Let-7 reduces the proliferation and migration of oral cancer cells via PI3K/AKT signaling pathway.

The involvement of let-7 in the occurrence and progression of various cancers has been well-documented. However, the precise molecular mechanisms underlying its impact on oral cancer development remain unclear. In this study, we aimed to elucidate the role of let-7 in oral cancer progression and investigate its underlying molecular mechanisms. The expression of let-7 and high mobility group A2 (HMGA2) mRNA was assessed using the quantitative reverse transcription polymerase chain reaction. Western blot analysis was employed to detect the expression of key proteins in the PI3K/AKT signaling pathway as well as HMGA2 protein levels. The targeting relationship between let-7 and HMGA2 was predicted through bioinformatics methods and confirmed via luciferase reporter gene assay. The effects of let-7 and HMGA2 on the functionality of oral cancer cells were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony formation assay, Transwell assay, wound healing assay, and Annexin V/PI apoptosis assay. Additionally, the impact of let-7 on the growth of oral cancer cells in vivo was investigated by inducing subcutaneous tumor formation in nude mice. Let-7 effectively suppresses the proliferation, migration, and invasion of oral cancer cells by inhibiting the activation of the PI3K/AKT signaling pathway. HMGA2, a downstream target gene of let-7, exhibits high expression in oral cancer. However, overexpression of HMGA2 diminishes the inhibitory effects induced by let-7 overexpression on the proliferation, migration, and invasion of oral cancer cells. The occurrence and progression of oral cancer cells are inhibited by Let-7 through the downregulation of HMGA2, potentially mediated by the inhibition of PI3K/AKT signaling pathway activation.

LncRNA HCG18 affects aortic dissection through the miR-103a-3p/HMGA2 axis by modulating proliferation and apoptosis of vascular smoothing muscle cells.

BACKGROUND: Aortic Dissection (AD) is a vascular disease with a high mortality rate and limited treatment strategies. The current research analyzed the function and regulatory mechanism of lncRNA HCG18 in AD. METHODS: HCG18, miR-103a-3p, and HMGA2 levels in the aortic tissue of AD patients were examined by RT-qPCR. After transfection with relevant plasmids, the proliferation of rat aortic Vascular Smoothing Muscle Cells (VSMCs) was detected by CCK-8 and colony formation assay, Bcl-2 and Bax was measured by Western blot, and apoptosis was checked by flow cytometry. Then, the targeting relationship between miR-103a-3p and HCG18 or HMGA2 was verified by bioinformation website analysis and dual luciferase reporter assay. Finally, the effect of HCG18 was verified in an AD rat model induced by ß-aminopropionitrile. RESULTS: HCG18 and HMGA2 were upregulated and miR-103a-3p was downregulated in the aortic tissues of AD patients. Downregulating HCG18 or upregulating miR-103a-3p enhanced the proliferation of VSMCs and limited cell apoptosis. HCG18 promoted HMGA2 expression by competing with miR-103a-3p and restoring HMGA2 could impair the effect of HCG18 downregulation or miR-103a-3p upregulation in mediating the proliferation and apoptosis of VSMCs. In addition, down-regulation of HCG18 could improve the pathological injury of the aorta in AD rats. CONCLUSION: HCG18 reduces proliferation and induces apoptosis of VSMCs through the miR-103a-3p/HMGA2 axis, thus aggravating AD.

Immunohistochemical characteristics of uterine lipoleiomyomas.

Lipoleiomyomas are rare variants of uterine leiomyomas rarely studied in the literature. We retrospectively studied 20 cases of uterine lipoleiomyomas showing that these lesions represent 0.7 % of all uterine leiomyomas diagnosed histologically. The patients did not experience any recurrence, and the tumors showed no morphological criteria of malignancy. They did not show significant p16, p53 or MiB1 expression. They showed diffuse and strong expression or estrogen and progesterone receptors by the smooth muscle component but without accompanying expression by the adipocytic component in one third of the cases. Androgen receptors were rarely expressed. They expressed in their majority HMGA2 in both components, while RB1 was usually not found. Fumarate hydratase (FH) is expressed by lipoleiomyomas, while they are negative for HMB45. In conclusion, uterine lipoleiomyomas are rare, benign tumors, characterized by HMGA2 expression, while they show no elements suspicious of malignancy, PEComas or FH deficiency. The role of RB1 in these tumors should be further explored.

[Hmga2 knockdown enhances osteogenic differentiation of adipose-derived mesenchymal stem cells and accelerates bone defect healing in mice].

OBJECTIVE: To investigate the role of high-mobility group AT-hook 2 (HMGA2) in osteogenic differentiation of adipose-derived mesenchymal stem cells (ADSCs) and the effect of Hmga2 knockdown for promoting bone defect repair. METHODS: Bioinformatics studies using the GEO database and Rstudio software identified HMGA2 as a key factor in adipogenic-osteogenic differentiation balance of ADSCs. The protein-protein interaction network of HMGA2 in osteogenic differentiation was mapped using String and visualized with Cytoscape to predict the downstream targets of HMGA2. Primary mouse ADSCs (mADSCs) were transfected with Hmga2 siRNA, and the changes in osteogenic differentiation of the cells were evaluated using alkaline phosphatase staining and Alizarin red S staining. The expressions of osteogenic markers Runt-related transcription factor 2 (RUNX2), osteopontin (OPN), and osteocalcein (OCN) in the transfected cells were detected using RT-qPCR and Western blotting. In a mouse model of critical-sized calvarial defects, mADSCs with Hmga2-knockdown were transplanted into the defect, and bone repair was evaluated 6 weeks later using micro-CT scanning and histological staining. RESULTS: GEO database analysis showed that HMGA2 expression was upregulated during adipogenic differentiation of ADSCs. Protein-protein interaction network analysis suggested that the potential HMGA2 targets in osteogenic differentiation of ADSCs included SMAD7, CDH1, CDH2, SNAI1, SMAD9, IGF2BP3, and ALDH1A1. In mADSCs, Hmga2 knockdown significantly upregulated the expressions of RUNX2, OPN, and OCN and increased cellular alkaline phosphatase activity and calcium deposition. In a critical-sized calvarial defect model, transplantation of mADSCs with Hmga2 knockdown significantly promoted new bone formation. CONCLUSION: HMGA2 is a crucial regulator of osteogenic differentiation in ADSCs, and Hmga2 knockdown significantly promotes osteogenic differentiation of ADSCs and accelerates ADSCs-mediated bone defect repair in mice.

HMGA2-mediated glutamine metabolism is required for Cd-induced cell growth and cell migration.

Cadmium (Cd) exposure significantly increases the risk of lung cancer. The demand for glutamine is increasing in cancers, including lung cancer. In this study, we investigated the role of glutamine metabolism in Cd-induced cell growth and migration. Firstly, we found that 2 µM Cd-treatment up-regulated the expression of ASCT2 (alanine, serine, cysteine-preferring transporter 2) and ASNS (asparagine synthetase) while downregulating mitochondrial glutaminase GLS1 in A549 cells. The same results were obtained in male BALB/c mice treated with 0.5 and 1 mg Cd/kg body weight. Subsequently, both glutamine deprivation and transfection with siASCT2 revealed that glutamine played a role in Cd-induced cell growth and migration. Furthermore, using 4-PBA (5 mM), an inhibitor of endoplasmic reticulum (ER) stress, Tm (0.1 µg/ml), an inducer of ER stress, siHMGA2, and over-expressing HMGA2 plasmids we demonstrated that ER stress/HMGA2 axis was involved in inducing ASCT2 and ASNS, while inhibiting GLS1. Additionally, the chromatin immunoprecipitation assay using an HMGA2 antibody revealed the direct binding of the HMGA2 to the promoter sequences of the ASCT2, ASNS, and GLS1 genes. Finally, dual luciferase reporter assay determined that HMGA2 increased the transcription of ASCT2 and ASNS while inhibiting the transcription of GLS1. Overall, we found that ER stress-induced HMGA2 controls glutamine metabolism by transcriptional regulation of ASCT2, ASNS and GLS1 to accelerate cell growth and migration during exposure to Cd at low concentrations. This study innovatively revealed the mechanism of Cd-induced cell growth which offers a fresh perspective on preventing Cd toxicity through glutamine metabolism.

A novel HMGA2/MPC-1/mTOR signaling pathway promotes cell growth via facilitating Cr (VI)-induced glycolysis.

Mitochondrial Pyruvate Carrier 1 (MPC1) is localized on mitochondrial outer membrane to mediate the transport of pyruvate from cytosol to mitochondria. It is also well known to act as a tumor suppressor. Hexavalent chromium (Cr (VI)) contamination poses a global challenge due to its high toxicity and carcinogenesis. This research was intended to probe the potential mechanism of MPC1 in the effect of Cr (VI)-induced carcinogenesis. First, Cr (VI)-treatments decreased the expression of MPC1 in vitro and in vivo. Overexpression of MPC1 inhibited Cr (VI)-induced glycolysis and migration in A549 cells. Then, high mobility group A2 (HMGA2) protein strongly suppressed the transcription of MPC1 by binding to its promoter, and HMGA2/MPC1 axis played an important role in oxidative phosphorylation (OXPHOS), glycolysis and cell migration. Furthermore, endoplasmic reticulum (ER) stress made a great effect on the interaction between HMGA2 and MPC1. Finally, the mammalian target of the rapamycin (mTOR) was determined to mediate MPC1-regulated OXPHOS, aerobic glycolysis and cell migration. Collectively, our data revealed a novel HMGA2/MPC-1/mTOR signaling pathway to promote cell growth via facilitating the metabolism reprogramming from OXPHOS to aerobic glycolysis, which might be a potential therapy for cancers.

Pathogenic sequence variant and microdeletion affecting HMGA2 in Silver-Russell syndrome: case reports and literature review.

Silver-Russell syndrome (SRS) is a representative imprinting disorder characterized by pre- and postnatal growth failure. We encountered two Japanese SRS cases with a de novo pathogenic frameshift variant of HMGA2 (NM_003483.6:c.138_141delinsCT, p.(Lys46Asnfs*16)) and a de novo ~ 3.4 Mb microdeletion at 12q14.2-q15 involving HMGA2, respectively. Furthermore, we compared clinical features in previously reported patients with various genetic conditions leading to compromised IGF2 expression, i.e., HMGA2 aberrations, PLAG1 aberrations, IGF2 aberrations, and H19/IGF2:IG-DMR epimutations (hypomethylations). The results provide further support for HMGA2 being involved in the development of SRS and imply some characteristic features in patients with HMGA2 aberrations.

Keratin-Positive Giant Cell Tumor of Bone and Soft Tissue With HMGA2::NCOR2 Fusion in Children Under 10 With Response to Imatinib Therapy: A Case Series.

HMGA2::NCOR2 keratin-positive giant cell tumors in children with response to imatinib in an infant.

Silencing LINC00987 ameliorates adriamycin resistance of acute myeloid leukemia via miR-4458/HMGA2 axis.

BACKGROUND: Most patients with acute myeloid leukemia (AML) eventually develop drug resistance, leading to a poor prognosis. Dysregulated long gene non coding RNAs (lincRNAs) have been implicated in chemoresistance in AML. Unfortunately, the effects of lincRNAs which participate in regulating the Adriamycin (ADR) resistance in AML cells remain unclear. Thus, the purpose of this study is to determine LINC00987 function in ADR-resistant AML. METHODS: In this study, ADR-resistant cells were constructed. LINC00987, miRNAs, and HMGA2 mRNA expression were measured by qRT-PCR. P-GP, BCRP, and HMGA2 protein were measured by Western blot. The proliferation was analyzed by MTS and calculated IC50. Soft agar colony formation assay and TUNEL staining were used to analyze cell colony formation and apoptosis. Xenograft tumor experiment was used to analyze the xenograft tumor growth of ADR-resistant AML. RESULTS: We found that higher expression of LINC00987 was observed in AML patients and associated with poor overall survival in AML patients. LINC00987 expression was increased in ADR-resistant AML cells, including ADR/MOLM13 and ADR/HL-60 cells. LINC00987 downregulation reduces ADR resistance in ADR/MOLM13 and ADR/HL-60 cells in vitro and in vivo, while LINC00987 overexpression enhanced ADR resistance in MOLM13 and HL-60 cells. Additionally, LINC00987 functions as a competing endogenous RNA for miR-4458 to affect ADR resistance in ADR/MOLM13 and ADR/HL-60 cells. HMGA2 is a target of miR-4458. LINC00987 knockdown and miR-4458 overexpression reduced HMGA2 expression. HMGA2 overexpression enhanced ADR resistance, which reversed the function of LINC00987 silencing in suppressing ADR resistance of ADR/MOLM13 and ADR/HL-60 cells. CONCLUSIONS: Downregulation of LINC00987 weakens ADR resistance by releasing miR-4458 to deplete HMGA2 in ADR/MOLM13 and ADR/HL-60. Therefore, LINC00987 may act as the therapeutic target for treating chemoresistant AML.

Peculiar nuclear atypia associated with MDM2 gene amplification in carcinoma ex-pleomorphic adenoma harbouring an alteration of HMGA2.

AIMS: Salivary gland neoplasms (SGN) exhibiting the HMGA2::WIF1 fusion are recognized by their resemblance to histology found in canalicular adenoma. Recently, ~20% of cases among 28 HMGA2::WIF1-rearranged-SGN showed malignancy and adverse outcomes (recurrence, distant metastasis, and disease-specific mortality). Among them, MDM2/CDK4 amplifications were identified in one case. This outcome suggests that the MDM2/CDK4 amplifications could be useful to predict an aggressive course of carcinoma ex-pleomorphic adenoma (CEPA). METHODS AND RESULTS: We investigated the correlation between HMGA2 fusion and MDM2 amplification in four salivary gland neoplasms, providing detailed clinicopathological features and outcomes. Cases were selected from different institutions. Histological examination, immunohistochemistry, fluorescence in situ hybridization (FISH), RNA sequencing, and whole-exome capture were performed. The cohort included four CEPA cases, all female, aged between 32 and 89 years. Tumours arose from the parotid gland with an average size of 24.5 mm. None exhibited recurrence or distant metastases during the 4-5 months of follow-up. Pathologically, all cases displayed a peculiar atypical nuclei with 'gear-like appearance'. Immunohistochemically, tumours exhibited a biphasic pattern with myoepithelial and ductal differentiation markers. All cases showed HMGA2 overexpression and MDM2 amplification by FISH and RNA sequencing. In a control cohort of MDM2 nonamplified CEPA cases, not exhibiting the peculiar nuclear atypia. CONCLUSIONS: Our findings suggest a strong correlation between HMGA2 alteration/MDM2 amplification and a peculiar nuclear atypia, advocating for their evaluation in biphasic tumours to facilitate accurate diagnosis and tailored posttumour removal monitoring. Further studies are warranted to validate these observations and elucidate their prognostic implications.

Uncovering the WWTR1::NCOA2 Gene fusion in low-grade myoepithelial-rich neoplasm with HMGA2 expression: A case report.

We describe a case of a pleomorphic adenoma (PA) arising from the para-tracheal accessory salivary gland in a 44-year-old male harboring a novel WWTR1::NCOA2 gene fusion. To our knowledge, this novel gene fusion has not been described previously in salivary gland tumors. The patient presented with hoarseness of voice. The radiological exam revealed a mass in the upper third of the trachea involving the larynx. Histologically, the tumor consisted of bland-looking monocellular eosinophilic epithelial cells arranged in cords and sheets separated by thin fibrous stroma, focally forming a pseudo-tubular pattern. In immunohistochemistry, the tumor cells demonstrated positivity for CK7, PS100, SOX10, and HMGA2; and negativity for CK5/6, p40 p63, and PLAG1. In addition, the clustering analysis clearly demonstrates a clustering of tumors within the PA group. In addition to reporting this novel fusion in the PA spectrum, we discuss the relevant differential diagnoses and briefly review of NCOA2 and WWTR1 gene functions in normal and neoplastic contexts.

Association of deletion polymorphism rs10573247 in the HMGA2 gene with the risk of breast cancer: bioinformatic and experimental analyses.

BACKGROUND: The high mobility group A2 (HMGA2) gene is expressed extensively during early embryonic development but is inactivated in adulthood, and it is also reactivated in various benign and malignant tumors, including breast cancer. We first assessed the potential functional significance of the unstudied deletion polymorphism rs10573247 at the 3'UTR of HMGA2 on miRNA binding using bioinformatic tools, and subsequently, the association between this polymorphism and breast cancer susceptibility was investigated. MATERIALS AND METHODS: We applied the RNAhybrid tool to predict the functional effects of polymorphism rs10573247 located within the 3' UTR of the HMGA2 gene on miRNA binding. Then, following DNA extraction, 141 breast cancer patients and 123 healthy controls were genotyped for polymorphism rs10573247 using RFLP-PCR with the restriction enzyme Eam1104I. RESULTS: Our bioinformatic data have shown that polymorphism rs10573247 is located in the region that serves as a potential target site for eight miRNAs binding. Among them, miR-3125 exhibited decreased binding affinity for the allele delTT (MFE = -21.8) when compared to the allele TT (MFE = -23.9), but miR-4476 increased binding affinity for the allele delTT (MFE = -22.4) compared to the allele TT (MFE = -22.2). In addition, our results showed that the genotype TT/delTT (p = 0.005) and the genotype delTT/delTT (p = 0.029) were significantly associated with an increased risk of developing breast cancer compared to the genotype TT/TT using RFLP-PCR. DISCUSSION AND CONCLUSION: Our findings suggest that polymorphism rs10573247 may contribute to the risk of breast cancer through the functional effect of this polymorphism on miRNA binding.

The emerging role and mechanism of HMGA2 in breast cancer.

High mobility group AT-hook 2 (HMGA2) is a member of the non-histone chromosomal high mobility group (HMG) protein family, which participate in embryonic development and other biological processes. HMGA2 overexpression is associated with breast cancer (BC) cell growth, proliferation, metastasis, and drug resistance. Furthermore, HMGA2 expression is positively associated with poor prognosis of patients with BC, and inhibiting HMGA2 signaling can stimulate BC cell progression and metastasis. In this review, we focus on HMGA2 expression changes in BC tissues and multiple BC cell lines. Wnt/ß-catenin, STAT3, CNN6, and TRAIL-R2 proteins are upstream mediators of HMGA2 that can induce BC invasion and metastasis. Moreover, microRNAs (miRNAs) can suppress BC cell growth, invasion, and metastasis by inhibiting HMGA2 expression. Furthermore, long noncoding RNAs (LncRNAs) and circular RNAs (CircRNAs) mainly regulate HMGA2 mRNA and protein expression levels by sponging miRNAs, thereby promoting BC development. Additionally, certain small molecule inhibitors can suppress BC drug resistance by reducing HMGA2 expression. Finally, we summarize findings demonstrating that HMGA2 siRNA and HMGA2 siRNA-loaded nanoliposomes can suppress BC progression and metastasis.

Chromatin modifier Hmga2 promotes adult hematopoietic stem cell function and blood regeneration in stress conditions.

The molecular mechanisms governing the response of hematopoietic stem cells (HSCs) to stress insults remain poorly defined. Here, we investigated effects of conditional knock-out or overexpression of Hmga2 (High mobility group AT-hook 2), a transcriptional activator of stem cell genes in fetal HSCs. While Hmga2 overexpression did not affect adult hematopoiesis under homeostasis, it accelerated HSC expansion in response to injection with 5-fluorouracil (5-FU) or in vitro treatment with TNF-α. In contrast, HSC and megakaryocyte progenitor cell numbers were decreased in Hmga2 KO animals. Transcription of inflammatory genes was repressed in Hmga2-overexpressing mice injected with 5-FU, and Hmga2 bound to distinct regions and chromatin accessibility was decreased in HSCs upon stress. Mechanistically, we found that casein kinase 2 (CK2) phosphorylates the Hmga2 acidic domain, promoting its access and binding to chromatin, transcription of anti-inflammatory target genes, and the expansion of HSCs under stress conditions. Notably, the identified stress-regulated Hmga2 gene signature is activated in hematopoietic stem progenitor cells of human myelodysplastic syndrome patients. In sum, these results reveal a TNF-α/CK2/phospho-Hmga2 axis controlling adult stress hematopoiesis.

Dysregulation of TCONS_00006091 contributes to the elevated risk of oral squamous cell carcinoma by upregulating SNAI1, IRS and HMGA2.

In this study, we aimed to study the role of TCONS_00006091 in the pathogenesis of oral squamous cellular carcinoma (OSCC) transformed from oral lichen planus (OLP). This study recruited 108 OSCC patients which transformed from OLP as the OSCC group and 102 OLP patients with no sign of OSCC as the Control group. ROC curves were plotted to measure the diagnostic values of TCONS_00006091, miR-153, miR-370 and let-7g, and the changes in gene expressions were measured by RT-qPCR. Sequence analysis and luciferase assays were performed to analyze the molecular relationships among these genes. Cell proliferation and apoptosis were observed via MTT and FCM. TCONS_00006091 exhibited a better diagnosis value for OSCC transformed from OLP. OSCC group showed increased TCONS_00006091 expression and decreased expressions of miR-153, miR-370 and let-7g. The levels of SNAI1, IRS and HMGA2 was all significantly increased in OSCC patients. And TCONS_00006091 was found to sponge miR-153, miR-370 and let-7g, while these miRNAs were respectively found to targe SNAI1, IRS and HMGA2. The elevated TCONS_00006091 suppressed the expressions of miR-153, miR-370 and let-7g, leading to the increased expression of SNAI1, IRS and HMGA2. Also, promoted cell proliferation and suppressed apoptosis were observed upon the over-expression of TCONS_00006091. This study demonstrated that the expressions of miR-153, miR-370 and let-7g were down-regulated by the highly expressed TCONS_00006091 in OSCC patients, which accordingly up-regulated the expressions of SNAI1, IRS and HMGA2, resulting in the promoted cell proliferation and suppressed cell apoptosis.

High glucose promotes atherosclerosis by regulating miRNA let7d-5p level.

BACKGROUND: MiRNA let7d-5p has been recently reported to be abnormally expressed in diabetes-associated atherosclerosis (AS). However, it still remains unknown how let7d-5p contributes to the process of atherosclerosis. METHODS: Twenty fresh tissues and a total of 28 wax block specimens from carotid endarterectomy procedures were obtained from the Luoyang Central Hospital affiliated to Zhengzhou University. The expression of let7d-5p was assessed using quantitative RT-PCR (qRT-PCR). A series of in vitro experiments was used to determine the roles of let7d-5p knockdown and overexpression in vascular smooth muscle cells (VSMCs). RESULTS: We discovered that the carotid plaques from diabetic patients had lower expression levels of miR let7d-5p. In VSMCs, the expression of miRNA let7d-5p was significantly lower in high glucose conditions compared with low glucose situations. The proliferation and migration of VSMCs were also inhibited by the overexpression of let7d-5p, whereas the opposite was true when let7d-5p was inhibited, according to gain and loss of function studies. Mechanically, let7d-5p might activate the GSK3ß/ß-catenin signaling pathway via binding to the high mobility group AT-Hook 2 (HMGA2) mRNA in VSMCs. Additionally, GLP-1RA liraglutide may prevent the migration and proliferation of VSMCs by raising let7d-5p levels. CONCLUSIONS: High glucose stimulated the proliferation and migration of VSMCs by regulating the let7d-5p/HMGA2/GSK3ß/ß-catenin pathway, and liraglutide may slow atherosclerosis by increasing the levels of miR let7d-5p.

Characterization of HMGA2 variants expands the spectrum of Silver-Russell syndrome.

Silver-Russell syndrome (SRS) is a heterogeneous disorder characterized by intrauterine and postnatal growth retardation. HMGA2 variants are a rare cause of SRS and its functional role in human linear growth is unclear. Patients with suspected SRS negative for 11p15LOM/mUPD7 underwent whole-exome and/or targeted-genome sequencing. Mutant HMGA2 protein expression and nuclear localization were assessed. Two Hmga2-knockin mouse models were generated. Five clinical SRS patients harbored HMGA2 variants with differing functional impacts: 2 stop-gain nonsense variants (c.49G>T, c.52C>T), c.166A>G missense variant, and 2 frameshift variants (c.144delC, c.145delA) leading to an identical, extended-length protein. Phenotypic features were highly variable. Nuclear localization was reduced/absent for all variants except c.166A>G. Homozygous knockin mice recapitulating the c.166A>G variant (Hmga2K56E) exhibited a growth-restricted phenotype. An Hmga2Ter76-knockin mouse model lacked detectable full-length Hmga2 protein, similarly to patient 3 and 5 variants. These mice were infertile, with a pygmy phenotype. We report a heterogeneous group of individuals with SRS harboring variants in HMGA2 and describe the first Hmga2 missense knockin mouse model (Hmga2K56E) to our knowledge causing a growth-restricted phenotype. In patients with clinical features of SRS but negative genetic screening, HMGA2 should be included in next-generation sequencing testing approaches.

Identifying Hmga2 preserving visual function by promoting a shift of Müller glia cell fate in mice with acute retinal injury.

BACKGROUND: Unlike in lower vertebrates, Müller glia (MG) in adult mammalian retinas lack the ability to reprogram into neurons after retinal injury or degeneration and exhibit reactive gliosis instead. Whether a transition in MG cell fate from gliosis to reprogramming would help preserve photoreceptors is still under exploration. METHODS: A mouse model of retinitis pigmentosa (RP) was established using MG cell lineage tracing mice by intraperitoneal injection of sodium iodate (SI). The critical time point for the fate determination of MG gliosis was determined through immunohistochemical staining methods. Then, bulk-RNA and single-cell RNA seq techniques were used to elucidate the changes in RNA transcription of the retina and MG at that time point, and new genes that may determine the fate transition of MG were screened. Finally, the selected gene was specifically overexpressed in MG cells through adeno-associated viruses (AAV) in the mouse RP model. Bulk-RNA seq technique, immunohistochemical staining methods, and visual function testing were used to elucidate and validate the mechanism of new genes function on MG cell fate transition and retinal function. RESULTS: Here, we found the critical time point for MG gliosis fate determination was 3 days post SI injection. Hmga2 was screened out as a candidate regulator for the cell fate transition of MG. After retinal injury caused by SI, the Hmga2 protein is temporarily and lowly expressed in MG cells. Overexpression of Hmga2 in MG down-regulated glial cell related genes and up-regulated photoreceptor related genes. Besides, overexpressing Hmga2 exclusively to MG reduced MG gliosis, made MG obtain cone's marker, and retained visual function in mice with acute retinal injury. CONCLUSION: Our results suggested the unique reprogramming properties of Hmga2 in regulating the fate transition of MG and neuroprotective effects on the retina with acute injury. This work uncovers the reprogramming ability of epigenetic factors in MG.

Effects of HMGA2 on the biological characteristics and stemness acquisition of gastric cancer cells.

BACKGROUND AND STUDY AIMS: The high mobility group A2 (HMGA2), a nonhistone nuclear binding protein, modulates transcription by altering the chromatin architecture of the target gene DNA in its specific AT-hooks region. HMGA2 overexpression has been observed in embryonic tissue and many malignant neoplasms. This study sought to verify whether HMGA2 plays a role in the biological functions of gastric cancer cells, such as cell proliferation, invasiveness, migration, and stem cell acquisition, and to provide some ideas for further research on the metastatic mechanism of gastric cancer. PATIENTS AND METHODS: HMGA2's effects on the proliferation, invasiveness, and migration capabilities of gastric cancer cells were individually detected by BrdU, Transwell, and wound healing assays. Western blotting and immunofluorescence were used to evaluate whether HMGA2 could promote the acquisition of gastric cancer cells. Biostatistical analyses were performed using SPSS 17.0 for Windows. RESULTS: HMGA2 expression levels in gastric cancer cell lines were significantly higher than those in human immortalized gastric epithelial cell lines (p < 0.01). Gastric cancer cell proliferation was inhibited when HMGA2 was overexpressed (p < 0.05). The invasiveness and migration capabilities of gastric cancer cells with HMGA2 overexpression were enhanced more than those of the corresponding control groups (p < 0.05). HMGA2 overexpression promotes the stemness acquisition of stem cells from gastric cancer cells. CONCLUSIONS: This study verified that the HMGA2 structural transcription factor promotes invasiveness, migration, and acquisition of gastric cancer cells. Furthermore, our findings provide significant insight for further research on the metastatic mechanism of gastric cancer.