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Gastric cancer represents a serious health problem worldwide, with insufficient molecular biomarkers and therapeutic options. Consequently, several efforts have been directed towards finding specific disease markers in order to develop new therapies capable of defeating gastric cancer. Attention has been pointed to cancer stem cells (CSCs) as they are primarily responsible for tumor initiation and recurrence, making them essential therapeutic targets. Using the SORE6-GFP reporter system, based on the expression of SOX2 and/or OCT4 to drive GFP expression, we isolated gastric cancer stem-like cells (SORE6+ cells) enriched in several molecules, including SOX2, C-MYC, KLF4, HIF-1α, NOTCH1 and HMGA1. Here, we explored the previously undisclosed link of HMGA1 with gastric CSCs. Our results indicated that HMGA1 can activate a transcriptional program that includes SOX2, C-MYC, and KLF4 and endows cells with CSC features. We further showed that chemical induction of gastric CSCs using ciclopirox (CPX) can be mediated by HMGA1. Finally, we showed that HMGA1 GFP+ cells were sensitive to monensin confirming the selective activity of this drug over CSCs. Thus, HMGA1 is a key player in the cellular reprogramming of gastric non-CSCs to cancer stem-like cells., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

HMGA1 is an abundant non-histone chromatin protein that has been implicated in embryonic development, cancer, and cellular senescence, but its specific role remains elusive. Here, we combine functional genomics approaches with graph theory to investigate how HMGA1 genomic deposition controls high-order chromatin networks in an oncogene-induced senescence model. While the direct role of HMGA1 in gene activation has been described previously, we find little evidence to support this. Instead, we show that the heterogeneous linear distribution of HMGA1 drives a specific 3D chromatin organization. HMGA1-dense loci form highly interactive networks, similar to, but independent of, constitutive heterochromatic loci. This, coupled with the exclusion of HMGA1-poor chromatin regions, leads to coordinated gene regulation through the repositioning of genes. In the absence of HMGA1, the whole process is largely reversed, but many regulatory interactions also emerge, amplifying the inflammatory senescence-associated secretory phenotype. Such HMGA1-mediated fine-tuning of gene expression contributes to the heterogeneous nature of senescence at the single-cell level. A similar 'buffer' effect of HMGA1 on inflammatory signalling is also detected in lung cancer cells. Our study reveals a mechanism through which HMGA1 modulates chromatin compartmentalization and gene regulation in senescence and beyond., (© 2024. The Author(s).)

N4-acetylcytidine (ac4C) is essential for the development and migration of tumor cells. According to earlier research, N-acetyltransferase 10 (NAT10) can increase messenger RNAs (mRNAs) stability by catalyzing the synthesis of ac4C. However, little is known about NAT10 expression and its role in the acetylation modifications in prostate cancer (PCa). Thus, the biological function of NAT10 in PCa is investigated in this study. Compared to paraneoplastic tissues, the expression of NAT10 is significantly higher in PCa. The NAT10 expression is strongly correlated with the pathological grade, clinical stage, Gleason score, T-stage, and N-stage of PCa. NAT10 has the ability to advance the cell cycle and the epithelial-mesenchymal transition (EMT), both of which raise the malignancy of tumor cells. Mechanistically, NAT10 enhance the stability of high mobility group AT-hook 1 (HMGA1) by acetylating its mRNA, thereby promoting cell cycle progression to improve cell proliferation. In addition, NAT10 improve the stability of Keratin 8 (KRT8) by acetylating its mRNA, which promotes the progression of EMT to improve cell migration. This findings provide a potential prognostic or therapeutic target for PCa., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Esophageal squamous cell carcinoma (ESCC) possesses a poor prognosis and treatment outcome. Dysregulated metabolism contributes to unrestricted growth of multiple cancers. However, abnormal metabolism, such as highly activated pentose phosphate pathway (PPP) in the progression of ESCC remains largely unknown. Herein, we report that high-mobility group AT-hook 1 (HMGA1), a structural transcriptional factor involved in chromatin remodeling, promoted the development of ESCC by upregulating the PPP. We found that HMGA1 was highly expressed in ESCC. Elevated HMGA1 promoted the malignant phenotype of ESCC cells. Conditional knockout of HMGA1 markedly reduced 4-nitroquinoline-1-oxide (4NQO)-induced esophageal tumorigenesis in mice. Through the metabolomic analysis and the validation assay, we found that HMGA1 upregulated the non-oxidative PPP. With the transcriptome sequencing, we identified that HMGA1 upregulated the expression of transketolase (TKT), which catalyzes the reversible reaction in non-oxidative PPP to exchange metabolites with glycolytic pathway. HMGA1 knockdown suppressed the PPP by downregulating TKT, resulting in the reduction of nucleotides in ESCC cells. Overexpression of HMGA1 upregulated PPP and promoted the survival of ESCC cells by activating TKT. We further characterized that HMGA1 promoted the transcription of TKT by interacting with and enhancing the binding of transcription factor SP1 to the promoter of TKT. Therapeutics targeting TKT with an inhibitor, oxythiamine, reduced HMGA1-induced ESCC cell proliferation and tumor growth. Together, in this study, we identified a new role of HMGA1 in ESCCs by upregulating TKT-mediated activation of PPP. Our results provided a new insight into the role of HMGA1/TKT/PPP in ESCC tumorigenesis and targeted therapy., (© 2024. The Author(s).)

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.

Parkinson's disease (PD) is a common neurodegenerative disease. Circular RNAs (circRNAs) have been confirmed to regulate neurodegenerative diseases. This study was aimed to explore hsa_circ_0054220 functions in PD. MPP-stimulated SH-SY5Y cells were established as the PD cell model. PD mouse model was established by MPTP. Gene expression in cells and tissues was tested by RT-qPCR. Cell viability and apoptosis were evaluated through CCK-8 and TUNEL assays. The interactions of RNAs were determined by RNA pull-down assay, RIP assay, and luciferase reporter assay. Circ_0054220 expressed at a high level in MPP-treated SH-SY5Y cells. Circ_0054220 inhibition promoted viability and suppressed apoptosis in MPP-stimulated cells. Furthermore, we found that circ_0054220 can competitively bind to miR-145 and miR-625 to upregulate high mobility group A1 (HMGA1) expression. HMGA1 was positively regulated by circ_0054220 and overexpressed in MPP-treated cells as well as the striatum (STR), substantia nigra pars compacta (SNpc), and serum of MPTP-induced mouse model of PD. HMGA1 overexpression counteracted the function of circ_0054220 silencing on cell apoptosis. Furthermore, HMGA1 inhibition notably alleviated motor dysfunction and increased the quantity of neurons in mice resembling PD. Circ_0054220 upregulates HMGA1 by the competitive endogenous RNAs (ceRNA) pattern to promote neural impairment in PD., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

High mobility group protein AT-hook 1 (HMGA1), an architectural transcription factor, has previously been reportedto play an essential role in architectural remodeling processes. However, its effects on cardiovascular diseases, particularly sepsis-induced cardiomyopathy, have remained unclear. The study aimed to investigate the role of HMGA1 in lipopolysaccharide-induced cardiomyopathy. Mice subjected to lipopolysaccharide for 12 h resulted in cardiac dysfunction. We used an adeno-associated virus 9 delivery system to achieve cardiac-specific expression of the HMGA1 gene in the mice. H9c2 cardiomyocytes were infected with Ad-HMGA1 to overexpress HMGA1 or transfected with si-HMGA1 to knock down HMGA1. Echocardiography was applied to measure cardiac function. RT-PCR was used to detect the transcriptional level of inflammatory cytokines. CD45 and CD68 immunohistochemical staining were used to detect inflammatory cell infiltration and TUNEL staining to evaluate the cardiomyocyte apoptosis, MitoSox was used to detect mitochondrial reactive oxygen species, JC-1 was used todetect Mitochondrial membrane potential. Our findings revealed that the overexpression of HMGA1 exacerbated myocardial inflammation and apoptosis in response to lipopolysaccharide treatment. Additionally, we also observed that H9c2 cardiomyocytes with HMGA1 overexpression exhibited enhanced inflammation and apoptosis upon stimulation with lipopolysaccharide for 12 h. Conversely, HMGA1 knockdown in H9c2 cardiomyocytes attenuated lipopolysaccharide-induced cardiomyocyte inflammation and apoptosis. Further investigations into the molecular mechanisms underlying these effects showed that HMGA1 promoted lipopolysaccharide-induced mitochondrial-dependent cardiomyocyte apoptosis. The study reveals that HMGA1 worsens myocardial inflammation and apoptosis in response to lipopolysaccharide treatment. Mechanically, HMGA1 exerts its effects by regulating the mitochondria-dependent apoptotic pathway., (© 2024. The Author(s).)

HMGA1 is a structural epigenetic chromatin factor that has been associated with tumor progression and drug resistance. Here, we reported the prognostic/predictive value of HMGA1 for trabectedin in advanced soft-tissue sarcoma (STS) and the effect of inhibiting HMGA1 or the mTOR downstream pathway in trabectedin activity. The prognostic/predictive value of HMGA1 expression was assessed in a cohort of 301 STS patients at mRNA (n = 133) and protein level (n = 272), by HTG EdgeSeq transcriptomics and immunohistochemistry, respectively. The effect of HMGA1 silencing on trabectedin activity and gene expression profiling was measured in leiomyosarcoma cells. The effect of combining mTOR inhibitors with trabectedin was assessed on cell viability in vitro studies, whereas in vivo studies tested the activity of this combination. HMGA1 mRNA and protein expression were significantly associated with worse progression-free survival of trabectedin and worse overall survival in STS. HMGA1 silencing sensitized leiomyosarcoma cells for trabectedin treatment, reducing the spheroid area and increasing cell death. The downregulation of HGMA1 significantly decreased the enrichment of some specific gene sets, including the PI3K/AKT/mTOR pathway. The inhibition of mTOR, sensitized leiomyosarcoma cultures for trabectedin treatment, increasing cell death. In in vivo studies, the combination of rapamycin with trabectedin downregulated HMGA1 expression and stabilized tumor growth of 3-methylcholantrene-induced sarcoma-like models. HMGA1 is an adverse prognostic factor for trabectedin treatment in advanced STS. HMGA1 silencing increases trabectedin efficacy, in part by modulating the mTOR signaling pathway. Trabectedin plus mTOR inhibitors are active in preclinical models of sarcoma, downregulating HMGA1 expression levels and stabilizing tumor growth., (© 2024. The Author(s).)

Esophageal carcinoma is amongst the prevalent malignancies worldwide, characterized by unclear molecular classifications and varying clinical outcomes. The PI3K/AKT/mTOR signaling, one of the frequently perturbed dysregulated pathways in human malignancies, has instigated the development of various inhibitory agents targeting this pathway, but many ESCC patients exhibit intrinsic or adaptive resistance to these inhibitors. Here, we aim to explore the reasons for the insensitivity of ESCC patients to mTOR inhibitors. We assessed the sensitivity to rapamycin in various ESCC cell lines by determining their respective IC50 values and found that cells with a low level of HMGA1 were more tolerant to rapamycin. Subsequent experiments have supported this finding. Through a transcriptome sequencing, we identified a crucial downstream effector of HMGA1, FKBP12, and found that FKBP12 was necessary for HMGA1-induced cell sensitivity to rapamycin. HMGA1 interacted with ETS1, and facilitated the transcription of FKBP12. Finally, we validated this regulatory axis in in vivo experiments, where HMGA1 deficiency in transplanted tumors rendered them resistance to rapamycin. Therefore, we speculate that mTOR inhibitor therapy for individuals exhibiting a reduced level of HMGA1 or FKBP12 may not work. Conversely, individuals exhibiting an elevated level of HMGA1 or FKBP12 are more suitable candidates for mTOR inhibitor treatment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The crucial role of high mobility group AT-hook 1 (HMGA1) proteins in nuclear processes such as gene transcription, DNA replication, and chromatin remodeling is undeniable. Elevated levels of HMGA1 have been associated with unfavorable clinical outcomes and adverse differentiation status across various cancer types. HMGA1 regulates a diverse array of biological pathways, including tumor necrosis factor-alpha/nuclear factor-kappa B (TNF-α/NF-κB), epidermal growth factor receptor (EGFR), Hippo, Rat sarcoma/extracellular signal-regulated kinase (Ras/ERK), protein kinase B (Akt), wingless-related integration site/beta-catenin (Wnt/beta-catenin), and phosphoinositide 3-kinase/protein kinase B (PI3-K/Akt). While researchers have extensively investigated tumors in the reproductive, digestive, urinary, and hematopoietic systems, mounting evidence suggests that HMGA1 plays a critical role as a tumorigenic factor in tumors across all functional systems. Given its broad interaction network, HMGA1 is an attractive target for viral manipulation. Some viruses, including herpes simplex virus type 1, human herpesvirus 8, human papillomavirus, JC virus, hepatitis B virus, human immunodeficiency virus type 1, severe acute respiratory syndrome Coronavirus 2, and influenza viruses, utilize HMGA1 influence for infection. This interaction, particularly in oncogenesis, is crucial. Apart from the direct oncogenic effect of some of the mentioned viruses, the hit-and-run theory postulates that viruses can instigate cancer even before being completely eradicated from the host cell, implying a potentially greater impact of viruses on cancer development than previously assumed. This review explores the interplay between HMGA1, viruses, and host cellular machinery, aiming to contribute to a deeper understanding of viral-induced oncogenesis, paving the way for innovative strategies in cancer research and treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Chemotherapy is a primary treatment for esophageal squamous cell carcinoma (ESCC). Resistance to chemotherapeutic drugs is an important hurdle to effective treatment. Understanding the mechanisms underlying chemotherapy resistance in ESCC is an unmet medical need to improve the survival of ESCC. Herein, we demonstrate that ferroptosis triggered by inhibiting high mobility group AT-hook 1 (HMGA1) may provide a novel opportunity to gain an effective therapeutic strategy against chemoresistance in ESCC. HMGA1 is upregulated in ESCC and works as a key driver for cisplatin (DDP) resistance in ESCC by repressing ferroptosis. Inhibition of HMGA1 enhances the sensitivity of ESCC to ferroptosis. With a transcriptome analysis and following-up assays, we demonstrated that HMGA1 upregulates the expression of solute carrier family 7 member 11 (SLC7A11), a key transporter maintaining intracellular glutathione homeostasis and inhibiting the accumulation of malondialdehyde (MDA), thereby suppressing cell ferroptosis. HMGA1 acts as a chromatin remodeling factor promoting the binding of activating transcription factor 4 (ATF4) to the promoter of SLC7A11, and hence enhancing the transcription of SLC7A11 and maintaining the redox balance. We characterized that the enhanced chemosensitivity of ESCC is primarily attributed to the increased susceptibility of ferroptosis resulting from the depletion of HMGA1. Moreover, we utilized syngeneic allograft tumor models and genetically engineered mice of HMGA1 to induce ESCC and validated that depletion of HMGA1 promotes ferroptosis and restores the sensitivity of ESCC to DDP, and hence enhances the therapeutic efficacy. Our finding uncovers a critical role of HMGA1 in the repression of ferroptosis and thus in the establishment of DDP resistance in ESCC, highlighting HMGA1-based rewiring strategies as potential approaches to overcome ESCC chemotherapy resistance. Schematic depicting that HMGA1 maintains intracellular redox homeostasis against ferroptosis by assisting ATF4 to activate SLC7A11 transcription, resulting in ESCC resistance to chemotherapy., (© 2024. The Author(s).)

Circ_UBAP2 is extensively engaged in regulating the development of various malignancies, containing osteosarcoma (OS). However, its biological significance and function are not fully understood. In this study, we found that circ_UBAP2 and HMGA1 levels were up-regulated, and miR-370-3p and miR-665 expressions were decreased in osteosarcoma tissues. Inhibition of circ_UBAP2 or HMGA1 expression in OS cells, cell viability, invasion and migration abilitities were notably hindered, and cell apoptosis abilities were increased. Bioinformatics analysis predicted that miR-665 and miR-370-3p were the downstream targets of circ_UBAP2, and the dual luciferase experiment demonstrated the correlation between them. In addition, inhibition of miR-665 and miR-370-3p expression could significantly reverse the impact of knocking down circ_UBAP2 on OS cells. HMGA1 was discovered to become the downstream target of both miR-665 and miR-370-3p. It was shown that over-expression of miR-665 or miR-370-3p notably stimulated the cell growth, invasion, and migration of osteosarcoma cells, while hindered cell apoptosis. Nevertheless, this effect could be reversed by concurrent over-expression of HMGA1. Our data strongly prove that circ_UBAP2 makes a vital impact on promoting the proliferation, invasion as well as migration of osteosarcoma cells via down-regulating the level of miR-665 and miR-370-3p, and later up-regulating the level of HMGA1. In conclusion, circ_UBAP2 is upregulated in osteosarcoma, and it competitively adsorbs miR-370-3p and miR-665, resulting in up-regulation of HMGA1, thus promoting OS development., (© 2023 Wiley Periodicals LLC.)

Objectives: Our group previously found that LINC00665 was upregulated in hepatocellular carcinoma (HCC) tissues through database analysis; however, the potential molecular mechanism of LINC00665 in HCC progression still needs further study., Methods: qRTPCR was performed to determine the differential expression of LINC00665 and let-7i in HCC cells. Dual-luciferase reporter assays were performed to analyze the interaction of LINC00665 and let-7i. CCK-8 assays, scratch assays, Transwell invasion assays, qRTPCR and western blotting were performed to determine the regulatory mechanism of LINC00665/let-7i/HMGA1 in HCC cells., Results: LINC00665 was upregulated in HCC cells compared with normal hepatocytes. A potential binding site between LINC00665 and let-7i was confirmed by dual-luciferase reporter assay. In HCC cells, inhibition of LINC00665 significantly reduced cell proliferation, migration and invasion ability via the let-7i/HMGA1 signaling axis., Conclusion: LINC00665 promotes the proliferation and invasion of HCC cells via the let-7i/HMGA1 signaling axis., Competing Interests: Declaration of Competing Interest The manuscript has not been published before and is not being considered for publication elsewhere. All authors have contributed to the creation of this manuscript for important intellectual content and read and approved the final manuscript. We declare there is no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Hu sheep is an excellent short fat-tailed breed in China. Fat deposition in Hu sheep tail affects carcass quality and consumes a lot of energy, leading to an increase in feed cost. The objective of this study was to analyze the effects of HMGA1 polymorphism on tail fat weight in Hu sheep. Partial coding and non-coding sequences of HMGA1 were amplified with PCR and single nucleotide polymorphisms (SNP) of HMGA1 in 1163 Hu sheep were detected using DNA sequencing and KASPar technology. RT-qPCR analysis was performed to test HMGA1 expression in different tissues. The results showed that the expression of HMGA1 was higher in the duodenum, liver, spleen, kidney, and lung than in the heart, muscle, rumen, tail fat, and lymph. A mutation, g.5312 C > T, was detected in HMGA1 ; g.5312 C > T was significantly associated with tail fat weight, relative weight of tail fat (body weight), and relative weight of tail fat (carcass) ( p  < 0.05). The tail fat weight of the TT genotype was remarkably higher than that of the CC and TC genotypes. Therefore, HMGA1 can be used as a genetic marker for marker-assisted selection of tail fat weight in Hu sheep.

Background: Lung cancer is the most common cancer in the world. High Mobility Group AT-Hook 1 (HMGA1) is found to be associated with the glycolytic pathway in a variety of cancers, and abnormal glycolysis function is one of the important characteristics of cancer cells. Therefore, this paper discusses the effect of HMGA1 on glycolysis of lung adenocarcinoma (LUAD) cells METHODS: The mRNA expression data were downloaded from TCGA-LUAD database. Groups were set according to the median expression of HMGA1, followed by GSEA enrichment analysis. The upstream transcriptional regulators of HMGA1 were predicted by bioinformatics. The correlation between HMGA1 and Transcription Factor AP-2 Alpha (TFAP2A) and their expression in LUAD tissues were analyzed as well. mRNA expression levels of HMGA1 and TFAP2A were detected by qRT-PCR. The binding of HMGA1 and TFAP2A was demonstrated by ChIP and dual luciferase reporter assays. Cell function experiments were utilized to assay proliferation, apoptosis, glycolysis ability of LUAD cells, and glycolysis-related protein expression in each treatment group., Results: HMGA1 was highly expressed in LUAD patients' tissues and enriched in the glycolytic pathway. Additionally, silencing HMGA1 markedly hampered cell proliferation and glycolysis, and promoted cell apoptosis. The upstream transcriptional regulator TFAP2A was predicted to be highly expressed in LUAD. ChIP and dual luciferase reporter assays confirmed the targeted relationship between HMGA1 and TFAP2A. Cell rescue assay confirmed that TFAP2A promoted glycolysis and LUAD progression by activating HMGA1., Conclusion: TFAP2A promotes glycolysis, proliferation and hampers apoptosis of LUAD cells by stimulating HMGA1. Hence, TFAP2A/HMGA1 may be a feasible therapeutic target for LUAD., Availability of Data and Materials: All the data within this manuscript could be gotten from corresponding author at reasonable request., Competing Interests: Declaration of Competing Interest The authors declare that they have no known conflict of interest., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Fos-related antigen 1 (Fra-1) is a nuclear transcription factor that regulates cell growth, differentiation, and apoptosis. It is involved in the proliferation, invasion, apoptosis and epithelial mesenchymal transformation of malignant tumor cells. Fra-1 is highly expressed in gastric cancer (GC), affects the cycle distribution and apoptosis of GC cells, and participates in GC occurrence and development. However, the detailed mechanism of Fra-1 in GC is unclear, such as the identification of Fra-1-interacting proteins and their role in GC pathogenesis. In this study, we identified tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein eta (YWHAH) as a Fra-1-interacting protein in GC cells using co-immunoprecipitation combined with liquid chromatography-tandem mass spectrometry. Experiments showed that YWHAH positively regulated Fra-1 mRNA and protein expression, and affected GC cell proliferation. Whole proteome analysis showed that Fra-1 affected the activity of the high mobility group AT-hook 1 (HMGA1)/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway in GC cells. Western blotting and flow cytometry confirmed that YWHAH activated HMGA1/PI3K/AKT/mTOR signaling pathway by positively regulating Fra-1 to affect GC cell proliferation. These results will help to discover new molecular targets for the early diagnosis, treatment, and prognosis prediction of GC., Competing Interests: The authors declare that they have no conflicts of interest to report regarding the present study., (© 2023 He et al.)

Metastasis is an obstacle to the clinical treatment of aggressive breast cancer (BC). Studies have shown that high mobility group A1 (HMGA1) is abnormally expressed in various cancers and mediates tumor proliferation and metastasis. Here, we provided more evidence that HMGA1 mediated epithelial to mesenchymal transition (EMT) through the Wnt/β-catenin pathway in aggressive BC. More importantly, HMGA1 knockdown enhanced antitumor immunity and improved the response to immune checkpoint blockade (ICB) therapy by upregulating programmed cell death ligand 1 (PD-L1) expression. Simultaneously, we revealed a novel mechanism by which HMGA1 and PD-L1 were regulated by the PD-L1/HMGA1/Wnt/β-catenin negative feedback loop in aggressive BC. Taken together, we believe that HMGA1 can serve as a target for the dual role of anti-metastasis and enhancing immunotherapeutic responses., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Colorectal cancer (CRC) substantially contributes to cancer-related deaths worldwide. Recently, a long non-coding RNA (lncRNA), LINC01614, has emerged as a vital gene regulator in cancer progression. Yet, how LINC01614 affects CRC progression remains enigmatic. Here, we defined LINC01614 expression in CRC, investigated the performance of CRC cells lacking LINC01614, and elucidated the underpinning mechanism. We observed that LINC01614 was upregulated in both CRC tissues and cell lines. LINC01614 knockdown repressed the proliferation and metastasis capacity of CRC cell lines. Consistently, an in vivo LINC01614 deficiency model exhibited slow tumor growth rate. Moreover, luciferase reporter assay, RNA pull-down, and immunoprecipitation confirmed that LINC01614 targeted miR-217-5p. LINC01614 knockdown reduced the expression of HMGA1 and N-cadherin, while increasing that of E-cadherin, resulting in decreased viability, proliferation, migration, and invasion capacity of CRC cells. Our results demonstrate that LINC01614 regulates CRC progression by modulating the miR-217-5p/HMGA1 axis, thus holding great potential as a prognostic biomarker for CRC diagnosis and treatment., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Jiwei Jia et al.)

Long non-coding RNA XIST promotes the development of various types of head and neck cancers, but its role in the progression of precancerous oral submucous fibrosis (OSF) has not been determined yet. As such, we aimed to examine whether XIST implicates in the regulation of myofibroblast activation. Our results showed that the expression of XIST was upregulated in OSF tissues and fibrotic buccal mucosal fibroblasts (fBMFs), and the silencing of XIST downregulated several myofibroblasts features. We demonstrated that elevation of let-7i after inhibition of XIST may lead to reduced myofibroblast activation. On the contrary, overexpression of high mobility group AT-Hook 1 (HMGA1) following the suppression of let-7i may result in enhanced myofibroblast activities. Moreover, we showed that the suppressive effect of silencing of XIST on myofibroblasts hallmarks was reversed by let-7i inhibition or HMGA1 overexpression, suggesting the pro-fibrotic property of XIST was mediated by downregulation of let-7i and upregulation of HMGA1. These findings revealed that myofibroblast activation of fBMFs may attribute to the alteration of the XIST/let-7i/HMGA1 axis. Therapeutic approaches to target this axis may serve as a promising direction to ameliorate the malignant progression of OSF., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

High mobility group A1 (HMGA1) chromatin regulators are upregulated in diverse tumors where they portend adverse outcomes, although how they function in cancer remains unclear. Pancreatic ductal adenocarcinomas (PDACs) are highly lethal tumors characterized by dense desmoplastic stroma composed predominantly of cancer-associated fibroblasts and fibrotic tissue. Here, we uncover an epigenetic program whereby HMGA1 upregulates FGF19 during tumor progression and stroma formation. HMGA1 deficiency disrupts oncogenic properties in vitro while impairing tumor inception and progression in KPC mice and subcutaneous or orthotopic models of PDAC. RNA sequencing revealed HMGA1 transcriptional networks governing proliferation and tumor-stroma interactions, including the FGF19 gene. HMGA1 directly induces FGF19 expression and increases its protein secretion by recruiting active histone marks (H3K4me3, H3K27Ac). Surprisingly, disrupting FGF19 via gene silencing or the FGFR4 inhibitor BLU9931 recapitulates most phenotypes observed with HMGA1 deficiency, decreasing tumor growth and formation of a desmoplastic stroma in mouse models of PDAC. In human PDAC, overexpression of HMGA1 and FGF19 defines a subset of tumors with extremely poor outcomes. Our results reveal what we believe is a new paradigm whereby HMGA1 and FGF19 drive tumor progression and stroma formation, thus illuminating FGF19 as a rational therapeutic target for a molecularly defined PDAC subtype.

Background: Long non-coding RNAs (lncRNAs) have been confirmed to play vital roles in tumorigenesis. LncRNA MYU has recently been reported as an oncogene in several kinds of tumors. However, MYU's expression status and potential involvement in ovarian cancer (OC) remain unclear. In this study, we explored the underlying role of MYU in OC. Methods and results: The expression of MYU was upregulated in OC tissues, and MYU's overexpression was significantly correlated with the FIGO stage and lymphatic metastasis. Knockdown of MYU inhibited cell proliferation in SKOV3 and A2780 cells. Mechanistically, MYU directly interacted with miR-6827-5p in OC cells; HMGA1 is a downstream target gene of miR-6827-5p. Furthermore, MYU knockdown increased the expression of miR-6827-5p and decreased the expression of HMGA1. Restoration of HMGA1 expression reversed the influence on cell proliferation caused by MYU knockdown. Conclusion: MYU functions as a ceRNA that positively regulates HMGA1 expression by sponging miR-6827-5p in OC cells, which may provide a potential target and biomarker for the diagnosis or prognosis of OC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Zheng, Wang, Chen and Chen.)

The high mobility group A1 (HMGA1) gene is overexpressed in malignant tumors, and its expression level correlates with the progression and metastasis of tumors. However, the specific role of HMGA1 in hepatocellular carcinoma (HCC) and relevant influencing approaches in tumor immunity remain unclear. In this study, the expression and clinical significance of HMGA1 in HCC immunity were analyzed. The expression levels of HMGA1 mRNA and protein in HCC tissue and normal liver tissue were analyzed based on the cancer genome atlas, the gene expression omnibus and the Human Protein Atlas databases. The correlation between HMGA1 and clinicopathological factors was analyzed, and survival was estimated based on the expression of HMGA1. Gene set cancer analysis and the TISIDB database were used to identify tumor-infiltrating immune cells and immune inhibitors. Gene set enrichment analysis was performed to determine the involved signaling pathway. The HMGA1 genetic alterations were identified with the cBioPortal for Cancer Genomics. The expression of HMGA1 mRNA and protein was significantly higher in HCC tissue and negatively correlated with survival. Neutrophils, Th17 cells, several immune inhibitors, and signaling pathways were positively correlated with the expression of HMGA1. Amplification was the main type of genetic alteration in HMGA1. These findings demonstrate that HMGA1 can be a therapeutic target and a potential biomarker to predict the prognosis of patients with HCC. HMGA1 may affect the progression of HCC by suppressing the immune function of these patients., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Hepatocellular carcinoma (LIHC) accounts for 90% of all liver cancers and is a serious health concern worldwide. Long noncoding RNAs (lncRNAs) have been observed to sponge microRNAs (miRNAs) and participate in the biological processes of LIHC. This study aimed to evaluate the role of the ST8SIA6-AS1-miR-142-3p-HMGA1 axis in regulating LIHC progression. RT-qPCR and western blotting were performed to determine the levels of ST8SIA6-AS1, miR-142-3p, and HMGA1 in LIHC. The relationship between ST8SIA6-AS1, miR-142-3p, and HMGA1 was assessed using luciferase assay. The role of the ST8SIA6-AS1-miR-142-3p-HMGA1 axis was evaluated in vitro using LIHC cells. Expression of ST8SIA6-AS1 and HMGA1 was significantly upregulated, whereas that of miR-142-3p was markedly lowered in LIHC specimens and cells. ST8SIA6-AS1 accelerated cell growth, invasion, and migration and suppressed apoptosis in LIHC. Notably, ST8SIA6-AS1 inhibited HMGA1 expression by sponging miR-142-3p in LIHC cells. In conclusion, sponging of miR-142-3p by ST8SIA6-AS1 accelerated the growth of cells while preventing cell apoptosis in LIHC cells, and the inhibitory effect of miR-142-3p was abrogated by elevating HMGA1 expression. The ST8SIA6-AS1-miR-142-3p-HMGA1 axis represents a potential target for the treatment of patients with LIHC., (© 2023. The Author(s).)

The protein high mobility group A1 (HMGA1) is an important regulator of chromatin organization and function. However, the mechanisms by which it exerts its biological function are not fully understood. Here, we report that the HMGA isoform, HMGA1a, nucleates into foci that display liquid-like properties in the nucleus, and that the protein readily undergoes phase separation to form liquid condensates in vitro. By bringing together machine-leaning modelling, cellular and biophysical experiments and multiscale simulations, we demonstrate that phase separation of HMGA1a is promoted by protein-DNA interactions, and has the potential to be modulated by post-transcriptional effects such as phosphorylation. We further show that the intrinsically disordered C-terminal tail of HMGA1a significantly contributes to its phase separation through electrostatic interactions via AT hooks 2 and 3. Our work sheds light on HMGA1 phase separation as an emergent biophysical factor in regulating chromatin structure., (© 2022 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

Uterine leiomyomas, or fibroids, are very common smooth muscle tumors that arise from the myometrium. They can be divided into distinct molecular subtypes. We have previously shown that 3'RNA-sequencing is highly effective in classifying archival formalin-fixed paraffin-embedded (FFPE) leiomyomas according to the underlying mutation. In this study, we performed 3'RNA-sequencing with 111 FFPE leiomyomas previously classified as negative for driver alterations in mediator complex subunit 12 (MED12), high mobility group AT-hook 2 (HMGA2), and fumarate hydratase (FH) by Sanger sequencing and immunohistochemistry. This revealed 43 tumors that displayed expression features typically seen in HMGA2-positive tumors, including overexpression of PLAG1. We explored 12 such leiomyomas by whole-genome sequencing to identify their underlying genomic drivers and to evaluate the feasibility of detecting chromosomal driver alterations from FFPE material. Four tumors with significant HMGA2 overexpression at the protein-level served as controls. We identified chromosomal rearrangements targeting either HMGA2, HMGA1, or PLAG1 in all 16 tumors, demonstrating that it is possible to detect chromosomal driver alterations in archival leiomyoma specimens as old as 18 years. Furthermore, two tumors displayed biallelic loss of DEPDC5 and one tumor harbored a COL4A5-COL4A6 deletion. These observations suggest that instead of only HMGA2-positive leiomyomas, a distinct leiomyoma subtype is characterized by rearrangements targeting either HMGA2, HMGA1, or PLAG1. The results indicate that the frequency of HMGA2-positive leiomyomas may be higher than estimated in previous studies where immunohistochemistry has been used. This study also demonstrates the feasibility of detecting chromosomal driver alterations from archival FFPE material., (© 2022 The Authors. Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)

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 IC 50 both in parental and epirubicin resistant cells thus suggesting that targeting HMGA1 could affect the efficacy of epirubicin treatment.

The study aimed to assess the HMGA1 gene expression level in NSCLC patients and to evaluate its association with selected clinicopathological features and overall survival of patients. The expression of the HMGA1, coding non-histone transcription regulator HMGA1, was previously proved to correlate with the ability of cancer cells to metastasize the advancement of the disease. The prognostic value of the HMGA1 expression level was demonstrated in some neoplasms, e.g., pancreatic, gastric, endometrial, hepatocellular cancer, but the knowledge about its role in non-small cell lung cancer (NSCLC) is still limited. Thus, the HMGA1 expression level was evaluated by real-time PCR method in postoperative tumor tissue and blood samples collected at the time of diagnosis, 100 days and 1 year after surgery from 47 NSCLC patients. Mean HMGA1 expression level in blood decreased systematically from the time of cancer diagnosis to 1 year after surgery. The blood HMGA1 expression level 1 year after surgery was associated with the tobacco smoking status of patients (p= 0.0230). Patients with high blood HMGA1 expression levels measured 100 days after surgery tend to have worse overall survival than those with low expression levels (p= 0.1197). Tumor HMGA1 expression level was associated with neither features nor the overall survival of NSCLC patients. Moreover, no correlation between HMGA1 expression level measured in tumor tissue and blood samples was stated. Blood HMGA1 mRNA level could be a promising factor in the prognostication of non-small cell lung cancer patients., (© 2022. The Author(s).)

Enhanced fatty acid synthesis provides proliferation and survival advantages for tumor cells. Apelin is an adipokine, which serves as a ligand of G protein-coupled receptors that promote tumor growth in malignant cancers. Here, we confirmed that apelin increased sterol regulatory element-binding protein 1 (SREBP1) activity and induced the expression of glutamine amidotransferase for deamidating high-mobility group A 1 (HMGA1) to promote fatty acid synthesis and proliferation of lung cancer cells. This post-translational modification stabilized the HMGA1 expression and enhanced the formation of the apelin-HMGA1-SREBP1 complex to facilitate SREBP1 activity for lipid metabolism and lung cancer cell growth. We uncovered the pivotal role of apelin-mediated deamidation of HMGA1 in lipid metabolism and tumorigenesis of lung cancer cells., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The deregulation of circular RNAs (circRNAs) is involved in cancer development. CircRNA polo-like kinase 1 (circPLK1) was reported to promote breast cancer development. However, the role of circPLK1 in malignant pleural mesothelioma (MPM) is unclear. The expression of circPLK1, miR-1294, and high mobility group AT-hook 1 (HMGA1) mRNA was measured by quantitative real-time PCR (qPCR). Cell viability was detected by CCK-8 assay. Colony formation ability was monitored by colony formation assay. Cell proliferation was detected by EdU assay. Cell migration and cell invasion were monitored by transwell assay. Cancer cell stemness was investigated by sphere formation assay. The protein levels of marker proteins and HMGA1 expression were measured by western blot analysis. The binding relationship between miR-1294 and circPLK1 or HMGA1 was validated by pull-down assay, dual-luciferase reporter assay or RIP assy. Animal study was performed to disclose the role of circPLK1 in vivo. Exosomes were identified by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). CircPLK1 was upregulated in MPM tumor tissues and cell lines. CircPLK1 knockdown suppressed the proliferation, migration, invasion and stemness of MPM cells. CircPLK1 contained a binding site for miR-1294 and thus bound to miR-1294 to sequester its expression. Inhibition of miR-1294 reversed the effects of circPLK1 knockdown. HMGA1 was a target of miR-1294, and circPLK1 bound to miR-1294 to increase the expression of HMGA1. MiR-1294 restoration also suppressed the proliferation, migration, invasion and stemness of MPM cells, while these effects were abolished by HMGA1 overexpression. In addition, circPLK1 knockdown inhibited tumor growth in vivo. CircPLK1 was overexpressed in exosomes derived from serum of MPM patients. CircPLK1 knockdown inhibited MPM cell proliferation, migration, invasion and stemness by targeting the miR-1294/HMGA1 pathway., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

High mobility group A1 (HMGA1) is a nonhistone chromatin structural protein characterized by no transcriptional activity. It mainly plays a regulatory role by modifying the structure of DNA. A large number of studies have confirmed that HMGA1 regulates genes related to tumours in the reproductive system, digestive system, urinary system and haematopoietic system. HMGA1 is rare in adult cells and increases in highly proliferative cells such as embryos. After being stimulated by external factors, it will produce effects through the Wnt/β-catenin, PI3K/Akt, Hippo and MEK/ERK pathways. In addition, HMGA1 also affects the ageing, apoptosis, autophagy and chemotherapy resistance of cancer cells, which are linked to tumorigenesis. In this review, we summarize the mechanisms of HMGA1 in cancer progression and discuss the potential clinical application of targeted HMGA1 therapy, indicating that targeted HMGA1 is of great significance in the diagnosis and treatment of malignancy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

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.

Objective: Gastric cancer is a prevalent malignant tumor with high morbidity and poor prognosis. Asiaticoside (AC) has antitumor effects, while its role in gastric cancer is elusive. Thus, this study investigated the effect of AC on gastric cancer progression., Methods: Cell viability and migration were determined using the CCK-8 and Transwell migration assay. Endoplasmic reticulum stress was detected through measuring the expressions of GRP78, Chop, and hnRNPA1 by Western blot. The luciferase assay confirmed the relationship between miR-635 and High Mobility Group AT-Hook 1 (HMGA1). The effect of AC on tumor growth was evaluated by establishing a xenograft tumor. The survival rate of mice was analyzed by Kaplan-Meier analysis., Results: AC suppressed gastric cancer cell viability and restrained cell migration. AC inhibited the expressions of the cell proliferation marker PCNA and EMT-related marker N-cadherin and increased E-cadherin expression. AC elevated the levels of GRP78 and Chop and suppressed the level of hnRNPA1. In addition, AC restrained gastric cancer proliferation and migration ability and induced endoplasmic reticulum stress by upregulating miR-635 expression. Furthermore, HMGA1 was proven to be a target of miR-635. AC constrained gastric cancer cell proliferation and migration and promoted endoplasmic reticulum stress by regulating HMGA1. Moreover, AC suppressed in vivo tumor growth and improved the survival time of mice. Additionally, AC elevated the expressions of miR-635, E-cadherin, GRP78, and Chop and inhibited Ki-67, HMGA1, N-cadherin, and hnRNPA1 expressions in tumor tissues of mice., Conclusion: AC suppressed gastric cancer progression and induced endoplasmic reticulum stress via the miR-635/HMGA1 axis, providing a valuable drug against gastric cancer., Competing Interests: The authors declare that they have no competing interest., (Copyright © 2022 Chao Zhang et al.)

Neuroendocrine tumors (NETs) are neoplasms derived from neuroendocrine cells. One of their main features is to often remain asymptomatic and clinically undetectable. High Mobility Group A (HMGA) proteins belong to a family of non-histone chromatinic proteins able to modulate gene expression through the interaction with DNA and transcription factors. They are overexpressed in most of the human malignancies, playing a critical role in carcinogenesis. However, their expression levels and their role in neuroendocrine carcinogenesis has not been exhaustively evaluated until now. Therefore, in this study, we have addressed the validity of using the expression of HMGA1 as a diagnostic marker and have investigated its role in NET carcinogenesis. The expression of HMGA1 has been evaluated by qRT-PCR and immunohistochemistry, using NET tissue microarrays, in a cohort of gastroenteropancreatic (GEP)-NET samples. The expression levels of HMGA1 have been then correlated with the main clinical features of NET samples. Finally, the contribution of HMGA1 overexpression to NET development has been addressed as far as the modulation of proliferation and migration abilities of NET cells is concerned. Here, we report that HMGA1 is overexpressed in GEP-NET samples, at both mRNA and protein levels, and that the silencing of HMGA1 protein expression interferes with the ability of NET cells to proliferate and migrate through the downregulation of Cyclin E, Cyclin B1 and EZH2. These results propose the HMGA proteins as new diagnostic and prognostic markers.

Myeloproliferative neoplasms (MPNs) transform to myelofibrosis (MF) and highly lethal acute myeloid leukemia (AML), although the actionable mechanisms driving progression remain elusive. Here, we elucidate the role of the high mobility group A1 (HMGA1) chromatin regulator as a novel driver of MPN progression. HMGA1 is upregulated in MPN, with highest levels after transformation to MF or AML. To define HMGA1 function, we disrupted gene expression via CRISPR/Cas9, short hairpin RNA, or genetic deletion in MPN models. HMGA1 depletion in JAK2V617F AML cell lines disrupts proliferation, clonogenicity, and leukemic engraftment. Surprisingly, loss of just a single Hmga1 allele prevents progression to MF in JAK2V617F mice, decreasing erythrocytosis, thrombocytosis, megakaryocyte hyperplasia, and expansion of stem and progenitors, while preventing splenomegaly and fibrosis within the spleen and BM. RNA-sequencing and chromatin immunoprecipitation sequencing revealed HMGA1 transcriptional networks and chromatin occupancy at genes that govern proliferation (E2F, G2M, mitotic spindle) and cell fate, including the GATA2 master regulatory gene. Silencing GATA2 recapitulates most phenotypes observed with HMGA1 depletion, whereas GATA2 re-expression partially rescues leukemogenesis. HMGA1 transactivates GATA2 through sequences near the developmental enhancer (+9.5), increasing chromatin accessibility and recruiting active histone marks. Further, HMGA1 transcriptional networks, including proliferation pathways and GATA2, are activated in human MF and MPN leukemic transformation. Importantly, HMGA1 depletion enhances responses to the JAK2 inhibitor, ruxolitinib, preventing MF and prolonging survival in murine models of JAK2V617F AML. These findings illuminate HMGA1 as a key epigenetic switch involved in MPN transformation and a promising therapeutic target to treat or prevent disease progression., (© 2022 by The American Society of Hematology.)

High Mobility Group A1 (HMGA1) is an architectural chromatin factor involved in the regulation of gene expression and a master regulator in Triple Negative Breast Cancer (TNBC). In TNBC, HMGA1 is overexpressed and coordinates a gene network that controls cellular processes involved in tumour development, progression, and metastasis formation. Here, we find that the expression of HMGA1 and of the microtubule-destabilizing protein stathmin correlates in breast cancer (BC) patients. We demonstrate that HMGA1 depletion leads to a downregulation of stathmin expression and activity on microtubules resulting in decreased TNBC cell motility. We show that this pathway is mediated by the cyclin-dependent kinase inhibitor p27 kip1 (p27). Indeed, the silencing of HMGA1 expression in TNBC cells results both in an increased p27 protein stability and p27-stathmin binding. When the expression of both HMGA1 and p27 is silenced, we observe a significant rescue in cell motility. These data, obtained in cellular models, were validated in BC patients. In fact, we find that patients with high levels of both HMGA1 and stathmin and low levels of p27 have a statistically significant lower survival probability in terms of relapse-free survival (RFS) and distant metastasis-free survival (DMFS) with respect to the patient group with low HMGA1, low stathmin, and high p27 expression levels. Finally, we show in an in vivo xenograft model that depletion of HMGA1 chemo-sensitizes tumour cells to paclitaxel, a drug that is commonly used in TNBC treatments. This study unveils a new interaction among HMGA1, p27, and stathmin that is critical in BC cell migration. Moreover, our data suggest that taxol-based treatments may be more effective in reducing the tumour burden when tumour cells express low levels of HMGA1., (© 2022. The Author(s).)

Background: miRNA-4701-5p has been reported to be a vital regulator in many diseases, including rheumatoid arthritis, and miRNA-4701-5p is evidenced to be participated in synovial invasion and joint destruction. In our report, we investigated the roles of miRNA-4701-5p in osteoarthritis (OA) and analyzed the molecular mechanism., Methods: Interleukin-1β (IL-1β) was applied for stimulating human chondrocyte CHON-001 cells to establish an OA injury model. mRNA levels and protein expression were measured using qRT-PCR and western blot assay, respectively. The proliferation ability and cytotoxicity of CHON-001 cells were checked using MTT assay and lactate dehydrogenase activity. The inflammation of chondrocytes was accessed by the secretion levels of interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor (TNF)-α. The apoptosis of chondrocytes was determined by flow cytometry assay. Bioinformatics software Starbase v2.0 analyzed the functional binding sites between miRNA-4701-5p and HMGA1 and the interaction was further confirmed using dual luciferase reporter analysis., Results: miRNA-4701-5p was down-regulated in the IL-1β-stimulated chondrocytes and HMGA1 directly targeted miRNA-4701-5p. Up-regulation of miRNA-4701-5p could alleviate IL-1β-treated CHON-001 cells inflammation and apoptosis, and reversed the cell proliferation decrease and cytotoxicity increase after IL-1β treatment. Nevertheless, all the roles of miRNA-4701-5p overexpression in CHON-001 cells could be reversed by HMGA1 up-regulation., Conclusions: miRNA-4701-5p could alleviate the inflammatory injury of IL-1β-treated CHON-001 cells via down-regulating HMGA1, indicating that miRNA-4701-5p/HMGA1 is a promising therapeutic target for OA., (© 2022. The Author(s).)

Chronic infection with hepatitis B virus (HBV) is associated with liver cirrhosis and hepatocellular carcinoma. Upon infection of hepatocytes, HBV covalently closed circular DNA (cccDNA) exists as histone-bound mini-chromosome, subjected to transcriptional regulation similar to chromosomal DNA. Here we identify high mobility group AT-hook 1 (HMGA1) protein as a positive regulator of HBV transcription that binds to a conserved ATTGG site within enhancer II/core promoter (EII/Cp) and recruits transcription factors FOXO3α and PGC1α. HMGA1-mediated upregulation of EII/Cp results in enhanced viral gene expression and genome replication. Notably, expression of endogenous HMGA1 was also demonstrated to be upregulated by HBV, which involves HBV X protein (HBx) interacting with SP1 transcription factor to activate HMGA1 promoter. Consistent with these in vitro results, chronic hepatitis B patients in immune tolerant phase display both higher intrahepatic HMGA1 protein levels and higher serum HBV markers compared to patients in inactive carrier phase. Finally, using a mouse model of HBV persistence, we show that targeting endogenous HMGA1 through RNA interference facilitated HBV clearance. These data establish HMGA1 as an important positive regulator of HBV that is reciprocally upregulated by HBV via HBx and also suggest the HMGA1-HBV positive feedback loop as a potential therapeutic target., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Oligodendrocyte precursor cells (OPCs) serve as progenitor cells of terminally differentiated oligodendrocytes. Past studies have confirmed the importance of epigenetic system in OPC differentiation to oligodendrocytes. High mobility group A1 (HMGA1) is a small non-histone nuclear protein that binds DNA and modifies the chromatin conformational state. However, it is still completely unknown about the roles of HMGA1 in the process of OPC differentiation. In this study, we prepared primary OPC cultures from the neonatal rat cortex and examined whether the loss- and gain-of-function of HMGA1 would change the mRNA levels of oligodendrocyte markers, such as Cnp , Mbp , Myrf and Plp during the process of OPC differentiation. In our system, the mRNA levels of Cnp , Mbp , Myrf and Plp increased depending on the oligodendrocyte maturation step, but the level of Hmga1 mRNA decreased. When HMGA1 was knocked down by a siRNA approach, the mRNA levels of Cnp , Mbp , Myrf and Plp were smaller in OPCs with Hmga1 siRNA compared to the ones in the control OPCs. On the contrary, when HMGA1 expression was increased by transfection of the Hmga1 plasmid, the mRNA levels of Cnp , Mbp , Myrf and Plp were slightly larger compared to the ones in the control OPCs. These data may suggest that HMGA1 participates in the process of OPC differentiation by regulating the mRNA expression level of myelin-related genes.

Aims: High-mobility group (HMG) proteins are oncogenic in different cancers, including cervical cancer; silencing their individual expression using sh-RNAs, siRNAs, and miRNAs has had anti-tumorigenic effects, but the consequences of their collective downregulation are not known. Since multiple gene targeting is generally very effective in cancer therapy, the present study highlighted the consequences of silencing the expression of HMGA1, A2, B1, and B3 using sh-RNAs or miR-142-3p (that can potentially target HMGA1, A2, B1, and B3) in cervical cancer cell lines., Main Methods: 3' UTR luciferase reporter assays were performed to validate HMGA1, A2, B1, and B3 as targets of miR-142-3p in human cervical cancer cells. Annexin V/PI dual staining and flow cytometry analyses were used to detect apoptotic cells. miR-142-3p-mediated regulation of cell death, colony formation, migration, and invasion was investigated in human cervical cancer cells together with in vivo metastasis in zebrafish., Key Findings: Concurrent knockdown of HMGA1, A2, B1, and B3 through their corresponding sh-RNAs inhibited cell viability and colony formation but induced apoptosis, and these effects were relatively reduced upon their individual knockdown. miR-142-3p targeted HMGA1, A2, B1, and B3 by binding to their 3'UTRs and induced apoptosis but inhibited proliferation, migration, and invasion of human cervical cancer cells. In addition, miR-142-3p expression decreased phospho-p65 and EMT-related proteins in cervical cancer cells and their in vivo metastatic potential upon implantation in zebrafish., Significance: These findings suggest that miR-142-3p acts as a tumor-suppressive miRNA by targeting HMGA1, A2, B1, and B3 and may serve as a potential therapeutic agent in human cervical cancer., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Circular RNAs are novel regulators in endometrial carcinoma. Hsa&#95;circ&#95;0039569 was reportedly upregulated in endometrial carcinoma; however, the functional roles and mechanisms of hsa&#95;circ&#95;0039569 need further investigation. Therefore, we used quantitative real-time PCR (qRT-PCR) to determine the mRNA levels of hsa&#95;circ&#95;0039569, miR-197 and high mobility group protein A1 (HMGA1). The protein level of HMGA1 was determined by Western blot. Cell Counting Kit-8 and colony formation assays were used to assess cell proliferation. Cell migration was measured via wound healing and Transwell assays. Transwell assay was also performed to determine cell invasion ability. Direct binding of the indicated molecules were verified by RNA binding protein immunoprecipitation (RIP) assay and dual luciferase reporter assay. The results revealed that hsa&#95;circ&#95;0039569 and HMGA1 were elevated, while miR-197 was downregulated in endometrial carcinoma. Moreover, hsa&#95;circ&#95;0039569 was positively correlated with the expression of HMGA1 and was negatively correlated with the level of miR-197. In addition, hsa&#95;circ&#95;0039569 facilitated the proliferation, migration and invasion of endometrial carcinoma cells. The underlying mechanism is that hsa&#95;circ&#95;0039569 serves as a sponge of miR-197 to repress the inhibitory effect of miR-197 on HMGA1. Furthermore, the miR-197/HMGA1 axis was implicated in endometrial carcinoma progression accelerated by hsa&#95;circ&#95;0039569. Collectively, hsa&#95;circ&#95;0039569 may promote the development of endometrial carcinoma by serving as an endogenous sponge of miR-197, increasing HMGA1 expression and identifying a novel target for endometrial carcinoma treatment.

Background: Long noncoding RNAs (lncRNAs) play important roles in almost every stage of cancer development. Given the competing endogenous RNA (ceRNA) hypothesis for the regulation of gene expression, we investigated the role of LINC00152 as a ceRNA in gastric cancer (GC) cells., Methods: Gastric cancer cell lines were used in this study. Mimics of miRNAs and siRNA were used to evaluate the interaction between LINC00152 and HMGA1. The quantitative real-time polymerase chain reaction was performed for analyzing gene expression at the transcriptional level. Flow cytometry assay of cell cycle and western blot analysis of related protein expression levels were performed. Online databases such as TCGA and TIMER were used to determine the possibility of HMGA1 and LINC00152 as GC markers and their role in immune infiltration., Results: Treating GC cell lines with LINC00152 siRNAs downregulated the expression of HMGA1. The cell cycle was arrested in the S phase following a reduction in LINC00152 or HMGA1 expression, whereas the expression of the cell cycle inhibitor P27 increased. In this study, we showed that acting as a ceRNA of HMGA1, LINC00152 has the same function as HMGA1, considering that it could control the cell cycle and promote GC cell proliferation. The TCGA database showed that LINC00152 might be used as a diagnostic marker for GC., Conclusions: These findings provide mechanistic insights into the role of LINC00152 as a ceRNA to regulate HMGA1 expression in GC cells, where it can promote the proliferation of the GC cells by regulating the expression of the P27., (© 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

CircRNAs (circular RNAs) have been implicated in the development and progression of a variety of cancers. The molecular pathways underlying the progression of NSCLC (Non-Small Cell Lung Cancer) and the associated regulation of circRNAs in NSCLC remain to be fully elucidated. In this study, we found that circPLK1 expression was upregulated in serum exosomes and tissues from NSCLC patients. The Kaplan-Meier survival analysis revealed that a high expression level of circPLK1 was associated with a poorer prognosis in NSCLC patients. Exosomes extracted from NSCLC serum could promote the replication, migration, and invasion of NSCLC cells and suppress apoptotic cell death. The overexpression of circPLK1 also promotes the malignant phenotype of NSCLC cells. Molecular analyses demonstrated that circPLK1 directly targets miR-1294 and negatively regulates its activity. And circPLK1 overexpression facilitates the progression of NSCLC by negatively regulating miR-1294 level and maintaining a high-level expression of HMGA1 (High Mobility Group Protein A1). Our study suggests that circPLK1 upregulation plays an important role in NSCLC progression by targeting miR-1294/HMGA1 axis. These data provide a theoretical basis for the development of therapeutic strategy targeting exosomal circPLK1 in NSCLC treatment.

Cholangiocarcinoma (CHOL) is often diagnosed at an advanced stage; therefore, exploring its key regulatory factors is important for earlier diagnosis and treatment. This study aimed to identify the mechanisms of long non-coding RNA (lncRNA) TMPO Antisense RNA 1 (TMPO-AS1), microRNA let-7 g-5p, and high-mobility group A1 (HMGA1) proteins in CHOL. Our results, through quantitative real-time PCR and Western blot detection, showed that TMPO-AS1 and HMGA1 were overexpressed while let-7 g-5p was underexpressed in CHOL. Cell function experiments in CHOL cells revealed that TMPO-AS1 knockdown inhibited cell proliferation, colony formation, and cell migration, but induced apoptosis. TMPO-AS1 knockdown also suppressed tumor growth in vivo. Together with luciferase assay and Western blotting, we found that TMPO-AS1 could sponge let-7 g-5p to promote HMGA1 expression. Moreover, HMGA1 overexpression attenuated the effect of TMPO-AS1 downregulation in CHOL cells. Overall, our findings identified the oncogenic effect of TMPO-AS1 on CHOL cells, which may put forward a novel methodology for CHOL diagnosis and therapy.

The important functions of long non‑coding RNAs in the malignancy of non‑small cell lung cancer (NSCLC) has been increasingly highlighted. However, whether LINC01748 functions in a crucial regulatory role still requires further research. The aim of the present study was to investigate the biological roles of LINC01748 in NSCLC. Furthermore, different experiments were utilized to investigate the mechanism of action of LINC01748 in 2 NSCLC cell lines. Reverse transcription‑quantitative PCR was used to measure mRNA expression levels. Cell Counting Kit‑8 assay, flow cytometry analysis and Transwell and Matrigel assays were also used to analyze, cell viability, apoptosis, and migration and invasion, respectively. A tumor xenograft model was used for in vivo experiments. RNA immunoprecipitation experiments, luciferase reporter assays and rescue experiments were used to investigate the mechanisms involved. Data from The Cancer Genome Atlas dataset and patients recruited into the present study showed that LINC01748 was overexpressed in NSCLC. Patients with high LINC01748 mRNA expression level had shorter overall survival rate compared with that in patients with low LINC01748 mRNA expression level. Then, knockdown of LINC01748 mRNA expression level reduced cell proliferation, migration and invasion, but increased cell apoptosis in vitro . Knockdown of LINC01748 also reduced tumor growth in vivo . Mechanistically, LINC01748 could act as a competing endogenous (ce)RNA to sponge microRNA(miR)‑520a‑5p, to increase the expression level of the target gene, high mobility group AT‑hook 1 (HMGA1) in the NSCLC cell lines. Furthermore, rescue experiments illustrated that the functions exerted by LINC01748 knockdown were negated by miR‑520a‑5p inhibition or HMGA1 overexpression. In summary, LINC01748 acted as a ceRNA by sponging miR‑520a‑5p, leading to HMGA1 overexpression, thus increasing the aggressiveness of the NSCLC cells. Accordingly, targeting the LINC01748/miR‑520a‑5p/HMGA1 pathway may benefit NSCLC therapy.

HMGA1 has been reported to be aberrantly expressed and correlate with the poor prognosis of many carcinomas. This study aimed to investigate the clinical significance and molecular mechanism of HMGA1 as a tumor-suppressing gene in hepatocellular carcinoma (HCC). Analysis of TCGA dataset by TANRIC website and R2 platform, we found that HMGA1 expression was significantly higher in HCC tissues compared to that in normal liver tissues and was associated with Edmondson grade. Patients with highly expressed HMGA1 had worse overall survival. Gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes analysis showed the potential relationships between HMGA1 and other genes in HCC. We also demonstrated that the downregulation of HMGA1 dramatically suppressed the proliferation and migration of HCC cells. Furthermore, ectopic expression of HMGA1 blocked G0/G1 to S transition. Subsequent investigation characterized HMGA1 as a direct target of miR-195-5p, and miR-195-5p downregulation abrogated the effect of HMGA1 on HCC proliferation, migration, and cell cycle arrest. In addition, we also demonstrated that miR-195-5p downregulation abrogated the effect of HMGA1 on HCC growth in vivo. Taken together, our data provide strong evidence that HMGA1 promotes HCC and is negatively regulated by the tumor-suppressor, miR-195-5p., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Gastric cancer is a serious health problem worldwide. Although its incidence is decreasing, the five-year survival rate remains low. Thus, it is essential to identify new biomarkers that could promote better diagnosis and treatment of patients with gastric cancer. High-mobility group AT-hook 1 (HMGA1) is a non-histone, chromatin-binding protein that has been found overexpressed in several tumor types. It has been correlated with invasion, metastasis, and drug resistance, leading to worse patient survival. The aim of this work was to evaluate the clinical value of HMGA1 in gastric cancer. HMGA1 expression was analyzed by immunohistochemistry in a single hospital series ( n = 323) of gastric adenocarcinoma cases (stages I to IV) with clinicopathological and treatment data. In this series, HMGA1 expression showed no significant relevance as a prognostic biomarker. Nevertheless, a significantly better overall survival was observed in cases with high levels of HMGA1 when they were treated with chemotherapy, compared to the nontreated ones, implying that they can benefit more from treatment than patients with low expression of HMGA1. We thereby show for the first time that HMGA1 expression has a substantial value as a biomarker of response to chemotherapy in gastric cancer.

Myosin heavy chain 9 (MYH9) plays an essential role in human diseases, including multiple cancers; however, little is known about its role in gliomas. In the present study, we revealed that HMGA1 and MYH9 were upregulated in gliomas and their expression correlated with WHO grade, and HMGA1 promoted the acquisition of malignant phenotypes and chemoresistance of glioma cells by regulating the expression of MYH9 through c-Jun-mediated transcription. Moreover, MYH9 interacted with GSK-3β to inhibit the expression of GSK-3β protein by promoting its ubiquitination; the downregulation of GSK-3β subsequently promoted the nuclear translocation of β-catenin, enhancing growth, invasion, migration, and temozolomide resistance in glioma cells. Expression levels of HMGA1 and MYH9 were significantly correlated with patient survival and should be considered as independent prognostic factors. Our findings provide new insights into the role of HMGA1 and MYH9 in gliomagenesis and suggest the potential application of HMGA1 and MYH9 in cancer therapy in the future., (© 2021. The Author(s).)

With the aid of next-generation sequencing technology, pseudogenes have been widely recognized as functional regulators in the development and progression of certain diseases, especially cancer. Our present study aimed to investigate the functions and molecular mechanisms of HSPB1-associated protein 1 pseudogene 1 (HSPB1P1) in renal cell carcinoma (RCC). HSPB1P1 expression at the mRNA levels was determined by quantitative real-time polymerase chain reaction, and its clinical significance was assessed. Cell viability was detected by Cell Counting Kit-8 assay. Cell migration and invasion were detected by transwell assays. The location of HSPB1P1 in RCC cells was detected by subcellular distribution analysis. The direct relationship between HSPB1P1 and miR-296-5p/HMGA1 axis was verified by dual-luciferase reporter assay and RNA immunoprecipitation assay. Our results identify the elevated expression of HSPB1P1 in RCC tissues and cell lines, which predicted advanced progression and poor prognosis in patients with RCC. Knockdown of HSPB1P1 suppressed cell proliferation, migration, and invasion, and reversed epithelial-mesenchymal transition process in RCC. HSPB1P1 was mostly enriched in the cytoplasm and functioned as a miRNA sponge for miR-296-5p and then regulated high-mobility group A1 expression. In conclusion, our study indicated that HSPB1P1 contributed to RCC progression by targeting the miR-296-5p/HMGA1 axis, and should be considered as a promising biomarker and therapeutic target for clinical applications., (© 2021 International Federation for Cell Biology.)

Purpose: Glioma is a malignant tumor in the central nervous system. Long non-coding RNA (lncRNA) RNF144A-AS1 exerts a regulatory effect in cancers, but its role in glioma remains obscure and needs to be further study., Methods: Expressions of RNF144A-AS1, miR-665 and High-mobility group A1 (HMGA1) in glioma tissues and/or cells were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The relationship between miR-665 and RNF144A-AS1/HMGA1 was determined by bioinformatics and Dual-Luciferase Reporter assay. The effect of RNF144A-AS1 on the biological functions of glioma cells was confirmed by loss and gain experiments (including cell counting kit 8, clone formation, wound healing, Transwell, qRT-PCR and western blot). The regulatory mechanism of RNF144A-AS1/miR-665/HMGA1 axis on glioma was confirmed by rescue experiments., Results: RNF144A-AS1 and HMGA1 were high-expressed in gliomas, and miR-665 was low-expressed in gliomas, which led to the increase of glioma cell viability, proliferation, migration and invasion ability and insufficient apoptosis ability. Overexpression of RNF144A-AS1 suppressed the expressions of Bax and cleaved caspase-3, and promoted Bcl-2 expression. RNF144A-AS1 up-regulated the expression of HMGA1 by targeting miR-665, thereby promoting the development of glioma cells., Conclusion: RNF144A-AS1/miR-665/HMGA1 axis implicated in the development of glioma., (Copyright © 2021. Published by Elsevier B.V.)