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Artesunate (ART) is a derivative of artemisinin and has anti-inflammatory, anti-tumor, and anti-angiogenic properties. Although ART has been implicated in osteoarthritis (OA), the mechanism needs to be further dissected. Here, we explored the effects of ART on the development of OA and the underlying mechanism using destabilization of the medial meniscus (DMM) surgical instability model. Mice with OA were developed using DMM and treated with ART. The pathological morphology of knee joint tissues was examined, and the degeneration of joint cartilage was assessed. Mouse knee chondrocytes were isolated and induced with IL-1ß, followed by ART treatment. ART alleviates OA in mice by elevating ubiquitin carboxyl-terminal hydrolase 7 (USP7) expression, and USP7 inhibitor (P22077) treatment mitigated the protective effects of ART on chondrocytes. We also showed that USP7 mediated the deubiquitination of forkhead box protein O1 (FoxO1), while FoxO1 alleviated chondrocyte injury. In addition, FoxO1 promoted metastasis-associated protein MTA1 (MTA1) transcription, and downregulation of MTA1 exacerbated chondrocyte injury. Our study identifies that USP7/FoxO1/MTA1 is a key signaling cascade in the treatment of ART on OA.

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Aging is an inevitable law of the process of life during which many physiological functions change. Brain aging is an important mechanism in the occurrence and development of degenerative diseases of the central nervous system. ß-Hydroxybutyrate (BHBA) is a water-soluble, endogenous small-molecule ketone that can cross the blood-brain barrier and induce neuroprotective effects. This study aimed to investigate the effects of BHBA on D-galactose (D-gal) induced aging in mice and its underlying mechanisms using in vitro and in vivo experiments. These results indicated that D-gal-induced senescence, oxidative stress, and inflammatory responses were inhibited by BHBA, and autophagy was promoted by BHBA. Mechanistically, we explored the role of metastasis-associated antigen-1 (MTA1) in D-gal-induced damaged in HT22 cells using small interfering RNA (siRNA). The results demonstrated that the expression of MTA1 was significantly increased by BHBA, which attenuated D-gal-induced aging, oxidative stress, and inflammatory responses, and promoted autophagy through the upregulation of MTA1. In conclusion, MTA1 may be a novel target for treating aging caused by neurological damage. BHBA improves brain aging by activating the MTA1 pathway.

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Persistent transcription of HBV covalently closed circular DNA (cccDNA) is critical for chronic HBV infection. Silencing cccDNA transcription through epigenetic mechanisms offers an effective strategy to control HBV. Long non-coding RNAs (lncRNAs), as important epigenetic regulators, have an unclear role in cccDNA transcription regulation. In this study, lncRNA sequencing (lncRNA seq) is conducted on five pairs of HBV-positive and HBV-negative liver tissue. Through analysis, HOXA-AS2 (HOXA cluster antisense RNA 2) is identified as a significantly upregulated lncRNA in HBV-infected livers. Further experiments demonstrate that HBV DNA polymerase (DNA pol) induces HOXA-AS2 after establishing persistent high-level HBV replication. Functional studies reveal that HOXA-AS2 physically binds to cccDNA and significantly inhibits its transcription. Mechanistically, HOXA-AS2 recruits the MTA1-HDAC1/2 deacetylase complex to cccDNA minichromosome by physically interacting with metastasis associated 1 (MTA1) subunit, resulting in reduced acetylation of histone H3 at lysine 9 (H3K9ac) and lysine 27 (H3K27ac) associated with cccDNA and subsequently suppressing cccDNA transcription. Altogether, the study reveals a mechanism to self-limit HBV replication, wherein the upregulation of lncRNA HOXA-AS2, induced by HBV DNA pol, can epigenetically suppress cccDNA transcription.

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The metastasis-associated protein 1/protein kinase B (MTA1/AKT) signaling pathway has been shown to cooperate in promoting prostate tumor growth. Targeted interception strategies by plant-based polyphenols, specifically stilbenes, have shown great promise against MTA1-mediated prostate cancer progression. In this study, we employed a prostate-specific transgenic mouse model with MTA1 overexpression on the background of phosphatase and tensin homolog (Pten) null (R26MTA1; Ptenf/f) and PC3M prostate cancer cells which recapitulate altered molecular pathways in advanced prostate cancer. Mechanistically, the MTA1 knockdown or pharmacological inhibition of MTA1 by gnetin C (dimer resveratrol) in cultured PC3M cells resulted in the marked inactivation of mammalian target of rapamycin (mTOR) signaling. In vivo, mice tolerated a daily intraperitoneal treatment of gnetin C (7 mg/kg bw) for 12 weeks without any sign of toxicity. Treatment with gnetin C markedly reduced cell proliferation and angiogenesis and promoted apoptosis in mice with advanced prostate cancer. Further, in addition to decreasing MTA1 levels in prostate epithelial cells, gnetin C significantly reduced mTOR signaling activity in prostate tissues, including the activity of mTOR-target proteins: p70 ribosomal protein S6 kinase (S6K) and eukaryotic translational initiation factor 4E (elF4E)-binding protein 1 (4EBP1). Collectively, these findings established gnetin C as a new natural compound with anticancer properties against MTA1/AKT/mTOR-activated prostate cancer, with potential as monotherapy and as a possible adjunct to clinically approved mTOR pathway inhibitors in the future.

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BACKGROUND: As a component of the nucleosome remodeling and deacetylating (NuRD) complex, metastasis-associated protein 1 (MTA1) has been reported to be abundant in male reproductive system and might participate in spermatogenesis and sperm maturation, whereas the precise functional role of MTA1 in these processes is still undetermined. OBJECTIVE: To investigate the effect and potential function of MTA1 in male fertility. MATERIALS AND METHODS: Mta1 knockout mice (Mta1-/- ) were employed to detect their reproductive phenotype. The pH value of Mta1-/- epididymal luminal fluid was measured, and the potential mechanism of MTA1 involved in regulating luminal acidification was detected in vivo and in vitro. A vasectomy model with abnormal pH of epididymal lumen was established to further detect the effect of MTA1 on epididymal luminal microenvironment. RESULTS: Mta1-/- mice were fertile without any detectable defects in spermatogenesis or sperm motility while the deficiency of MTA1 could acidify the initial segment of epididymis to a certain extent. MTA1 could interact with estrogen receptor alpha (ERα) and inhibit the transcription of ERα target gene, hydrogen exchanger 3 (NHE3), and ultimately affect the epididymal luminal milieu. After vasectomy, the Mta1-/- mice presented a more acidic epididymal lumen which was closer to the normal state compared to the wild-type model. DISCUSSION AND CONCLUSION: MTA1 is dispensable for male fertility in mice, but plays a potentially important function in regulating luminal acidification of the epididymis.

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Adipose tissue-derived stem cells (ADSCs) are a kind of stem cells with multi-directional differentiation potential, which mainly restore tissue repair function and promote cell regeneration. It can be directionally differentiated into Schwann-like cells to promote the repair of peripheral nerve injury. Glial cell line-derived neurotrophic factor (GDNF) plays an important role in the repair of nerve injury, but the underlying mechanism remains unclear, which seriously limits its further application.The study aimed to identify the molecular mechanism by which overexpression of glial cell line-derived neurotrophic factor (GDNF) facilitates the differentiation of ADSCs into Schwann cells, enhancing nerve regeneration after injury. In vitro, ADSCs overexpressing GDNF for 48 h exhibited changes in their morphology, with 80% of the cells having two or more prominences. Compared with that of ADSCs, GDNF-ADSCs exhibited increased expression of the Schwann cell marker S100, nerve damage repair-related factors.ADSC cells in normal culture and ADSC cells were overexpressing GDNF(GDNF-ADSCs) were analysed using TMT-Based Proteomic Analysis and revealed a significantly higher expression of MTA1 in GDNF-ADSCs than in control ADSCs. Hes1 expression was significantly higher in GDNF-ADSCs than in ADSCs and decreased by MTA1 silencing, along with a simultaneous decrease in the expression of S100 and nerve damage repair factors. These findings indicate that GDNF promotes the differentiation of ADSCs into Schwann cells and induces factors that accelerate peripheral nerve damage repair.

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In eukaryotes, N6-methyladenosine (m6A) RNA modification plays a crucial role in governing the fate of RNA molecules and has been linked to various developmental processes. However, the phyletic distribution and functions of genetic factors responsible for m6A modification remain largely unexplored in fungi. To get insights into the evolution of m6A machineries, we reconstructed global phylogenies of potential m6A writers, readers, and erasers in fungi. Substantial copy number variations were observed, ranging from up to five m6A writers in early-diverging fungi to a single copy in the subphylum Pezizomycotina, which primarily comprises filamentous fungi. To characterize m6A factors in a phytopathogenic fungus Fusarium graminearum, we generated knockout mutants lacking potential m6A factors including the sole m6A writer MTA1. However, the resulting knockouts did not exhibit any noticeable phenotypic changes during vegetative and sexual growth stages. As obtaining a homozygous knockout lacking MTA1 was likely hindered by its essential role, we generated MTA1-overexpressing strains (MTA1-OE). The MTA1-OE5 strain showed delayed conidial germination and reduced hyphal branching, suggesting its involvement during vegetative growth. Consistent with these findings, the expression levels of MTA1 and a potential m6A reader YTH1 were dramatically induced in germinating conidia, followed by the expression of potential m6A erasers at later vegetative stages. Several genes including transcription factors, transporters, and various enzymes were found to be significantly upregulated and downregulated in the MTA1-OE5 strain. Overall, our study highlights the functional importance of the m6A methylation during conidial germination in F. graminearum and provides a foundation for future investigations into m6A modification sites in filamentous fungi.IMPORTANCEN6-methyladenosine (m6A) RNA methylation is a reversible posttranscriptional modification that regulates RNA function and plays a crucial role in diverse developmental processes. This study addresses the knowledge gap regarding phyletic distribution and functions of m6A factors in fungi. The identification of copy number variations among fungal groups enriches our knowledge regarding the evolution of m6A machinery in fungi. Functional characterization of m6A factors in a phytopathogenic filamentous fungus Fusarium graminearum provides insights into the essential role of the m6A writer MTA1 in conidial germination and hyphal branching. The observed effects of overexpressing MTA1 on fungal growth and gene expression patterns of m6A factors throughout the life cycle of F. graminearum further underscore the importance of m6A modification in conidial germination. Overall, this study significantly advances our understanding of m6A modification in fungi, paving the way for future research into its roles in filamentous growth and potential applications in disease control.

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SCOPE: Resistance of castrate-resistant prostate cancer (CRPC) to enzalutamide (Enz) involves the expression of constitutively active androgen receptor splice variant (AR-V7). In addition to altered AR pathways, CRPC is characterized by "non-AR-driven" signaling, which includes an overexpression of metastasis-associated protein 1 (MTA1). Combining natural compounds with anticancer drugs may enhance drug effectiveness while reducing adverse effects. In this study, the in vitro and in vivo anticancer effects of Gnetin C (GnC) alone and in combination with Enz against CRPC are examined. METHODS AND RESULTS: The effects of GnC alone and in combination with Enz are assessed by cell viability, clonogenic survival, cell migration, and AR and MTA1 expression using 22Rv1 cells. The tumor growth in vivo is assessed by bioluminescent imaging, western blots, RT-PCR, and IHC. GnC alone and in combined treatment inhibit cell viability, clonogenic survival and migration, and AR and MTA1 expression in 22Rv1 cells. The underlying AR- and MTA1-targeted anticancer mechanisms of treatments in vivo involve inhibition of proliferation and angiogenesis, and induction of apoptosis. CONCLUSION: The findings demonstrate that GnC alone and GnC combined with Enz effectively inhibits AR- and MTA1-promoted tumor-progression in advanced CRPC, which indicates its potential as a novel therapeutic approach for CRPC.

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We previously identified a cell cycle-dependent periodic subcellular distribution of cancer metastasis-associated antigen 1 (MTA1) and unraveled a novel role of MTA1 in inhibiting spindle damage-induced spindle assembly checkpoint (SAC) activation in cancer cells. However, the more detailed subcellular localization of MTA1 in mitotic cells and its copartner in SAC regulation in cancer cells are still poorly understood. Here, through immunofluorescent colocalization analysis of MTA1 and alpha-tubulin in mitotic cancer cells, we reveal that MTA1 is dynamically localized to the spindle apparatus throughout the entire mitotic process. We also demonstrated a reversible upregulation of MTA1 expression upon spindle damage-induced SAC activation, and time-lapse imaging assays indicated that MTA1 silencing delayed the mitotic metaphase-anaphase transition in cancer cells. Further investigation revealed that MTA1 interacts and colocalizes with Translocated Promoter Region (TPR) on spindle microtubules in mitotic cells, and this interaction is attenuated on SAC activation. TPR is well-implicated in SAC regulation via binding the MAD1-MAD2 complex, however, no interactions between MTA1 and MAD1 or MAD2 were detected in our coimmunoprecipitation (co-IP) assays, suggesting that the MTA1-TPR may represent a distinct SAC-associated complex separate from the previously reported TPR-MAD1/MAD2 complex. Our data provide new insights into the subcellular localization and molecular function of MTA1 in SAC regulation in cancer, and indicate that intervention of the MTA1-TPR interaction may be effective to modulate SAC and hence chromosomal instability (CIN) in tumorigenesis.

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Liver metastasis is the most fatal event of colon cancer patients. Warburg effect has been long challenged by the fact of upregulated oxidative phosphorylation (OXPHOS), while its mechanism remains unclear. Here, metastasis-associated antigen 1 (MTA1) is identified as a newly identified adenosine triphosphate (ATP) synthase modulator by interacting with ATP synthase F1 subunit alpha (ATP5A), facilitates colon cancer liver metastasis by driving mitochondrial bioenergetic metabolism reprogramming, enhancing OXPHOS; therefore, modulating ATP synthase activity and downstream mTOR pathways. High-throughput screening of an anticancer drug shows MTA1 knockout increases the sensitivity of colon cancer to mitochondrial bioenergetic metabolism-targeted drugs and mTOR inhibitors. Inhibiting ATP5A enhances the sensitivity of liver-metastasized colon cancer to sirolimus in an MTA1-dependent manner. The therapeutic effects are verified in xenograft models and clinical cases. This research identifies a new modulator of mitochondrial bioenergetic reprogramming in cancer metastasis and reveals a new mechanism on upregulating mitochondrial OXPHOS as the reversal of Warburg effect in cancer metastasis is orchestrated.

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BACKGROUND: The effect of circular RNAs (circRNAs) is widely studied in various human cancers, including breast cancer (BC). Herein, circUSPL1 has been recognized as a new regulator for BC progression. However, the detailed biological function and molecular mechanism of circUSPL1 in BC remain vague. METHODS: The expression level of circUSPL1, miR-1296-5p and metastasis associated 1 (MTA1) was examined by quantitative reverse transcription PCR. BC cell proliferation, migration, invasion, apoptosis and aerobic glycolysis were analyzed by colony formation assay, 5-ethynyl-2'-deoxyuridine assay, wound healing assay, transwell assay, flow cytometry and glycolysis corresponding kits, respectively. The protein level of Bcl-2, Bax, HK2, GLUT1 and MTA1 was evaluated by western blot analysis. The relationship of miR-1296-5p and circUSPL1 or MTA1 was affirmed using dual-luciferase reporter or RIP assays. A murine xenograft model was conducted to analyze the tumor growth in vivo. RESULTS: CircUSPL1 and MTA1 expression level was increased, but miR-1296-5p was particularly reduced in BC tissues and cells. CircUSPL1 deficiency significantly inhibited BC cell proliferation, migration, invasion, glycolysis, and promoted cell apoptosis. In addition, circUSPL1 directly targeted miR-1296-5p, and downregulation of miR-1296-5p eliminated the inhibitory action of circUSPL1 knockdown. Additionally, overexpression of miR-1296-5p repressed cell malignant properties, while the suppressive effects were overturned by MTA1 elevation. Lastly, silencing of circUSPL1 inhibited tumor growth by sponging miR-1296-5p and regulating MTA1. CONCLUSION: CircUSPL1 deficiency repressed BC cell malignant phenotypes through reducing MTA1 via targeting miR-1296-5p, which might provide a theoretical basis for BC treatment.

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PURPOSE: Vulvar cancer is the fourth most common malignancy of the female genital tract after endometrial, ovarian, and cervical carcinoma and affects mainly elderly women. In 2020 there were registered more than 17,000 deaths worldwide related to vulvar carcinoma. Data about target-based therapies and predictive biomarkers for vulva carcinomas are rare so far. The metastasis-associated gene MTA1 is a transcriptional repressor with a potential effect on cancer. Expression of MTA1 was found to be significantly enhanced in gynecological malignancies as breast or ovarian cancer tissues with advanced cancer stages and higher FIGO grading, indicating an important role of MTA1 in the progression of those tumor entities. Due to the lack of information around MTA1 and its significance regarding vulvar carcinoma, this study focuses on the expression of MTA1 in vulvar carcinoma and its correlation to clinicopathological characteristics and prognosis. METHODS: A total of 157 paraffin-embedded vulvar cancer tissues were immunohistochemically stained and examined for MTA1 expression by using the immunoreactive score. Subsequently, the values were correlated with clinicopathological parameters. RESULTS: MTA1 was found to be expressed in 94% of the patients in the cytoplasm and 91% in the nucleus. Cytoplasmatic expression of MTA1 was significantly increased in non-keratinizing squamous cell carcinoma and in vulvar carcinoma of the condylomatous type, compared to keratinizing squamous cell carcinoma and vulvar carcinoma of the verrucous type. High MTA1 expression in the nucleus was associated with advanced tumor size as well as higher FIGO grading. In addition, p16 negative vulvar carcinomas showed a higher nuclear expression of MTA1 compared to p16 positive vulvar carcinomas. Suprisingly, Kaplan-Meier analysis showed a significantly lower disease-free survival in tumor samples without a nuclear expression of MTA1. CONCLUSIONS: MTA1 was identified as a negative prognostic marker for vulvar carcinoma associated with advanced tumor stage and FIGO grading. A possible explanation could be that the antibody used for this study does not bind to a possible mutation in the C terminal region of MTA leading to negative immunohistochemical staining and this can be correlated with early recurrence in patients with vulvar carcinoma.

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BACKGROUND: Thyroid cancer is one of the malignancy cancers. CircRNA, a non-coding RNA, plays an important role in the development of cancer. The relationship and roles of circ_0124055, miR-486-3p and MTA1 in thyroid cancer have not been reported. METHODS: Real-time quantitative polymerase chain reaction (RT-qPCR) was performed to analyze the RNA levels of circ_0124055, miR-486-3p and MTA1. Western blot was conducted to analyze the protein levels of MTA1, Epithelial cadherin (E-cadherin) and Neuro cadherin (N-cadherin). Subcellular localization assay was used to analyze circ_0124055 location in thyroid cancer cells. Colony formation assay and 5-Ethynyl-2'-deoxyuridine (EdU) assay were carried out to analyze cell proliferation. Cell migration and invasion were analyzed by wound-healing assay and transwell assay. Flow cytometry assay was performed to investigate cell apoptosis. Dual-luciferase reporter assay and RIP assay were employed to analyze the interactions among circ_0124055, miR-486-3p and MTA1. Immunohistochemical (IHC) assay was performed to assess the expression of Ki67, MTA1 and E-cadherin in tumor tissues. Thyroid cancer tumor growth in vivo was evaluated by tumor xenograft mouse model assay. RESULTS: The expression of circ_0124055 was up-regulated in tumor tissues and cells. Knockdown of circ_0124055 could inhibit thyroid cancer cell proliferation, migration and invasion and promote cell apoptosis, accompanied by the dysregulation of E-cadherin and N-cadherin expression. Circ_0124055 could target miR-486-3p, and miR-486-3p could target MTA1. MiR-486-3p inhibitor could restore the effect of circ_0124055 knockdown in the progression of thyroid cancer. Moreover, MTA1 overexpression weakened the inhibitory effects of miR-486-3p mimics on the progression of thyroid cancer. Further, circ_0124055 could influence tumor growth in vivo. CONCLUSION: Circ_0124055 promoted the progression of thyroid cancer cells through the miR-486-3p /MTA1 axis.

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Nutritional chemoprevention is particularly suitable for prostate cancer. Gnetin C, a resveratrol dimer found abundantly in the melinjo plant (Gnetum gnemon), may possess more potent biological properties compared to other stilbenes. We examined the effects of gnetin C in a high-risk premalignant transgenic mouse model overexpressing tumor-promoting metastasis-associated protein 1 (MTA1) on the background of Pten heterozygosity (R26MTA1; Pten+/f; Pb-Cre+). Mice were fed diets supplemented with the following compounds: pterostilbene (70 mg/kg diet); gnetin C, high dose (70 mg/kg diet); and gnetin C, low dose (35 mg/kg diet). Prostate tissues were isolated after 17 weeks and examined for histopathology and molecular markers. Serum was analyzed for cytokine expression. Gnetin C-supplemented diets substantially delayed the progression of preneoplastic lesions compared to other groups. Prostate tissues from gnetin C-fed mice showed favorable histopathology, with decreased severity and number of prostatic intraepithelial neoplasia (PIN) foci, reduced proliferation, and angiogenesis. A decreased level of MTA1, concurrent with the trend of increasing phosphatase and tensin homolog expression and reduced interleukin 2 (IL-2) levels in sera, were also detected in gnetin C-fed mice. Importantly, gnetin C did not exert any visible toxicity in mice. Our findings demonstrate that a gnetin C-supplemented diet effectively blocks MTA1-promoted tumor progression activity in high-risk premalignant prostate cancer, which indicates its potential as a novel form of nutritional interception for prostate cancer chemoprevention.

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Accumulated experimental data have suggested that natural plant products may be effective miRNA-modulating chemopreventive and therapeutic agents. Dietary polyphenols such as flavonoids, stilbenes, and lignans, among others, have been intensively studied for their miRNA-mediated cardioprotective, antioxidant, anti-inflammatory and anticancer properties. The aim of this review is to outline known stilbene-regulated miRNAs in cancer, with a special focus on the interplay between various miRNAs and MTA1 signaling in prostate cancer. MTA1 is an epigenetic reader and an oncogenic transcription factor that is overexpressed in advanced prostate cancer and metastasis. Not surprisingly, miRNAs that are linked to MTA1 affect cancer progression and the metastatic potential of cells. Studies led to the identification of MTA1-associated pro-oncogenic miRNAs, which are regulated by stilbenes such as resveratrol and pterostilbene. Specifically, it has been shown that inhibition of the activity of the MTA1 regulated oncogenic miR-17 family of miRNAs, miR-22, and miR-34a by stilbenes leads to inhibition of prostatic hyperplasia and tumor progression in mice and reduction of proliferation, survival and invasion of prostate cancer cells in vitro. Taken together, these findings implicate the use of resveratrol and its analogs as an attractive miRNA-mediated chemopreventive and therapeutic strategy in prostate cancer and the use of circulating miRNAs as potential predictive biomarkers for clinical development.

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Objective: To determine the effect of tumor metastasis-associated gene 1 (MTA1) on the sensitivity of HeLa cells to radiotherapy, and to clarify its molecular mechanism. Methods: The transcriptome differences between MTA1 knocked down Hela cells and control cells were analyzed, and the differentially expressed genes (DEGs) was used to perform Gene-Set Enrichment Analysis (GSEA) and Gene Ontology (GO) cluster analysis. Flow cytometry was used to detect apoptosis in MTA1-overexpressed HeLa cells and control cells before and after 10 Gy X-ray irradiation. Cloning formation assay and real-time cellular analysis (RTCA) were used to monitor the cell proliferation before and after 2 Gy X-ray irradiation. To dissect the underlying molecular mechanisms of MTA1 affecting the sensitivity of radiotherapy, the proteins encoded by the DEGs were selected to construct a protein-protein interaction network, the expression of γ-H2AX was detected by immunofluorescence assay, and the expression levels of γ-H2AX, ß-CHK2, PARP and cleaved caspase 3 were measured by western blot. Results: By transcriptome sequencing analysis, we obtained 649 DEGs, of which 402 genes were up-regulated in MTA1 knockdown HeLa cells and 247 genes were down-regulated. GSEA results showed that DEGs associated with MTA1 were significantly enriched in cellular responses to DNA damage repair processes. The results of flow cytometry showed that the apoptosis rate of MTA1 over-expression group (15.67±0.81)% after 10 Gy X-ray irradiation was significantly lower than that of the control group [(40.27±2.73)%, P<0.001]. After 2 Gy X-ray irradiation, the proliferation capacity of HeLa cells overexpressing MTA1 was higher than that of control cells (P=0.024). The numbers of colon in MTA1 over-expression group before and after 2 Gy X-ray irradiation were (176±7) and (137±7) respectively, higher than (134±4) and (75±4) in control HeLa cells (P<0.05). The results of immunofluorescence assay showed that there was no significant expression of γ-H2AX in MTA1 overexpressed and control HeLa cells without X-ray irradiation. Western blot results showed that the expression level of ß-CHK2 in MTA1-overexpressing HeLa cells (1.04±0.06) was higher than that in control HeLa cells (0.58±0.25, P=0.036) after 10 Gy X-ray irradiation. The expression levels of γ-H2AX, PARP, and cleaved caspase 3 were 0.52±0.13, 0.52±0.22, and 0.63±0.18, respectively, in HeLa cells overexpressing MTA1, which were lower than 0.87±0.06, 0.78±0.12 and 0.90±0.12 in control cells (P>0.05). Conclusions: This study showed that MTA1 is significantly associated with radiosensitivity in cervical cancer HeLa cells. MTA1 over-expression obviously reduces the sensitivity of cervical cancer cells to X-ray irradiation. Mechanism studies initially indicate that MTA1 reduces the radiosensitivity of cervical cancer cells by inhibiting cleaved caspase 3 to suppress apoptosis and increasing ß-CHK2 to promote DNA repair.

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Distant metastasis is the main cause of death in non-small cell lung cancer (NSCLC) patients. The mechanism of metastasis-associated protein 1(MTA1) in NSCLC has not been fully elucidated. This study aimed to reveal the mechanism of MTA1 in the invasion and metastasis of NSCLC. Bioinformatics analysis and our previous results showed that MTA1 was highly expressed in NSCLC tissues and correlated with tumor progression. Knockout of MTA1 by CRISPR/Cas9 significantly inhibited the migration and invasion of H1299 cells, but enhanced cell adhesion. Stable overexpression of MTA1 by lentivirus transfection had opposite effects on migration, invasion and adhesion of A549 cells. The results of in vivo experiments in nude mouse lung metastases model confirmed the promotion of MTA1 on invasion and migration. Tight junction protein 1 (TJP1) was identified by immunoprecipitation and mass spectrometry as an interacting protein of MTA1 involved in cell adhesion. MTA1 inhibited the expression level of TJP1 protein and weakened the tight junctions between cells. More importantly, the rescue assays confirmed that the regulation of MTA1 on cell adhesion, migration and invasion was partially attenuated by TJP1. In Conclusion, MTA1 inhibits the expression level of TJP1 protein co-localized in the cytoplasm and membrane of NSCLC cells, weakens the tight junctions between cells, and changes the adhesion, migration and invasion capabilities of cells, which may be the mechanism of MTA1 promoting the invasion and metastasis of NSCLC. Thus, targeting the MTA1-TJP1 axis may be a promising strategy for inhibiting NSCLC metastasis.

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Prostate cancer (PCa) is the most frequent cancer of the male genitourinary system and the second most common cancer in men worldwide. PCa has become one of the leading diseases endangering men's health in Asia in recent years, with a large increase in morbidity and mortality. MTA1 (metastasis-associated antigen-1), a transcriptional coregulator involved in histone deacetylation and nucleosome remodeling, is a member of the MTA family. MTA1 is involved in cell signaling, chromosomal remodeling, and transcriptional activities, all of which are important for epithelial cell progression, invasion, and growth. MTA1 has been demonstrated to play a significant role in the formation, progression, and metastasis of PCa, and MTA1 expression is specifically linked to PCa bone metastases. Therefore, MTA1 may be a potential target for PCa prevention and treatment. Here, we reviewed the structure, function, and expression of MTA1 in PCa as well as drugs that target MTA1 to highlight a potential new treatment for PCa.

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OBJECTIVES: MicroRNAs (miRNAs) have been considered as a new class of novel diagnostic and predictive biomarker in many diseases. However, there are few studies on miRNA in osteosarcoma (OS). This study aimed to investigate the roles of miR-30 on OS occurrence and development. METHODS: PCR was used to detect mRNA levels of miR-30 and MTA1 in cancer tissues, adjacent non-cancerous tissues from OS patients. Western blot was used to detect MTA1 protein expression in all tissues and cell lines (hFOb1.19,Saos-2, MG63, and U2OS). The correlation between miR-30 and MTA1 was predicted through bioinformatics software, and identified by a luciferase reporting experiment. In vitro, functional test detected the specific effects of miR-30 and MTA1 on the development of OS. RESULTS: miR-30 expression was significantly reduced, while the expression of MTA1 was increased in OS tissues and cells. Luciferase reporting experiment showed that miR-30 sponged MTA1 which was negatively correlated with miR-30 expression. Furthermore, rescue tests revealed that MTA1 restrained the functions of miR-30 on cell proliferation and migration of OS. CONCLUSION: Our finding showed that miR-30 modulated the proliferation and migration by targeting MTA1 in OS.

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