conversely, we found the downregulated expression of miRNA-7 and -148b in metastatic tumors. In metastatic tumors, significant reductions were observed in DIO1 activity (11-fold), TFF3 gene expression (8-fold), TPO expression (4-fold), and SLC26A7 expression (2.6-fold). All the markers exhibited high sensitivity (84.5–90.6%) in detecting metastatic PTMC, although the specificity proved to be low. The use of molecular markers to predict lymphogenic metastatic spread in patients with PTMC could enhance existing risk grading systems. Such assessments can already be applicable at the preoperative stage. Full article

Head and Neck Squamous Cell Carcinoma (HNSCC) ranks sixth in incidence and seventh in cancer mortality worldwide. Approximately 30% of HNSCC cases are related to human papillomavirus (HPV) infection, the oropharynx being the anatomical subsite most associated with HPV infection. Traditionally, HPV-positive HNSCC has been considered to have better treatment response and clinical outcome. However, HPV-positive HNSCC is a heterogeneous group since 30% of the cases present early relapse, which implies that there are differences in molecular profiles within HPV-positive patients. In this study, we used bioinformatic data analysis from open-access repositories to compare molecular profiles differentially expressed between HPV-positive and -negative HNSCC patients. Using the TCGA HNSCC transcriptomic data, we identified a group of genes, whose expression is related to clinical outcome in patients. Our findings were validated in an independent cohort confirming that the expression levels of FABP4, HMGA2, S100A10, GDNF, SLC7A,2 and GPR18 genes were associated with overall survival (OS) exclusively in HPV-positive HNSCC patients, while ST6GALNAC1 expression was associated with OS in HPV-negative HNSCC. The expression of OS-related genes was independent of tumor stage and history of alcoholism. Our findings suggest that transcriptional profiles in HPV-positive HNSCC are an excellent source of information for the search for potential prognostic biomarkers. 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

Thyroid cancer is the most prevalent endocrine malignancy, and papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy. While PTC generally has a favorable prognosis, a subset dedifferentiates into aggressive forms. However, the molecular mechanisms responsible for aggressiveness and dedifferentiation are still poorly understood. We previously showed that HMGA2, a non-histone architectural transcription factor overexpressed in PTC, is involved in cell invasion. This study aimed to further analyze the role of HMGA2 in PTC tumorigenesis by exploring the expression of thyroid-specific and EMT-related genes following HMGA2 knockdown in thyroid cancer cell lines. Then, the clinical relevance of our data was evaluated in vivo. HMGA2 silencing did not modulate the expression of EMT related genes but led to the increased expression of thyroid differentiation genes. Our data also suggest that the MAPK pathway induces thyroid cell dedifferentiation through HMGA2. On the other hand, forskolin, promoting thyroid differentiation, decreased HMGA2 expression. The negative correlations between HMGA2 and thyroid-specific gene expressions were confirmed in a transgenic mouse model of PTC and in human PTC. Finally, we showed that HMGA2 inhibition by suramin reduced cell invasion and induced differentiation expression in vitro, indicating a new therapeutic strategy for treating thyroid cancer. 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

Loss of the glutathione-S-transferases Theta 2 (Gstt2) expression is associated with an improved response to intravesical Mycobacterium bovis, Bacillus Calmette-Guérin (BCG) immunotherapy for non-muscle-invasive bladder cancer (NMIBC) patients who receive fewer BCG instillations. To delineate the cause, Gstt2 knockout (KO) and wildtype (WT) C57Bl/6J mice were implanted with tumors before treatment with BCG or saline. RNA was analyzed via single-cell RNA sequencing (scRNA-seq) and real-time polymerase chain reaction (RT-PCR). BCG induced PD-L1 expression in WT mice bladders, while pro-inflammatory TNF-α was upregulated in KO bladders. ScRNA-seq analysis showed that Gstt2 WT mice bladders had a higher proportion of matrix remodeling fibroblasts, M2 macrophages, and neuronal cells. In KO mice, distinct tumor cell types, activated fibroblasts, and M1 macrophages were enriched in the bladders. In WT bladders, the genes expressed supported tumorigenesis and immunosuppressive PD-L1 expression. In contrast, Gstt2 KO bladders expressed genes involved in inflammation, immune activation, and tumor suppression. An 11-gene signature (Hmga2, Peak 1, Kras, Slc2a1, Ankfn1, Ahnak, Cmss1, Fmo5, Gphn, Plec, Gstt2), derived from the scRNA-seq analysis predicted response in NMIBC patients (The Cancer Genome Atlas (TCGA) database). In conclusion, our results indicate that patients with WT Gstt2 may benefit from anti-PD-L1 checkpoint inhibition therapy. Full article

Bovine herpesvirus 1 (BoHV-1) productive infection induces the generation of DNA double-strand breaks (DSBs), which may consequently lead to cell apoptosis. In response to DSBs, the DNA damage repair-related protein 53BP1 is recruited to the sites of DSBs, leading to the formation of 53BP1foci, which are crucial for the repair of damaged DNA and maintaining genomic integrity by repairing DSBs. In this study, we discovered that HMGA1 may play a significant role in counteracting virus infection-induced DNA damage, as the siRNA-mediated knockdown of HMGA1 protein expression or inhibition of HMGA1 activity by the chemical inhibitor Netropsin uniformly exacerbates the DNA damage induced by BoHV-1 productive infection. Interestingly, HMGA1 may positively regulate 53BP1 expression, and treatment with Netropsin reduced the accumulation of 53BP1 protein in the nucleus, suggesting that HMGA1 may potentially influence 53BP1’s nuclear localization. However, this effect was reversed in the context of virus infection. Furthermore, Netropsin treatment restored the disruption of 53BP1 foci caused by virus infection, which is consistent with our findings that Netropsin enhances the nuclear accumulation of 53BP1. Collectively, these results indicate that HMGA1 is involved in countering DNA damage induced by virus infection. HMGA1 does indeed modulate the nuclear accumulation of 53BP1 protein, but this effect is counteracted by virus infection. Therefore, the biological function of HMGA1 in countering virus infection-induced DNA damage may be independent of its regulation of 53BP1 signaling. This is the first report suggesting that HMGA1 may be implicated in virus infection-induced DNA damage, although the precise mechanism remains to be elucidated. Furthermore, we report for the first time an interaction between HMGA1 and 53BP1, which is disrupted following virus infection. Full article

This paper presents a comprehensive comparative analysis of biomarkers for head and neck cancer (HNC), a prevalent but molecularly diverse malignancy. We detail the roles of key proteins and genes in tumourigenesis and progression, emphasizing their diagnostic, prognostic, and therapeutic relevance. Our bioinformatic validation reveals crucial genes such as AURKA, HMGA2, MMP1, PLAU, and SERPINE1, along with microRNAs (miRNA), linked to HNC progression. OncomiRs, including hsa-miR-21-5p, hsa-miR-31-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-196a-5p, and hsa-miR-200c-3p, drive tumourigenesis, while tumour-suppressive miRNAs like hsa-miR-375 and hsa-miR-145-5p inhibit it. Notably, hsa-miR-155-3p correlates with survival outcomes in addition to the genes RAI14, S1PR5, OSBPL10, and METTL6, highlighting its prognostic potential. Future directions should focus on leveraging precision medicine, novel therapeutics, and AI integration to advance personalized treatment strategies to optimize patient outcomes in HNC care. Full article

Objective: The goal of this study was to compare the results of CNV detection by three different methods using 13 paired carcinoma samples, as well as to perform a statistical analysis of the agreement. Methods: CNV was studied using NanoString nCounter v2 Cancer CN Assay (Nanostring), Illumina Infinium CoreExome microarrays (CoreExome microarrays) and digital droplet PCR (ddPCR). Results: There was a good level of agreement (PABAK score > 0.6) between the CoreExome microarrays and the ddPCR results for finding CNVs. There was a moderate level of agreement (PABAK values ≈ 0.3–0.6) between the NanoString Assay results and microarrays or ddPCR. For 83 out of 87 target genes studied (95%), the agreement between the CoreExome microarrays and NanoString nCounter was characterized by PABAK values < 0.75, except for MAGI3, PDGFRA, NKX2-1 and KDR genes (>0.75). The MET, HMGA2, KDR, C8orf4, PAX9, CDK6, and CCND2 genes had the highest agreement among all three approaches. Conclusions: Therefore, to get a better idea of how to genotype an unknown CNV spectrum in tumor or normal tissue samples that are very different molecularly, it makes sense to use at least two CNV detection methods. One of them, like ddPCR, should be able to quantitatively confirm the results of the other. Full article

Uncovering genes associated with muscle growth and body size will benefit the molecular breeding of meat Hu sheep. HMGA2 has proven to be an important gene in mouse muscle growth and is associated with the body size of various species. However, its roles in sheep are still limited. Using sheep myoblast as a cell model, the overexpression of HMGA2 significantly promoted sheep myoblast proliferation, while interference with HMGA2 expression inhibited proliferation, indicated by qPCR, EdU, and CCK-8 assays. Furthermore, the dual-luciferase reporter system indicated that the region NC_056056.1: 154134300-154134882 (-618 to -1200 bp upstream of the HMGA2 transcription start site) was one of the habitats of the HMGA2 core promoter, given the observation that this fragment led to a ~3-fold increase in luciferase activity. Interestingly, SNP rs428001129 (NC_056056.1:g.154134315 C>A) was detected in this fragment by Sanger sequencing of the PCR product of pooled DNA from 458 crossbred sheep. This SNP was found to affect the promoter activity and was significantly associated with chest width at birth and two months old, as well as chest depth at two and six months old. The data obtained in this study demonstrated the phenotypic regulatory role of the HMGA2 gene in sheep production traits and the potential of rs428001129 in marker-assisted selection for sheep breeding in terms of chest width and chest depth. Full article

The “AT-hook” is a peculiar DNA-binding domain that interacts with DNA in the minor groove in correspondence to AT-rich sequences. This domain has been first described in the HMGA protein family of architectural factors and later in various transcription factors and chromatin proteins, often in association with major groove DNA-binding domains. In this review, using a literature search, we identified about one hundred AT-hook-containing proteins, mainly chromatin proteins and transcription factors. After considering the prototypes of AT-hook-containing proteins, the HMGA family, we review those that have been studied in more detail and that have been involved in various pathologies with a particular focus on cancer. This review shows that the AT-hook is a domain that gives proteins not only the ability to interact with DNA but also with RNA and proteins. This domain can have enzymatic activity and can influence the activity of the major groove DNA-binding domain and chromatin docking modules when present, and its activity can be modulated by post-translational modifications. Future research on the function of AT-hook-containing proteins will allow us to better decipher their function and contribution to the different pathologies and to eventually uncover their mutual influences. 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

3-Hydroxy-3-methylglutaric acidemia (HMGA) is a neurometabolic inherited disorder characterized by the predominant accumulation of 3-hydroxy-3-methylglutaric acid (HMG) in the brain and biological fluids of patients. Symptoms often appear in the first year of life and include mainly neurological manifestations. The neuropathophysiology is not fully elucidated, so we investigated the effects of intracerebroventricular administration of HMG on redox and bioenergetic homeostasis in the cerebral cortex and striatum of neonatal rats. Neurodevelopment parameters were also evaluated. HMG decreased the activity of glutathione reductase (GR) and increased catalase (CAT) in the cerebral cortex. In the striatum, HMG reduced the activities of superoxide dismutase, glutathione peroxidase, CAT, GR, glutathione S-transferase, and glucose-6-phosphate dehydrogenase. Regarding bioenergetics, HMG decreased the activities of succinate dehydrogenase and respiratory chain complexes II–III and IV in the cortex. HMG also decreased the activities of citrate synthase and succinate dehydrogenase, as well as complex IV in the striatum. HMG further increased DRP1 levels in the cortex, indicating mitochondrial fission. Finally, we found that the HMG-injected animals showed impaired performance in all sensorimotor tests examined. Our findings provide evidence that HMG causes oxidative stress, bioenergetic dysfunction, and neurodevelopmental changes in neonatal rats, which may explain the neuropathophysiology of HMGA. Full article