Sex-Specific Response to A1BG Loss Results in Female Dilated Cardiomyopathy.

Background: Cardiac disease often manifests differently in terms of frequency and pathology between men and women. However, the mechanisms underlying these differences are not fully understood. The glycoprotein A1BG is necessary for proper cardiac function in females but not males. Despite this, the role of A1BG in the female heart remains poorly studied. Methods: To determine the sex differential function of A1BG, we generated a novel conditional A1bg allele and a novel conditional A1bg Rosa26 knockin allele. Histology, electrocardiography, transcriptional profiling (RNA-seq), transmission electron microscopy, western blot analyses, mass spectrometry, and immunohistochemistry were used to assess cardiac structure and function. Results: The study reveals that the absence of A1BG results in significant cardiac dysfunction in female but not male mice. Gene expression underscores that A1BG plays a critical role in metabolic processes and the integrity of intercalated discs in female cardiomyocytes. This dysfunction may be related to sex-specific A1BG cardiac interactomes and manifests as structural and functional alterations in the left ventricle indicative of dilated cardiomyopathy, thus suggesting a sex-specific requirement for A1BG in cardiac health. Conclusion: The loss of A1BG in cardiomyocytes leads to dilated cardiomyopathy in females, not males.

Exosome-derived lncRNA A1BG-AS1 attenuates the progression of prostate cancer depending on ZC3H13-mediated m6A modification.

BACKGROUND: Exosome-derived long non-coding RNAs (lncRNAs) and N6-methyladenosine (m6A) modifications of lncRNAs have been shown crucial functions in prostate cancer (PCa). Herein, we aim to investigate the detailed mechanism of exosome-derived lncRNA A1BG-AS1 in PCa process. METHODS: PCa cell exosomes were extracted, exosomal marker proteins (CD63, CD9) were detected utilizing western blotting, and exosomes with overexpressing A1BG-AS1 were co-cultured with targeted PCa cells. qRT-PCR was used to detect A1BG-AS1 expression and m6A methyltransferase ZC3H13 in PCa. Transwell, colony formation and CCK-8 assays were utilized to assess the invasion, migration, and proliferation ability of PCa cells. Then, we performed actinomycin D and MeRIP assays to analyze the regulatory effect of ZC3H13 on A1BG-AS1 mRNA stability and m6A modification level. RESULTS: We observed that A1BG-AS1 and ZC3H13 expression was restricted in PCa tumors. The invasion, proliferation and migratory capacities of PCa cells could be inhibited by up-regulating A1BG-AS1 or by co-culturing with exosomes that up-regulate A1BG-AS1. Additionally, ZC3H13 promoted stable A1BG-AS1 expression by regulating the m6A level of A1BG-AS1. CONCLUSION: Exosomal A1BG-AS1 was m6A-modified by the m6A methyltransferase ZC3H13 to stabilize expression and thus prevent PCa cell malignancy. These findings offer a possible target for clinical therapy of PCa.

A1BG-AS1 promotes the biological functions of osteosarcoma cells via regulating the microRNA-148a-3p/USP22 axis and stabilizing the expression of SIRT1 through deubiquitinase function.

BACKGROUND: The study aims to explore the role of A1BG antisense RNA 1 (A1BG-AS1), microRNA (miR)-148a-3p and ubiquitin-specific protease 22 (USP22) on osteosarcoma (OS) cell growth. RESEARCH DESIGN & METHODS: A1BG-AS1, miR-148a-3p, USP22, and silent information regulator 2 homolog 1 (SIRT1) levels in OS tissues and cells were determined. The effects of A1BG-AS1, miR-148a-3p, and USP22 on the biological functions of OS cells were examined by functional assays. In vivo assay was conducted to observe the effect of A1BG-AS1 on OS growth in vitro. The relationship of A1BG-AS1, miR-148a-3p, and USP22 was analyzed by bioinformatics analysis, RNA-fluorescence in situ hybridization, luciferase activity, and RNA binding protein immunoprecipitation assays. The relation between USP22 and SIRT1 was evaluated by immunoprecipitation. RESULTS: A1BG-AS1 and USP22 were highly expressed, and miR-148a-3p was lowly expressed in OS tissues and cells. Down-regulation of A1BG-AS1 and USP22 or up-regulation of miR-148a-3p impaired the malignant behaviors of OS cells. A1BG-AS1 sponged miR-148a-3p, and miR-148a-3p targeted USP22, thereby inhibiting USP22 expression. Up-regulating USP22 reversed the A1BG-AS1 suppression-induced phenotypic inhibition of OS cells. USP22 affected the biological functions of OS cells by deubiquitinating SIRT1. CONCLUSION: A1BG-AS1 facilitates the biological functions of OS cells via mediating the miR-148a-3p/USP22 axis.

Cardiac proteomics reveals sex chromosome-dependent differences between males and females that arise prior to gonad formation.

Sex disparities in cardiac homeostasis and heart disease are well documented, with differences attributed to actions of sex hormones. However, studies have indicated sex chromosomes act outside of the gonads to function without mediation by gonadal hormones. Here, we performed transcriptional and proteomics profiling to define differences between male and female mouse hearts. We demonstrate, contrary to current dogma, cardiac sex disparities are controlled not only by sex hormones but also through a sex-chromosome mechanism. Using Turner syndrome (XO) and Klinefelter (XXY) models, we find the sex-chromosome pathway is established by X-linked gene dosage. We demonstrate cardiac sex disparities occur at the earliest stages of heart formation, a period before gonad formation. Using these datasets, we identify and define a role for alpha-1B-glycoprotein (A1BG), showing loss of A1BG leads to cardiac defects in females, but not males. These studies provide resources for studying sex-biased cardiac disease states.

Long non-coding RNA A1BG-AS1 promotes tumorigenesis in breast cancer by sponging microRNA-485-5p and consequently increasing expression of FLOT1 expression.

The dysregulated long non-coding RNA A1BG antisense RNA 1 (A1BG-AS1) has been implicated in the oncogenicity of hepatocellular carcinoma. Using reverse transcription quantitative polymerase chain reaction in this study, we detected A1BG-AS1 expression in breast cancer and elucidated the regulatory functions and exact mechanisms of A1BG-AS1 in breast cancer cells. The regulatory functions of A1BG-AS1 were examined in vitro using the Cell Counting Kit-8 assay, flow cytometric, and Transwell migration and invasion assays and in vivo through tumor xenograft experiments. In addition, we performed bioinformatics analysis, luciferase reporter assay, RNA immunoprecipitation, and rescue experiments to verify the interaction among A1BG-AS1, microRNA-485-5p (miR-485-5p), and flotillin-1 (FLOT1) in breast cancer. We found A1BG-AS1 to be highly expressed in breast cancer tissues and cell lines. In terms of function, depleted A1BG-AS1 markedly suppressed cell proliferation, accelerated cell apoptosis, and hindered cell migration and invasion in breast cancer. Furthermore, A1BG-AS1 interference reduced tumor growth in vivo. Mechanistic investigations confirmed that A1BG-AS1 directly interacted with miR-485-5p as a molecular sponge. We demonstrated that FLOT1 is a direct target of miR-485-5p, which could be positively regulated by A1BG-AS1 by competing for miR-485-5p. Rescue experiments clearly showed that the downregulation of miR-485-5p and upregulation of FLOT1 were capable of reversing the anticancer activities of A1BG-AS1 deficiency in terms of breast cancer cell malignancy. A1BG-AS1 acts as a miR-485-5p sponge and subsequently increases FLOT1 expression in breast cancer cells, ultimately facilitating cancer progression. Hence, the A1BG-AS1/miR-485-5p/FLOT1 pathway might offer a novel therapeutic perspective for breast cancer.

Unraveling the LRC Evolution in Mammals: IGSF1 and A1BG Provide the Keys.

Receptors of the leukocyte receptor cluster (LRC) play a range of important functions in the human immune system. However, the evolution of the LRC remains poorly understood, even in m\ammals not to mention nonmammalian vertebrates. We conducted a comprehensive bioinformatics analysis of the LRC-related genes in the publicly available genomes of six species that represent eutherian, marsupial, and monotreme lineages of mammals. As a result, the LRCs of African elephant and armadillo were characterized, two new genes, IGSF1 and A1BG, were attributed to the LRC of eutherian mammals, the LRC gene content was substantially extended in the short-tailed opossum and Tasmanian devil and, finally, four LRC genes were identified in the platypus genome. These findings have for the first time provided a solid basis for inference of the LRC phylogeny across mammals. Our analysis suggests that the mammalian LRC family likely derived from two ancestral genes, which evolved in a lineage-specific manner by expansion/contraction, extensive exon shuffling, and sequence divergence. The striking structural and functional diversity of eutherian LRC molecules appears largely lineage specific. The only family member retained in all the three mammalian lineages is a collagen-binding receptor OSCAR. Strong sequence conservation of a transmembrane domain known to associate with FcRγ suggests an adaptive role of this domain subtype in the LRC evolution.

Proteomic alterations of HDL in youth with type 1 diabetes and their associations with glycemic control: a case-control study.

BACKGROUND: Patients with type 1 diabetes (T1DM) typically have normal or even elevated plasma high density lipoprotein (HDL) cholesterol concentrations; however, HDL protein composition can be altered without a change in cholesterol content. Alteration of the HDL proteome can result in dysfunctional HDL particles with reduced ability to protect against cardiovascular disease (CVD). The objective of this study was to compare the HDL proteomes of youth with T1DM and healthy controls (HC) and to evaluate the influence of glycemic control on HDL protein composition. METHODS: This was a cross-sectional case-control study. Blood samples were obtained from patients with T1DM and HC. HDL was isolated from plasma by size-exclusion chromatography and further purified using a lipid binding resin. The HDL proteome was analyzed by mass spectrometry using label-free SWATH peptide quantification. RESULTS: Samples from 26 patients with T1DM and 13 HC were analyzed and 78 HDL-bound proteins were measured. Youth with T1DM had significantly increased amounts of complement factor H related protein 2 (FHR2; adjusted P < 0.05), compared to HC. When patients were analyzed based on glucose control, several trends emerged. Some proteins were altered in T1DM and not influenced by glycemic control (e.g. FHR2) while others were partially or completely corrected with optimal glucose control (e.g. alpha-1-beta glycoprotein, A1BG). In a subgroup of poorly controlled T1DM patients, inter alpha trypsin inhibitor 4 (ITIH4) was dramatically elevated (P < 0.0001) and this was partially reversed in patients with optimal glucose control. Some proteins including complement component C3 (CO3) and albumin (ALB) were significantly different only in T1DM patients with optimal glucose control, suggesting a possible effect of exogenous insulin. CONCLUSIONS: Youth with T1DM have proteomic alterations of their HDL compared to HC, despite similar concentration of HDL cholesterol. The influence of these compositional changes on HDL function are not yet known. Future efforts should focus on investigating the role of these HDL associated proteins in regard to HDL function and their role in CVD risk in patients with T1DM. Trial registration NCT02275091.

lncRNA A1BG-AS1 suppresses proliferation and invasion of hepatocellular carcinoma cells by targeting miR-216a-5p.

Extensive evidence indicate that long noncoding RNAs (lncRNAs) regulates the tumorigenesis and progression of hepatocellular carcinoma (HCC). However, the expression and biological function of lncRNA A1BG antisense RNA 1 (A1BG-AS1) were poorly known in HCC. Here, we found the underexpression of A1BG-AS1 in HCC via analysis of The Cancer Genome Atlas database. Further analyses confirmed that A1BG-AS1 expression in HCC was markedly lower than that in noncancerous tissues based on our HCC cohort. Clinical association analysis revealed that low A1BG-AS1 expression correlated with poor prognostic features, such as microvascular invasion, high tumor grade, and advanced tumor stage. Follow-up data indicated that low A1BG-AS1 level evidently correlated with poor clinical outcomes of HCC patients. Moreover, forced expression of A1BG-AS1 repressed proliferation, migration, and invasion of HCC cells in vitro. Conversely, A1BG-AS1 knockdown promoted these malignant behaviors in HepG2 cells. Mechanistically, A1BG-AS1 functioned as a competing endogenous RNA by directly sponging miR-216a-5p in HCC cells. Notably, miR-216a-5p restoration rescued A1BG-AS1 attenuated proliferation, migration and invasion of HCCLM3 cells. A1BG-AS1 positively regulated the levels of phosphatase and tensin homolog and SMAD family member 7, which were reduced by miR-216a-5p in HCC cells. Altogether, we conclude that A1BG-AS1 exerts a tumor suppressive role in HCC progression.

A1BG and C3 are overexpressed in patients with cervical intraepithelial neoplasia III.

The present study aimed to analyze sera proteins in females with cervical intraepithelial neoplasia, grade III (CIN III) and in healthy control females, in order to identify a potential biomarker which detects lesions that have a greater probability of cervical transformation. The present study investigated five sera samples from females who were Human Papilloma Virus (HPV) 16+ and who had been histopathologically diagnosed with CIN III, as well as five sera samples from healthy control females who were HPV-negative. Protein separation was performed using two-dimensional (2D) gel electrophoresis and the proteins were stained with Colloidal Coommassie Blue. Quantitative analysis was performed using ImageMaster 2D Platinum 6.0 software. Peptide sequence identification was performed using a nano-LC ESIMS/MS system. The proteins with the highest Mascot score were validated using western blot analysis in an additional 55 sera samples from the control and CIN III groups. The eight highest score spots that were found to be overexpressed in the CIN III sera group were identified as α-1-B glycoprotein (A1BG), complement component 3 (C3), a pro-apolipoprotein, two apolipoproteins and three haptoglobins. Only A1BG and C3 were validated using western blot analysis, and the bands were compared between the two groups using densitometry analysis. The relative density of the bands of A1BG and C3 was found to be greater in all of the serum samples from the females with CIN III, compared with those of the individuals in the control group. In summary, the present study identified two proteins whose expression was elevated in females with CIN III, suggesting that they could be used as biomarkers for CIN III. However, further investigations are required in order to assess the expression of A1BG and C3 in different pre-malignant lesions.