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HMGA2, as a transcription factor, facilitates oncogenesis and malignant progression by coordinating cell cycle dysregulation, compromising DNA repair machinery, and suppressing cancer cell apoptosis. However, its roles in prognostication and tumor immune microenvironment modulation in endometrial cancer (EC) remain incompletely defined. We systematically analyzed HMGA2 expression patterns and clinical prognostic value in EC using bioinformatics strategies, including TCGA and GTEX data mining, as well as single gene expression analysis. Functional enrichment analysis (GSEA and KEGG) identified HMGA2-associated pathways. The correlation between HMGA2 and immune infiltration was assessed via TIMER and TISIDB. Subsequent (proliferation, migration, colony formation) and (xenograft models) experimental were used to validate HMGA2's role in promoting EC progression. The correlation between HMGA2 and macrophage markers (CD86 and CD206) was validated through clinical tissue samples by IHC. Finally, a recurrence-predictive nomogram incorporating HMGA2 with clinicopathological parameters was established. HMGA2 exhibited significant upregulation in endometrial cancer (EC) tissues and correlated with poor patient prognosis. Immunoassay showed that high expression of HMGA2 was negatively correlated with infiltration of various immune cells, especially M1 macrophages. Cytological experiments showed that knocking down HMGA2 significantly inhibited EC cell proliferation, migration, invasion, and drug resistance, while overexpression of HMGA2 promoted the above phenotype; Animal experiments showed that knocking down HMGA2 significantly inhibited the growth of EC tumors and the expression of M1 macrophage marker CD86. The combination of HMGA2 inhibitors and targeted macrophage immunotherapy (CD47 monoclonal antibody) had the better tumor suppression effect. Clinical sample analysis found that high expression of HMGA2 was significantly negatively correlated with CD86 and positively correlated with CD206 expression. Patients with low HMGA2 expression showed enhanced immune therapy responsiveness. The nomogram model based on HMGA2 and clinical pathological parameters showed better predictive performance (AUC=0.855, sensitivity=79.0%, specificity=76.8%). HMGA2 is a potential diagnostic and prognostic biomarker for the EC. HMGA2 may drive the occurrence and development of EC by inhibiting the infiltration of immune cells, especially M1 macrophages. Therapeutic targeting of HMGA2 is a novel strategy for EC intervention.

Purpose Fetal growth is a complex process involving maternal, placental and fetal factors. The etiology of fetal growth retardation remains unknown in many cases. The aim of this study is to identify novel human mutations and genes related to Silver–Russell syndrome (SRS), a syndromic form of fetal growth retardation, usually caused by epigenetic downregulation of the potent fetal growth factor IGF2. Methods Whole-exome sequencing was carried out on members of an SRS familial case. The candidate gene from the familial case and two other genes were screened by targeted high-throughput sequencing in a large cohort of suspected SRS patients. Functional experiments were then used to link these genes into a regulatory pathway. Results We report the first mutations of the PLAG1 gene in humans, as well as new mutations in HMGA2 and IGF2 in six sporadic and/or familial cases of SRS. We demonstrate that HMGA2 regulates IGF2 expression through PLAG1 and in a PLAG1-independent manner. Conclusion Genetic defects of the HMGA2 – PLAG1 – IGF2 pathway can lead to fetal and postnatal growth restriction, highlighting the role of this oncogenic pathway in the fine regulation of physiological fetal/postnatal growth. This work defines new genetic causes of SRS, important for genetic counseling.

The long noncoding RNA (lncRNA) H19 has been recently characterized as an oncogenic lncRNA in some tumors. However, the role of H19 in pancreatic ductal adenocarcinoma (PDAC) remains unclear. In this study, we found that not only the levels of H19 was overexpressed in PDAC compared with adjacent normal tissues, but also H19 expression was upregulated remarkably in primary tumors which subsequently metastasized, compared to those did not metastasis. Subsequently, the efficacy of knockdown of H19 by H19-small interfering RNA (siRNA) was evaluated in vitro, and we found that downregulation of H19 impaired PDAC cell invasion and migration. We further demonstrated that H19 promoted PDAC cell invasion and migration at least partially by increasing HMGA2-mediated epithelial-mesenchymal transition (EMT) through antagonizing let-7. This study suggests an important role of H19 in regulating metastasis of PDAC and provides some clues for elucidating the lncRNA-miRNA functional network in cancer.

High mobility group AT-hook 2 (HMGA2) has been associated with increased cell proliferation and cell cycle dysregulation, leading to the ontogeny of varied tumor types and their metastatic potentials, a frequently used index of disease prognosis. In this review, we deepen our understanding of HMGA2 pathogenicity by exploring the mechanisms by which HMGA2 misexpression and ectopic expression induces mesenchymal and epithelial tumorigenesis respectively and distinguish the pathogenesis of benign from malignant mesenchymal tumors. Importantly, we highlight the regulatory role of let-7 microRNA family of tumor suppressors in determining HMGA2 misexpression events leading to tumor pathogenesis and focused on possible mechanisms by which HMGA2 could propagate lymphangioleiomyomatosis (LAM), benign mesenchymal tumors of the lungs. Lastly, we discuss potential therapeutic strategies for epithelial and mesenchymal tumorigenesis based on targeting the HMGA2 signaling pathway.

Background RNA cargo in exosomes, especially microRNAs (miRNAs), play an important role in the chemotherapy drug resistance of human cancers. However, the role and mechanism of exosomal miR-107 on multidrug resistance of gastric cancer cells was still not clear. In this study, we sought to explore whether exosomal miR-107 could reverse the resistance of gastric cancer cells to the chemotherapy drugs. Methods We extracted exosomes from sensitive (SGC-7901, MGC-803) and resistant (SGC-7901/5-FU) gastric cancer cells by ultracentrifugation and the isolated exosomes were identified using transmission electron microscopy (TEM) and dynamic light scattering analysis (DLS). The expression of miR-107 and high mobility group A2 (HMGA2) were detected by real-time quantitative PCR (RT-qPCR). MTT assay was used to investigate the effect of exosomes on gastric cancer cells growth in vitro. The uptake of exosomes by recipient cells were observed using a fluorescence microscope. The predicted target relationship between miR-107 and HMGA2 was verified by gauss -luciferase reporter assay. The expression of HMGA2, p-mTOR/mTOR, P-gp and other exosomal indicated marker proteins was detected by western blot. Results Our results indicated that the isolated exosomes were typically cup-like lipid bilayer membranes structure. SGC-7901/5-FU cells were cross-resistant to chemotherapy drug cisplatin (CDDP), and the sensitive cells-secreted exosomes drastically reversed the resistance of the resistant GC cells to the chemotherapeutic drugs, which was verified by exosomal inhibitor GW4896. Mechanistically, the reversal effect was mainly mediated by exosome-secreted miR-107 through downregulating the expression of target molecular HMGA2 and inhibiting HMGA2/mTOR/P-gp pathway, which were supported by results from luciferase reporter assay and rescue assay. Conclusions These findings demonstrated that exosome-transmitted miR-107 significantly enhanced the sensitivity of resistant gastric cancer cells to chemotherapeutic agents by mediating the HMGA2/mTOR/P-gp axis and exosomal miR-107 may be a novel target in gastric cancers treatment.

Exposure to microgravity results in cardiovascular deconditioning, with endothelial cell apoptosis recognized as a pivotal initiating event. However, the mechanosensitive mechanisms underlying this process remain poorly understood. Here, we demonstrate that the expression of mechanosensitive ion channel protein PIEZO1 is upregulated in human umbilical vein endothelial cells (HUVECs) under simulated microgravity. Functional studies revealed that PIEZO1 activation promotes endothelial apoptosis under simulated microgravity conditions. Proteomic analysis following PIEZO1 knockdown revealed extensive alterations in biological processes associated with apoptosis. Furthermore, we found that PIEZO1 activation triggers calcium influx, leading to elevated expression of the HMGA2. Moreover, we identify that PIEZO1 activation induces calcium influx, which subsequently elevates the expression of HMGA2. The knockdown of HMGA2 significantly mitigated microgravity-induced endothelial apoptosis, indicating its role in PIEZO1-mediated apoptosis. These findings reveal a novel PIEZO1–Ca2+–HMGA2 axis critical for microgravity-induced endothelial apoptosis, providing mechanistic insight into cardiovascular adaptation to spaceflight and potential therapeutic targets for countermeasure development.

Purpose HMGA2 has frequently been found in benign as well as malignant tumors and a significant association between HMGA2 overexpression and poor survival in different malignancies was described. In pancreatic ductal adenocarcinoma (PDAC), nuclear HMGA2 expression is associated with tumor dedifferentiation and presence of lymph node metastasis. Nevertheless, the impact of HMGA2 occurrence in other cell compartments is unknown. Methods Intracellular distribution of HMGA2 was analyzed in PDAC ( n  = 106) and peritumoral, non-malignant ducts ( n  = 28) by immunohistochemistry. Findings were correlated with clinico-pathological data. Additionally, intracellular HMGA2 presence was studied by Western blotting of cytoplasmic and nuclear fractions of cultured cells. Results HMGA2 was found in the cytoplasm and in the nucleus of cultured cells. In human tumor tissue, HMGA2 was also frequently found in the cytoplasm and the nucleus of tumor cells, however, nuclear staining was generally stronger. Direct comparison from tumor tissue with corresponding non-neoplastic peritumoral tissue revealed significantly stronger expression in tumors ( p  = 0.003). Of note, the nuclear staining was significantly stronger in lymph node metastatic cell nuclei compared to primary tumor cell nuclei ( p  = 0.049). Interestingly, cytoplasmic staining positively correlated with lymph vessel ( p  = 0.004) and venous invasion ( p  = 0.046). Conclusion HMGA2 is a prognostic marker in PDAC. Firstly, we found a positive correlation for cytoplasmic HMGA2 expression with lympho-vascular invasion and, secondly, we found a significantly stronger nuclear expression of HMGA2 in cancer-positive lymph node nuclei compared to primary tumor cell nuclei. So far, the role of cytoplasmic HMGA2 is nearly unknown, however, our data lend support to the hypothesis that cytoplasmic HMGA2 expression is involved in nodal spread.

Recent identification of somatic MED12 mutations in most uterine leiomyomas brings a new venue for the study of the tumorigenesis of leiomyomas. We are particularly interested in the correlation of MED12 and HMGA2 gene products in leiomyomas and leiomyosarcomas with and without MED12 mutations. To address these issues, in this study we examined MED12 mutations in a large cohort of usual type leiomyomas (178 cases) and uterine leiomyosarcomas (32 cases). We found that 74.7% (133/178) of leiomyomas had MED12 mutations, which was consistent with several independent studies. In contrast, only 9.7% (3/32) of leiomyosarcomas harbored MED12 mutations. Expression analysis by western blot and immunohistochemistry revealed that those leiomyomas with complex MED12 mutations had significantly lower protein products than the matched myometrium. Interestingly, most leiomyosarcomas without MED12 mutations also had very low levels of MED12 expression in comparison to the matched myometrium. These findings suggest a potential functional role of MED12 in both benign and malignant uterine smooth muscle tumors. When we further examined HMGA2 expression in all leiomyomas and leiomyosarcomas, we found that HMGA2 overexpression was exclusively present in those leiomyomas with no MED12 mutation, accounting for 10.1% (18/178) of total leiomyomas and 40% (18/45) of non-MED12 mutant leiomyomas. Twenty-five percent (8/32) of leiomyosarcomas had HMGA2 overexpression, and no MED12 mutations were found in HMGA2 positive leiomyosarcoma. These findings strongly suggest that MED12 mutations and HMGA2 overexpression are independent genetic events that occur in leiomyomas, and they may act differently in the tumorigenesis of uterine leiomyomas.

Uterine smooth muscle tumors range from benign leiomyomas to malignant leiomyosarcomas. Based on numerous molecular studies, leiomyomas and leiomyosarcomas mostly lack shared mutations and the majority of tumors are believed to develop through distinct mechanisms. To further characterize the molecular variability among uterine smooth muscle tumors, and simultaneously insinuate their potential malignant progression, we examined the frequency of known genetic leiomyoma driver alterations ( MED12 mutations, HMGA2 overexpression, biallelic FH inactivation) in 65 conventional leiomyomas, 94 histopathological leiomyoma variants (18 leiomyomas with bizarre nuclei, 22 cellular, 29 highly cellular, and 25 mitotically active leiomyomas), and 51 leiomyosarcomas. Of the 210 tumors analyzed, 107 had mutations in one of the three driver genes. No tumor had more than one mutation confirming that all alterations are mutually exclusive. MED12 mutations were the most common alterations in conventional and mitotically active leiomyomas and leiomyosarcomas, while leiomyomas with bizarre nuclei were most often FH deficient and cellular tumors showed frequent HMGA2 overexpression. Highly cellular leiomyomas displayed the least amount of alterations leaving the majority of tumors with no known driver aberration. Our results indicate that based on the molecular background, histopathological leiomyoma subtypes do not only differ from conventional leiomyomas, but also from each other. The presence of leiomyoma driver alterations in nearly one third of leiomyosarcomas suggests that some tumors arise through leiomyoma precursor lesion or that these mutations provide growth advantage also to highly aggressive cancers. It is clinically relevant to understand the molecular background of various smooth muscle tumor subtypes, as it may lead to improved diagnosis and personalized treatments in the future.

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.