A+T rich interaction domain protein 3a (Arid3a) impairs Mertk-mediated efferocytosis in cholestasis.

BACKGROUND & AIMS: Macrophages are key elements in the pathogenesis of cholestatic liver diseases. Arid3a plays a prominent role in the biologic properties of hematopoietic stem cells, B lymphocytes and tumor cells, but its ability to modulate macrophage function during cholestasis remains unknown. METHODS: Gene and protein expression and cellular localization were assessed by q-PCR, immunohistochemistry, immunofluorescence staining and flow cytometry. We generated myeloid-specific Arid3a knockout mice and established three cholestatic murine models. The transcriptome was analyzed by RNA-seq. A specific inhibitor of the Mertk receptor was used in vitro and in vivo. Promoter activity was determined by chromatin immunoprecipitation-seq against Arid3a and a luciferase reporter assay. RESULTS: In cholestatic murine models, myeloid-specific deletion of Arid3a alleviated cholestatic liver injury (accompanied by decreased accumulation of macrophages). Arid3a-deficient macrophages manifested a more reparative phenotype, which was eliminated by in vitro treatment with UNC2025, a specific inhibitor of the efferocytosis receptor Mertk. Efferocytosis of apoptotic cholangiocytes was enhanced in Arid3a-deficient macrophages via upregulation of Mertk. Arid3a negatively regulated Mertk transcription by directly binding to its promoter. Targeting Mertk in vivo effectively reversed the protective phenotype of Arid3a deficiency in macrophages. Arid3a was upregulated in hepatic macrophages and circulating monocytes in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Mertk was correspondingly upregulated and negatively correlated with Arid3a expression in PBC and PSC. Mertk+ cells were located in close proximity to cholangiocytes, while Arid3a+ cells were scattered among immune cells with greater spatial distances to hyperplastic cholangiocytes in PBC and PSC. CONCLUSIONS: Arid3a promotes cholestatic liver injury by impairing Mertk-mediated efferocytosis of apoptotic cholangiocytes by macrophages during cholestasis. The Arid3a-Mertk axis is a promising novel therapeutic target for cholestatic liver diseases. IMPACT AND IMPLICATIONS: Macrophages play an important role in the pathogenesis of cholestatic liver diseases. This study reveals that macrophages with Arid3a upregulation manifest a pro-inflammatory phenotype and promote cholestatic liver injury by impairing Mertk-mediated efferocytosis of apoptotic cholangiocytes during cholestasis. Although we now offer a new paradigm to explain how efferocytosis is regulated in a myeloid cell autonomous manner, the regulatory effects of Arid3a on chronic liver diseases remain to be further elucidated.

ARID3A plays a key regulatory role in palmitic acid-stimulated milk fat synthesis in mouse mammary epithelial cells.

Palmitic acid (PA) can stimulate milk fat synthesis in mammary gland, but the specific mechanism is still unclear. In our research, we aim to explore the role and corresponding mechanism of AT-rich interaction domain 3A (ARID3A) in milk fat synthesis stimulated by PA. We found that ARID3A protein level in mouse mammary gland tissues during lactation was much higher than that during puberty and involution. ARID3A knockdown and gene activation showed that ARID3A stimulated the synthesis of triglycerides and cholesterol in HC11 cells, secretion of free fatty acids from cells and lipid droplet formation in cells. ARID3A also promoted the expression and maturation of SREBP1 in HC11 cells. PA stimulated ARID3A protein expression and SREBP1 expression and maturation in a dose-dependent manner, and the PI3K specific inhibitor LY294002 blocked the stimulation of PA on ARID3A expression. ARID3A knockdown blocked the stimulation of PA on SREBP1 protein expression and maturation. We further showed that ARID3A was localized in the nucleus and PA stimulated this localization, and ARID3A knockdown blocked the stimulation of PA on the mRNA expression of SREBP1. To sum up, our data reveal that ARID3A is a key mediator for PA to promote SREBP1 mRNA expression and stimulate milk fat synthesis in mammary epithelial cells.

ARID3a from the ARID family: structure, role in autoimmune diseases and drug discovery.

The AT-rich interaction domain (ARID) family of DNA-binding proteins is a group of transcription factors and chromatin regulators with a highly conserved ARID domain that recognizes specific AT-rich DNA sequences. Dysfunction of ARID family members has been implicated in various human diseases including cancers and intellectual disability. Among them, ARID3a has gained increasing attention due to its potential involvement in autoimmunity. In this article we provide an overview of the ARID family, focusing on the structure and biological functions of ARID3a. It explores the role of ARID3a in autoreactive B cells and its contribution to autoimmune diseases such as systemic lupus erythematosus and primary biliary cholangitis. Furthermore, we also discuss the potential for drug discovery targeting ARID3a and present a plan for future research in this field.

Comprehensive analysis identified a reduction in ATP1A2 mediated by ARID3A in abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is characterized by abdominal aorta dilatation and progressive structural impairment and is usually an asymptomatic and potentially lethal disease with a risk of rupture. To investigate the underlying mechanisms of AAA initiation and progression, seven AAA datasets related to human and mice were downloaded from the GEO database and reanalysed in the present study. After comprehensive bioinformatics analysis, we identified the enriched pathways associated with inflammation responses, vascular smooth muscle cell (VSMC) phenotype switching and cytokine secretion in AAA. Most importantly, we identified ATPase Na+ /K+ transporting subunit alpha 2 (ATP1A2) as a key gene that was significantly decreased in AAA samples of both human and mice; meanwhile, its reduction mainly occurred in VSMCs of the aorta; this finding was validated by immunostaining and Western blot in human and mouse AAA samples. Furthermore, we explored the potential upstream transcription factors (TFs) that regulate ATP1A2 expression. We found that the TF AT-rich interaction domain 3A (ARID3A) bound the promoter of ATP1A2 to suppress its expression. Our present study identified the ARID3A-ATP1A2 axis as a novel pathway in the pathological processes of AAA, further elucidating the molecular mechanism of AAA and providing potential therapeutic targets for AAA.

ARID3A promotes the chemosensitivity of colon cancer by inhibiting AKR1C3.

ARID3A is upregulated in colorectal cancer and can promote the proliferation and metastasis of cancer cells. However, patients with higher level of ARID3A have a better prognosis. This study aimed to uncover the mechanism by which ARID3A benefits the prognosis of colon cancer. Our results indicated that ARID3A upregulation enhanced the chemosensitivity of colon cancer cells to 5-fluorouracil (5-FU), whereas ARID3A downregulation inhibited the chemosensitivity of colon cancer cells to 5-FU. Through database analysis, we found that AKR1C3, a drug resistance-related gene, was the target of ARID3A. Moreover, AKR1C3 was downregulated in colon cancer tissues compared to normal tissues. Next, we assessed the interaction between AKR1C3 and ARID3A, and found that ARID3A inhibited the transcription of AKR1C3, leading to the downregulation of AKR1C3 in colon cancer cells. We also verified that AKR1C3 inhibited the chemosensitivity of colon cancer cells to 5-FU. Moreover, patients with higher ratio of ARID3A to AKR1C3 had a better prognosis. This study suggested that ARID3A promoted chemosensitivity of colon cancer cells by inhibiting AKR1C3 in colon cancer. The ratio of ARID3A to AKR1C3 is a good marker to predict the prognosis of colon cancer patients.

Arid3a is essential to execution of the first cell fate decision via direct embryonic and extraembryonic transcriptional regulation.

Despite their origin from the inner cell mass, embryonic stem (ES) cells undergo differentiation to the trophectoderm (TE) lineage by repression of the ES cell master regulator Oct4 or activation of the TE master regulator Caudal-type homeobox 2 (Cdx2). In contrast to the in-depth studies of ES cell self-renewal and pluripotency, few TE-specific regulators have been identified, thereby limiting our understanding of mechanisms underlying the first cell fate decision. Here we show that up-regulation and nuclear entry of AT-rich interactive domain 3a (Arid3a) drives TE-like transcriptional programs in ES cells, maintains trophoblast stem (TS) cell self-renewal, and promotes further trophoblastic differentiation both upstream and independent of Cdx2. Accordingly, Arid3a(-/-) mouse post-implantation placental development is severely impaired, resulting in early embryonic death. We provide evidence that Arid3a directly activates TE-specific and trophoblast lineage-specific genes while directly repressing pluripotency genes via differential regulation of epigenetic acetylation or deacetylation. Our results identify Arid3a as a critical regulator of TE and placental development through execution of the commitment and differentiation phases of the first cell fate decision.

ARID3A regulates autophagy related gene BECN1 expression and inhibits proliferation of osteosarcoma cells.

Osteosarcoma (OS) is the most common primary malignant bone tumor which has unclear pathobiology. Hence, enlightening the exact molecular mechanism underlying osteosarcoma progression is crucial for developing new treatment strategies. One member of the ARID family of DNA binding proteins is ARID3A that is implicated in osteosarcoma pathogenesis. ARID3A could bind E2F1 and regulate the transcription of E2F1 targets. At the same time, BECN1 is a well-characterized autophagy regulator gene that is a direct target of E2F1. The present study aimed to investigate the effect of ARID3A on the expression of BECN1 in osteosarcoma cells. First, we determined gene expression levels of ARID3A, BECN1, and E2F1 in U-2 OS by qPCR and confirmed with online datasets from GEO database. In addition, the prognostic value of these genes was also evaluated from Kaplan-Meier plotter database. Next, ARID3A was overexpressed and silenced in order to investigate the effect of ARID3A on BECN1 expression and proliferation of U-2 OS cells. Our results demonstrated that BECN1 was negatively correlated with E2F1 and positively correlated with ARID3A based on initial expression and prognostic effect in OS. Overexpression of ARID3A upregulated BECN1 while silenced ARID3A downregulated BECN1 expression in U-2 OS cells. Additionally, silencing of ARID3A promoted colony formation and proliferation, whereas overexpression of ARID3A suppressed colony formation and proliferation of U-2 OS cells. Taken together, these results indicate that ARID3A could function as tumor suppressor and affect the expression level of BECN1 in U-2 OS cells.

MiR-574-5p promotes the differentiation of human cardiac fibroblasts via regulating ARID3A.

Cardiac fibrosis after myocardial infarction (MI) is mainly associated with cardiac fibroblasts and its differentiation is the key pathological process. However, the cellular mechanism of fibroblast-to-myofibroblast conversion has not been clarified and a deeper mechanistic understanding is needed. We found that miR-574-5p was up-regulated in TGF-ß-induced myofibroblast differentiation. Silencing transiently miR-574-5p in HCFs, we found that suppression of miR-574-5p decreased myofibroblasts differentiation as validated by expression levels of fibrosis related genes, EDU imaging assay, wound healing assay and transwell assays. Conversely, overexpression of miR-574-5p displayed opposite results. ARID3A was verified as a direct target gene of miR-574-5p and decreased level of ARID3A forced fibroblast-to-myofibroblast differentiation of TGF-ß-induced HCFs. Our data suggests that miR-574-5p plays a pivotal role in human cardiac fibroblasts (HCFs) myofibroblast differentiation and demonstrates that miR-574-5p and arid3a may be a novel therapeutic target for cardiac fibrosis.

TLR engagement induces ARID3a in human blood hematopoietic progenitors and modulates IFNα production.

The DNA binding protein AT-rich interacting domain 3a (ARID3a)2 is expressed in healthy human hematopoietic cord blood progenitors where its modulation influences myeloid versus B lineage development. ARID3a is also variably expressed in subsets of adult peripheral blood hematopoietic progenitors where the consequences of ARID3a expression are unknown. In B lymphocytes, Toll-like receptor (TLR)3 signaling induces ARID3a expression in association with Type I interferon inflammatory cytokines. We hypothesized that TLR ligand stimulation of peripheral blood hematopoietic progenitors would induce ARID3a expression resulting in interferon production, and potentially influencing lineage decisions. Our data revealed that the TLR9 agonist CpG induces ARID3a expression with interferon alpha synthesis in human hematopoietic progenitors. However, ARID3a expression was not associated with increased B lineage development. These results demonstrate the need for further experiments to better define how pathogen-associated responses influence hematopoiesis.

Long noncoding RNA ERICD interacts with ARID3A via E2F1 and regulates migration and proliferation of osteosarcoma cells.

Long noncoding RNA (lncRNA) dysregulation is known to be taking part in majority of cancers, including osteosarcoma. In one of our previous studies, we showed that lncRNA MEG3 is being regulated by microRNA-664a (miR-664a) suppresses the migratory potential of osteosarcoma cells (U-2OS). We now report a novel lncRNA, namely, ERICD, which is linked to the transcription factor AT-rich interaction domain 3A (ARID3A) in U-2OS cells. We show that ARID3A binds to ERICD and indirectly interacts with each other via the E2F transcription factor 1 (E2F1). Furthermore, small interfering RNA (siRNA)-mediated knockdown of ERICD inhibited cell migration, formation of colonies, and proliferation in U-2OS cells. Overexpression of ARID3A inhibited cell migration, colony formation, and proliferation, whereas siRNA-mediated knockdown of ARID3A promoted cell migration, colony formation, and proliferation. Our findings indicate that ARID3A and lncRNA ERICD have plausible tumor suppressive and oncogenic functions, respectively, in osteosarcoma. Our data demonstrate the converse interaction between ARID3A and lncRNA ERICD that target DNA-binding proteins and dysregulation of their expression through E2F1 augments osteosarcoma progression. The cell rescue experiment also indicated E2F1 to be involved in the regulation of ARID3A and ERICD.

ARID3a expression in human hematopoietic stem cells is associated with distinct gene patterns in aged individuals.

BACKGROUND: Immunologic aging leads to immune dysfunction, significantly reducing the quality of life of the elderly. Aged-related defects in early hematopoiesis result in reduced lymphoid cell development, functionally defective mature immune cells, and poor protective responses to vaccines and pathogens. Despite considerable progress understanding the underlying causes of decreased immunity in the elderly, the mechanisms by which these occur are still poorly understood. The DNA-binding protein ARID3a is expressed in a subset of human hematopoietic progenitors. Inhibition of ARID3a in bulk human cord blood CD34+ hematopoietic progenitors led to developmental skewing toward myeloid lineage at the expense of lymphoid lineage cells in vitro. Effects of ARID3a expression in adult-derived hematopoietic stem cells (HSCs) have not been analyzed, nor has ARID3a expression been assessed in relationship to age. We hypothesized that decreases in ARID3a could explain some of the defects observed in aging. RESULTS: Our data reveal decreased frequencies of ARID3a-expressing peripheral blood HSCs from aged healthy individuals compared with young donor HSCs. Inhibition of ARID3a in young donor-derived HSCs limits B lineage potential, suggesting a role for ARID3a in B lymphopoiesis in bone marrow-derived HSCs. Increasing ARID3a levels of HSCs from aged donors in vitro alters B lineage development and maturation. Finally, single cell analyses of ARID3a-expressing HSCs from young versus aged donors identify a number of differentially expressed genes in aged ARID3A-expressing cells versus young ARID3A-expressing HSCs, as well as between ARID3A-expressing and non-expressing cells in both young and aged donor HSCs. CONCLUSIONS: These data suggest that ARID3a-expressing HSCs from aged individuals differ at both molecular and functional levels compared to ARID3a-expressing HSCs from young individuals.

ARID3a gene profiles are strongly associated with human interferon alpha production.

Type I interferons (IFN) causes inflammatory responses to pathogens, and can be elevated in autoimmune diseases such as systemic lupus erythematosus (SLE). We previously reported unexpected associations of increased numbers of B lymphocytes expressing the DNA-binding protein ARID3a with both IFN alpha (IFNα) expression and increased disease activity in SLE. Here, we determined that IFNα producing low density neutrophils (LDNs) and plasmacytoid dendritic cells (pDCs) from SLE patients exhibit strong associations between ARID3a protein expression and IFNα production. Moreover, SLE disease activity indices correlate most strongly with percentages of ARID3a+ LDNs, but were also associated, less significantly, with IFNα expression in LDNs and pDCs. Hierarchical clustering and transcriptome analyses of LDNs and pDCs revealed SLE patients with low ARID3a expression cluster with healthy controls and identified gene profiles associated with increased proportions of ARID3a- and IFNα-expressing cells of each type. These data identify ARID3a as a potential transcription regulator of IFNα-related inflammatory responses and other pathways important for SLE disease activity.

Human effector B lymphocytes express ARID3a and secrete interferon alpha.

Previously, we determined that enhanced disease activity in patients with systemic lupus erythematosus (SLE) was associated with dramatic increases in numbers of B lymphocytes expressing the transcription factor ARID3a. Our data now indicate ARID3a is important for interferon alpha (IFNa) expression and show a strong association between ARID3a expression and transcription of genes associated with lupus IFN signatures. Furthermore, both ARID3a and IFNa production were elicited in healthy control B cells upon stimulation with the TLR 9 agonist, CpG. Importantly, secretion of IFNa from ARID3a+ healthy B lymphocytes stimulated increased IFNa production in plasmacytoid dendritic cells. These data identify ARID3a+ B cells as a novel type of effector B cell, and link ARID3a expression in B lymphocytes to IFN-associated inflammatory responses in SLE.

A developmentally plastic adult mouse kidney cell line spontaneously generates multiple adult kidney structures.

Despite exciting new possibilities for regenerative therapy posed by the ability to induce pluripotent stem cells, recapitulation of three-dimensional kidneys for repair or replacement has not been possible. ARID3a-deficient mouse tissues generated multipotent, developmentally plastic cells. Therefore, we assessed the adult mouse ARID3a-/- kidney cell line, KKPS5, which expresses renal progenitor surface markers as an alternative cell source for modeling kidney development. Remarkably, these cells spontaneously developed into multicellular nephron-like structures in vitro, and engrafted into immunocompromised medaka mesonephros, where they formed mouse nephron structures. These data implicate KKPS5 cells as a new model system for studying kidney development.

Critical role of ARID3B in the expression of pro-apoptotic p53-target genes and apoptosis.

ARID3A and ARID3B are transcriptional targets of p53. Recently, it has been reported that ARID3A plays a critical role in the transcriptional activation of pro-arrest p21 in response to DNA damage. However, the role of ARID3B in the p53 regulatory pathway remains poorly understood. Here we show that ARID3A and ARID3B specifically bind to putative ARID3-binding sites in p53 target genes in vitro and in vivo. ARID3B and, to a lesser extent, ARID3A silencing blocked transcriptional activation of pro-apoptotic p53 target genes, such as PUMA, PIG3, and p53. Furthermore, ectopic ARID3B, to a lesser extent, ARID3A expression activated the pro-apoptotic gene expression, and only ARID3B induced apoptosis. Finally, ARID3B but not ARID3A silencing blocked apoptosis induction following DNA damage. These results indicated that, although ARID3B and ARID3A share overlapping functions, ARID3B play a key role in the expression of pro-apoptotic p53-target genes and apoptosis.

ARID3A enhances chemoresistance of pancreatic cancer via inhibiting PTEN-induced ferroptosis.

Currently, chemotherapy remains occupying a pivotal place in the treatment of pancreatic ductal adenocarcinoma (PDAC). Nonetheless, the emergence of drug resistance in recent years has limited the clinical efficacy of chemotherapeutic agents, especially gemcitabine (GEM). Through bioinformatics analysis, AT-rich Interactive Domain-containing Protein 3A (ARID3A), one of transcription factors, is discovered to possibly participate in this progress. This study thoroughly investigates the potential role of ARID3A in the malignant progression and GEM chemoresistance of PDAC and explores the underlying mechanisms. The results indicate that ARID3A knockdown suppresses tumor development and enhances the sensitivity of PDAC cells to GEM in vitro and vivo. Mechanically, CUT&Tag profiling sequencing, RNA-sequencing and functional studies demonstrates that decreased ARID3A expression alleviates the transcriptional inhibition of phosphatase and tensin homolog (PTEN), consequently leading to glutathione peroxidase 4 (GPX4) depletion and increased lipid peroxidation levels. Activated ferroptosis induced by the inhibition of GPX4 subsequently restricts tumor progression and reduces GEM resistance in PDAC. This research identifies the ferroptosis regulatory pathway of ARID3A-PTEN-GPX4 axis and reveals its critical role in driving the progression and chemoresistance of pancreatic cancer. Notably, both inhibition of ARID3A and enhancement of ferroptosis can increase chemosensitivity to GEM, which offers a promising opportunity for developing therapeutic strategies to combat acquired chemotherapy resistance in pancreatic cancer.

ARID3A and ARID3B exert direct regulatory control over the long non-coding RNAs (lncRNAs) MALAT1 and NORAD within the context of non-small cell lung cancer (NSCLC).

Lung cancer, known for its high mortality rates and poor prognosis, remains one of the most prevalent cancer types. Early detection and effective treatment methods are crucial for improving survival rates. Non-small cell lung cancer (NSCLC) accounts for approximately 85 % of all lung cancer cases. Long non-coding RNAs (lncRNAs), which play vital roles in various biological processes, have been implicated in the development of cancer and can impact key therapeutic targets in different cancer types. In NSCLC, the dysregulation of specific lncRNAs, such as MALAT1 and NORAD, has been associated with neoplastic initiation, progression, metastasis, tumor angiogenesis, chemoresistance, and genomic instability. Both MALAT1 and NORAD directly regulate the expression of the transcription factor E2F1, thereby influencing cell cycle progression. Additionally, MALAT1 has been reported to affect the expression of p53 target genes, leading to cell cycle progression through the repression of p53 promoter activity. NORAD, on the other hand, is indirectly regulated by p53. The AT-rich interaction domain (ARID) family of DNA-binding proteins, particularly ARID3A and ARID3B, are involved in various biological processes such as cell proliferation, differentiation, and development. They also play significant roles in E2F-dependent transcription and are transcriptional targets of p53. The intricate balance between promoting cellular proliferation through the pRB-E2F pathway and inducing growth arrest through the p53 pathway underscores the crucial regulatory role of ARID3A, ARID3B, and their interaction with lncRNAs MALAT1 and NORAD. In this study, we aimed to investigate the potential interactive and functional connections among ARID3A, ARID3B, MALAT1, and NORAD in NSCLC, considering their involvement in the pRB-E2F and p53 pathways. Our findings strongly suggest that ARID3A and ARID3B play a regulatory role in controlling MALAT1 and NORAD in NSCLC. Specifically, our study demonstrates that the activities of MALAT1 and NORAD were markedly increased upon the overexpression of ARID3A and ARID3B. Therefore, we can conclude that ARID3A and ARID3B likely contribute significantly to the oncogenic functions of MALAT1 and NORAD in NSCLC. Consequently, targeting ARID3A and ARID3B could hold promise as a therapeutic approach in NSCLC, given their direct control over the expression of MALAT1 and NORAD.

Several genetic variants associated with systemic sclerosis in a Chinese Han population.

BACKGROUND: Systemic sclerosis (SSc) is a connective tissue disease with ethnic differences. Single-nucleotide polymorphisms (SNPs) in the ARID3A, CXCR5, and TNFSF8 genes have been reported to be associated with various autoimmune diseases. The aim of this study was to investigate the association between these SNPs and susceptibility to SSc in a Chinese Han population. METHODS: A case-control study was conducted in 342 patients with SSc and 694 ethnically matched healthy controls. SNPs in ARID3A, CXCR5, and TNFSF8 were genotyped using a Sequenom MassArray iPLEX system, and allele association analyses were performed using the PLINK v1.90 software. RESULTS: Our study demonstrated that the ARID3A rs10415976 G and CXCR5 rs77871618 T alleles were suggestively associated with patients with SSc (P = 0.049 and P = 0.024, respectively) and TNFSF8 rs1555457 T allele was strongly associated with SSc (P = 0.003). Patients carrying the ARID3A rs350146 TT and TNFSF8 rs1555457 TT genotypes had a significant increased risk of SSc (P = 0.03 and P = 0.004, respectively). Moreover, rs10415976, rs77871618, and rs1555457 were associated with SSc in an additive genetic model (P < 0.05). rs62132345 and rs1555457 were associated with SSc in the dominant genetic model (P < 0.05). rs350146 was associated with SSc in the recessive genetic model (P = 0.029). CONCLUSIONS: ARID3A rs10415976, ARID3A rs350146, and CXCR5 rs77871618 were suggestively associated with SSc and TNFSF8 rs1555457 was strongly associated with SSc in the Chinese Han population in this study. Key Points • This case-control study determined that ARID3A rs10415976, ARID3A rs350146 and CXCR5 rs77871618 were suggestively associated with SSc and TNFSF8 rs1555457 was strongly associated with SSc in the Chinese Han population. • The differences in these results compared with previous studies may be a result of ethnic and racial differences.

MiR-361-3p promotes tumorigenesis of osteosarcoma cells via targeting ARID3A.

MiR-361-3p has been reported in several types of human cancer. However, the expression profile and biological functions of miR-361-3p in osteosarcoma remain uncovered. The expression profiles of miR-361-3p in osteosarcoma tissues and cell lines were evaluated using RT-qPCR. In 88 osteosarcoma patients, survival analysis was performed using Kaplan-Meier curves; while prognostic significance of miR-361-3p was analyzed using Cox regression analysis. The effects of miR-361-3p on cell proliferation, migration and invasion capacities were analyzed using CCK-8 and transwell assays. The target genes of miR-361-3p were assessed using luciferase reporter assay, RT-qPCR, Western blot and rescue experiments. Xenograft assay was conducted to test tumor growth ability. MiR-361-3p was found to be upregulated in human osteosarcoma tissues and cell lines. The expression of miR-361-3p was observed to be closely associated with TNM stage and lung metastasis. High expression of miR-361-3p was found to be capable of predicting poor clinical prognosis in osteosarcoma patients. Whilst overexpression of miR-361-3p was demonstrated to promote the proliferation, migration and invasion of osteosarcoma cells; knockdown of miR-361-3p was shown to exhibit an opposite inhibitory effect. Bioinformatics analysis and luciferase reporter assays confirmed that ARID3A is a direct target of miR-361-3p. Functional assays demonstrated that osteosarcoma cell proliferation, migration and invasion were promoted by miR-361-3p via negative regulation of ARID3A. Finally, overexpression of ARID3A was shown to partially reverse the tumor-promoting effect of miR-361-3p. Besides, in vivo assays revealed that miR-361-3p overexpression facilitated tumor growth in nude mice. In conclusion, this study indicates that miR-361-3p is a crucial prognostic biomarker of osteosarcoma, and that targeting of miR-361-3p/ARID3A axis may be a promising strategy in osteosarcoma therapy.