Metastasis-associated Protein 1 Expression Research Articles

Molecular Efficacy of Gnetin C as Dual-Targeted Therapy for Castrate-Resistant Prostate Cancer.

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. 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. 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.

Nicotinic Acid-Mediated Modulation of Metastasis-Associated Protein 1 Methylation and Inflammation in Brain Arteriovenous Malformation.

We explored metastasis-associated protein 1 (MTA1) promoter methylation in the development of brain arteriovenous malformation (BAVM). The clinical data of 148 sex- and age-matched BAVMs and controls were collected, and the MTA1 DNA methylation in peripheral white blood cells (WBC) was assessed by bisulfite pyrosequencing. Among them, 18 pairs of case-control samples were used for WBC mRNA detection, 32 pairs were used for WBC MTA1 protein measurement, and 50 pairs were used for plasma inflammatory factor analysis. Lipopolysaccharide (LPS) treatment was used to induce an inflammatory injury cell model of human brain microvascular endothelial cells (BMECS). 5-Aza-2'-deoxycytidine (5-AZA), nicotinic acid (NA), and MTA1 siRNAs were used in functional experiments to examine BMECS behaviors. RT-qPCR, Western blot, and ELISA or cytometric bead arrays were used to measure the expression levels of MTA1, cytokines, and signaling pathway proteins in human blood or BMECS. The degree of MTA1 promoter methylation was reduced in BAVM compared with the control group and was inversely proportional to MTA1 expression. Plasma ApoA concentrations in BAVM patients were significantly lower than those in controls and correlated positively with MTA1 promoter methylation and negatively with MTA1 expression. The expression of cytokine was markedly higher in BAVM than in controls. Cell experiments showed that 5-AZA decreased the methylation level of MTA1 and increased the expression of MTA1 protein. LPS treatment significantly increased cytokine concentrations (p < 0.05). NA and MTA1 silencing could effectively reverse the LPS-mediated increase in IL-6 and TNF-α expression through the NF-κB pathway. Our study indicated that NA may regulate MTA1 expression by affecting promoter DNA methylation, improve vascular inflammation through the NF-κB pathway, and alleviate the pathological development of BAVM.

Stathmin1 promotes lymph node metastasis in hypopharyngeal squamous cell carcinoma via regulation of HIF‑1α/VEGF‑A axis and MTA1 expression.

Extensive neck lymph node metastasis (LNM) is an important clinical feature of hypopharyngeal squamous cell carcinoma (HSCC). Stathmin1 (STMN1) is closely associated with LNM in numerous human cancers. In the present study, the association between STMN1 and neck LNM in HSCC and the underlying molecular mechanisms were explored. First, postoperative samples of HSCC were screened and the association between STMN1 and neck LNM in HSCC was analyzed. Then, cell functional experiments were performed to assess the potential of STMN1 to promote invasion and migration. Subsequently, the potential target genes and pathways of STMN1 were predicted using bioinformatics analysis. Finally, the obtained target genes and pathways of STMN1 were validated by reverse transcription-quantitative PCR (RT-qPCR) and western blot analyses to confirm the potential mechanisms by which STMN1 promotes LNM in HSCC. As a result, a total of 117 postoperative samples of HSCC were screened, and STMN1 was proven to be associated with neck LNM in HSCC. Further, cell functional experiments established that high expression of STMN1 could actually promote FaDu cell invasion and metastasis. Bioinformatics analysis revealed that high expression of STMN1 was associated with the activation of hypoxia inducible factor-1alpha (HIF-1α) pathway and increased expression of metastasis-associated protein 1 (MTA1). Finally, RT-qPCR and western blot analyses confirmed that STMN1 promotes the expression levels of HIF-1α/vascular endothelial growth factor (VEGF)-A and MTA1 in FaDu cell lines. In conclusion, it was found that high expression of STMN1 promoted neck LNM in HSCC and the potential mechanisms may be via regulation of the HIF-1α/VEGF-A axis and MTA1 expression.

Upregulation of MTA1 in Colon Cancer Drives A CD8+ T Cell-Rich But Classical Macrophage-Lacking Immunosuppressive Tumor Microenvironment.

BackgroundThe MTA1 protein encoded by metastasis-associated protein 1 (MTA1) is a key component of the ATP-dependent nucleosome remodeling and deacetylase (NuRD) complex, which is widely upregulated in cancers. MTA1 extensively affects downstream gene expression by participating in chromatin remodeling. Although it was defined as a metastasis-associated gene in first reports and metastasis is a process prominently affected by the tumor microenvironment, whether it affects the microenvironment has not been investigated. In our study, we elucidated the regulatory effect of MTA1 on tumor-associated macrophages (TAMs) and how this regulation affects the antitumor effect of cytotoxic T lymphocytes (CTLs) in the tumor microenvironment of colorectal cancer.MethodsWe detected the cytokines affected by MTA1 expression via a cytokine antibody array in control HCT116 cells and HCT116 cells overexpressing MTA1. Multiplex IHC staining was conducted on a colorectal cancer tissue array from our cancer cohort. Flow cytometry (FCM) was performed to explore the polarization of macrophages in the coculture system and the antitumor killing effect of CTLs in the coculture system. Bioinformatics analysis was conducted to analyze the Cancer Genome Atlas (TCGA) colorectal cancer cohort and single-cell RNA-seq data to assess the immune infiltration status of the TCGA colorectal cancer cohort and the functions of myeloid cells.ResultsMTA1 upregulation in colorectal cancer was found to drive an immunosuppressive tumor microenvironment. In the tumor microenvironment of MTA1-upregulated colorectal cancer, although CD8+ T cells were significantly enriched, macrophages were significantly decreased, which impaired the CTL effect of the CD8+ T cells on tumor cells. Moreover, upregulated MTA1 in tumor cells significantly induced infiltrated macrophages into tumor-associated macrophage phenotypes and further weakened the cytotoxic effect of CD8+ T cells.ConclusionUpregulation of MTA1 in colorectal cancer drives an immunosuppressive tumor microenvironment by decreasing the microphages from the tumor and inducing the residual macrophages into tumor-associated microphage phenotypes to block the activation of the killing CTL, which contributes to cancer progression.

MTA1 Expression Can Stratify the Risk of Patients with Multifocal Non-Small Cell Lung Cancers ≤3 cm.

PurposeCurrently, there is no uniform standard to guide postoperative adjuvant chemotherapy for patients with multifocal non-small cell lung cancers (NSCLCs) ≤3 cm. Therefore, there is an urgent need to explore prognostic molecular markers to identify high-risk patients with multifocal NSCLCs ≤3 cm. We aimed to explore the potential value of metastasis-associated protein 1(MTA1) expression in risk stratification of patients with multifocal NSCLCs ≤3 cm.MethodsWe retrospectively analyzed the clinical data and postoperative survival data of patients with multifocal NSCLCs ≤3 cm. Paraffin-embedded tissue sections were used for immunohistochemistry. Semiquantitative immunoreactivity scoring (IRS) system was used to evaluate the nuclear expression of MTA1. SPSS software (version 23.0) was used to analyze the data.ResultsThe IRS of MTA1 nuclear expression in 259 lesions of 119 patients ranged from 2.2 to 11.7 (median: 5.6). Our results showed that MTA1 expression was highest in high-risk pathological subtypes of lung adenocarcinoma. MTA1 expression in multiple primary lung cancers (MPLCs) was lower than that in intrapulmonary metastases (IPMs). The median follow-up duration was 25.97 months. The disease-free survival (DFS) of patients with MPLCs was significantly better than that of patients with IPMs, and the DFS of patients with high MTA1 expression was significantly worse than that of patients with low MTA1 expression. Multivariate Cox analysis showed that high MTA1 expression (hazard ratio: 7.937, 95% confidence interval: 2.433–25.64, p =0.001) was a statistically significant predictor of worse DFS in patients with multifocal NSCLCs ≤3 cm.ConclusionMTA1 expression can stratify the risk in patients with multifocal NSCLCs ≤3 cm. Patients with MTA1 immunohistochemical score >5.6 are at a high risk of postoperative recurrence, and these patients may benefit from postoperative adjuvant chemotherapy.

MTA1, a metastasis‑associated protein, in endothelial cells is an essential molecule for angiogenesis.

Our previous study revealed that metastasis-associated protein 1 (MTA1), which is expressed in vascular endothelial cells, acts as a tube formation promoting factor. The present study aimed to clarify the importance of MTA1 expression in tube formation using MTA1-knockout (KO) endothelial cells (MTA1-KO MSS31 cells). Tube formation was significantly suppressed in MTA1-KO MSS31 cells, whereas MTA1-overexpression MTA1-KO MSS31 cells regained the ability to form tube-like structures. In addition, western blotting analysis revealed that MTA1-KO MSS31 cells showed significantly higher levels of phosphorylation of non-muscle myosin heavy chain IIa, which resulted in suppression of tube formation. This effect was attributed to a decrease of MTA1/S100 calcium-binding protein A4 complex formation. Moreover, inhibition of tube formation in MTA1-KO MSS31 cells could not be rescued by stimulation with vascular endothelial growth factor (VEGF). These results demonstrated that MTA1 may serve as an essential molecule for angiogenesis in endothelial cells and be involved in different steps of the angiogenic process compared with the VEGF/VEGF receptor 2 pathway. The findings showed that endothelial MTA1 and its pathway may serve as promising targets for inhibiting tumor angiogenesis, further supporting the development of MTA1-based antiangiogenic therapies.

Melatonin combined with sorafenib synergistically inhibit the invasive ability through targeting metastasis-associated protein 2 expression in human renal cancer cells.

Objectives:Renal cell carcinoma (RCC) was the most common and lethal urological malignancy with the dismal outcome when distant metastasis. Melatonin was known as a potential oncostatic agent against several types of malignancy and sorafenib had been considered as an agent to treat RCC, but the synergistic effects of melatonin and sorafenib on human RCC have not been elucidated.Materials and Methods:Human renal cancer cell lines (Caki-1 and ACHN) were treated with melatonin combined with sorafenib were detected the cell growth and cell cycle by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay and flow cytometry. The ability of cell migration/invasion was performed with in vitro migration and invasion assay. The proteins and mRNA expression of metastasis-associated protein 2 (MTA2) from the RCC cells were measured by quantitative reverse transcription-polymerase chain reaction and western blotting. Clinical significance of MTA2 in RCC tissues was analyzed from The Cancer Genome Atlas database by using TISIDB software.Results:Our results showed that melatonin combined with sorafenib, sorafenib or melatonin-treated alone did not induce the cytotoxic effects or cell cycle arrest in human RCC cells and HK2 cells. Additionally, cotreatment with melatonin and sorafenib synergistically reduced migration and invasion in human Caki-1 and ACHN cells through synergistically suppression of MTA2 expression. Bioinformatics analysis showed that MTA2 expression significantly correlated with overall survival (P < 0.002), tumor grade (P < 0.001) and tumor stage (P < 0.001) in human RCC.Conclusion:Our results demonstrated that concomitantly used melatonin and sorafenib could significantly reduce the abilities of migration and invasion of RCC cells through inhibiting MTA2. We considered that this novel promising combination strategy towards the treatment of RCC, but further studies are warranted.

Membranous CD44v6 is upregulated as an early event in colorectal cancer: Downregulation is associated with circulating tumor cells and poor prognosis.

Previous studies have reported that CD44 variant 6 (CD44v6) and metastasis-associated protein 1 (MTA1) are contributing factors to cancer progression. The present study aimed to evaluate the expression profiles for associations with patients' demographic data, clinicopathological characteristics, the presence of partial epithelial-to-mesenchymal transition (pEMT), metastatic potential based on the presence of CK20+ CEA+ CXCR4+ circulating tumor cells (CTCs) and prognosis (median follow-up, 45 months). Thus, frozen tissue samples from 31 patients with stage I–III colorectal cancer (CRC), 15 benign colorectal polyps and seven normal colorectal tissues were analyzed to detect membranous (m)CD44v6 and MTA1 expression via flow cytometry. The results demonstrated that the mCD44v6 and MTA1 expression profiles were significantly correlated (rs=+0.786, P<0.001). Notably, MTA1 expression was not associated with any of the clinicopathological characteristics assessed. The percentage of mCD44v6-positive cells within tumors was higher in the right-sided cancer lesions (P=0.014), suggesting that proximal and distal CRCs are distinct clinicopathological entities. Furthermore, downregulated mCD44v6 expression was significantly associated with the presence of CTCs (P=0.017). This association was stronger for pEMT (co-expression of N- and E-cadherin mRNAs) primary lesions (P=0.009). In addition, patients with CRC with low levels of mCD44v6 had unfavorable survival outcomes (P=0.037). Taken together, these results suggest that targeted analysis of membranous CD44v6 as opposed to membranous-cytoplasmic expression is important in determining the prognosis of patients with CRC. Furthermore, downregulated mCD44v6 expression in malignancies presenting CTCs reinforces the importance of tumor-stroma reciprocal influence during the metastatic process and encourages the assessment of relevant therapeutic strategies.

Prognostic value of MTA1, SOX4 and EZH2 expression in esophageal squamous cell carcinoma.

Esophageal cancer has always been one of the major malignant tumor types affecting the health of the Chinese population. Metastasis-associated protein 1 (MTA1), SOX4 and enhancer of zeste homolog 2 (EZH2) are all potent inducers of invasion and metastasis in esophageal squamous cell carcinoma (ESCC). However, the role of these signaling molecules and their implication in ESCC have remained largely elusive. In the present study, the effects of MTA1, SOX4 and EZH2 on the prognosis of patients with ESCC were explored. Immunohistochemistry was used to examine the expression levels of MTA1, SOX4 and EZH2. The χ2 test was used to analyze the association between protein expression and clinicopathological parameters. Kaplan-Meier curves and Cox proportional hazards model survival analysis was performed to investigate the effects of the three proteins examined on disease prognosis. The results indicated that MTA1 may be used as a prognostic and diagnostic marker for ESCC. To the best of our knowledge, the present study was the first to demonstrate that MTA1-SOX4 signaling is associated with prognosis in ESCC. However, no significant association was noted between SOX4 and EZH2 in the present study, which was inconsistent with previously reported findings. The function of the MTA1-SOX4-EZH2 axis and the interactions of the proteins involved require further investigation.

High Expression of MTA1 Predicts Unfavorable Survival in Patients With Oral Squamous Cell Carcinoma.

Metastasis-associated protein 1 (MTA1) plays a role in ATP-dependent nucleosome disruption activity and histone deacetylase activity and may indicate DNA methylation activity. MTA1 may also be involved in the progression of oral squamous cell carcinoma (OSCC). MTA1 immunoreactivity was analyzed using immunohistochemical (IHC) staining analysis in specimens from 281 OSCC patients. Kaplan-Meier analysis was used to determine the prognostic value of MTA1 for overall survival. High MTA1 expression was significantly associated with female gender and lymph node metastasis. Multivariate analyses showed the independent prognostic role of high MTA1 expression in patients with OSCC of poorer mean survival. MTA1 expression, detected by IHC staining, could be an independent prognostic marker for patients of OSCC.

SiMTA1-Loaded Exosomes Enhanced Chemotherapeutic Effect of Gemcitabine in Luminal-b Type Breast Cancer by Inhibition of EMT/HIF-α and Autophagy Pathways.

Advanced breast cancer holds a poor prognosis for chemotherapy and endocrine therapy resistance. Autophagy is one of the main causes of tumor drug-therapy failure, and increasing evidence shows that EMT also is responsible for that. Metastasis-associated protein1 (MTA1) is up regulated in lots of tumors, which leads to tumor progression and drug resistance. However, the role of MTA1 in chemotherapeutic resistance in luminal-b breast cancer is still unclear. In this paper, our research shows that higher expression of MTA1 accompanies with worse prognosis in luminal-b breast cancer. Knockdown of MTA1 enhances the sensitivity of MCF-7 to gemcitabine and weakens the metastasis ability of MCF-7 in vitro and in vivo. Further, we find that knockdown of MTA1 strengthens the gemcitabine-mediated tumor growth inhibition effect in vivo, through reversion of the EMT process and inhibition of the autophagy process. Furthermore, our research builds the siMTA1-loaded exosomes, which increases the gemcitabine-mediated tumor growth inhibition effect in vivo.

P.760 Effects of novel cholinesterase inhibitors on mitochondrial respiration and MAO activity - in vitro study

Based on the lately identified role for the interstitial cells of Cajal (ICCs) of mouse prostate in catecholamine production, as well as the well-established role for the master coregulator metastasis-associated protein 1 (MTA1) in inflammation, we probed into the functional link between aberrant MTA1 expression and pathogenesis of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) using both a MTA1−/− mouse model of experimental autoimmune prostatitis (EAP) and an in vitro chronic prostatitis model in cultured murine ICCs. EAP-induced MTA1 expression was enriched in ICCs of mouse prostate. EAP resulted in a higher increase in the pelvic pain response in MTA1−/− mice compared to WT mice. Consistently, the ICCs from MTA1−/− mice produced higher levels of catecholamines upon induction of in vitro chronic prostatitis. Mechanistically, MTA1 could directly suppress the transcription of Aadc, a rate-limiting enzyme during catecholamine synthesis, in a HDAC2-depdendent manner. Importantly, treatment with AADC inhibitor NSD-1015 significantly ameliorated EAP-elicited pain response and catecholamine overactivity in MTA1−/− mice. Taken together, our findings reveal an inherent regulatory role of the MTA1/AADC pathway in the maintenance of catecholamine production homeostasis in prostate ICCs, and also point to a potential use of HDAC inhibitors and/or AADC inhibitors to treat CP/CPPS.

MTA1, a Target of Resveratrol, Promotes Epithelial-Mesenchymal Transition of Endometriosis via ZEB2

Endometriosis is a benign disease that shares some malignant features. Epithelial-mesenchymal transition (EMT) is involved in the pathogenesis of endometriosis. Metastasis-associated protein 1 (MTA1) plays an important role in various cancers by promoting EMT, yet there are no studies on its function in endometriosis. In the present study, we found that MTA1 was highly expressed in the ectopic endometrium of endometriosis patients and that the expression of MTA1 was related to the revised American Fertility Society stage. MTA1 facilitated endometrial stroma cell proliferation, migration, and invasion by inducing EMT, and the promotion function and MTA1 expression were suppressed by resveratrol, a natural polyphenol. Moreover, we revealed that MTA1 induced EMT through interaction with ZEB2. The findings in a mouse endometriosis model further showed that MTA1 and ZEB2 were upregulated in ectopic tissues and that resveratrol inhibited the growth of ectopic lesions and expression of MTA1 and ZEB2. Taken together, we demonstrate that MTA1 is a protein that promotes EMT via interacting with ZEB2 in the pathogenesis of endometriosis, and may be a target of resveratrol.

Circular RNA circ-NCOR2 accelerates papillary thyroid cancer progression by sponging miR-516a-5p to upregulate metastasis-associated protein 2 expression.

ObjectivePapillary thyroid cancer (PTC) is one of the most prevalent endocrine malignancies and the fifth most common cancer in women. Circular RNAs (circRNAs) have been shown to play vital functions in cancers, but few studies have focused on the functions and mechanism of dysregulated circRNAs in PTC.MethodsQuantitative reverse transcription PCR was used to measure circ-NCOR2 levels in PTC tissues and cell lines. The functions of circ-NCOR2 in PTC were examined by analysis using the cell counting kit-8, clone forming, flow cytometry, and Transwell experiments. Bioinformatic analysis and dual luciferase reporter gene testing were used to identify the mechanisms of circ-NCOR2.ResultsCirc-NCOR2 overexpression was observed in PTC tissues and cells. Silenced or overexpressed expression of circ-NCOR2 strikingly attenuated or facilitated, respectively, the growth, migration, and invasion of PTC cells. Mechanistically, miR-615a-5p was identified as the target of circ-NCOR2. Moreover, circ-NCOR2 enhanced the expression of metastasis-associated protein 2 (MTA2) by sponging miR-615a-5p, thereby facilitating PTC cell progression.ConclusionsTaken together, our findings reveal a novel circ-NCOR2/miR-615a-5p/MTA2 axis in PTC, which could become a potential therapeutic target for this disease.

Associations of MTA1 expression with CT features, pathology and prognosis of elderly patients with non-small cell lung cancer.

Associations of metastasis-associated protein 1 (MTA1) expression with computed tomography (CT) features, pathology and prognosis of elderly patients with non-small cell lung cancer (NSCLC), and its clinical significance were explored. A total of 98 elderly patients with NSCLC were selected and underwent CT examination. The expression of MTA1 in carcinoma tissues and para-carcinoma normal tissues was detected via immunohistochemistry, and its associations with CT features, pathology and prognosis were analyzed. The results manifested that the expression of MTA1 in carcinoma tissues was significantly higher than that in para-carcinoma normal tissues, and it was associated with the degree of differentiation, stage and lymph node metastasis (P<0.05). Besides, the high expression of MTA1 was also related to the spicule sign, pleural indentation and lymph node metastasis (P<0.05) as well as the CT perfusion parameter capillary permeability (PMB) (P<0.05), but not to blood volume (BV), blood flow (BF) or time to peak (TTP). Moreover, the patients with high expression of MTA1 had significantly shorter survival time and a remarkably lower 5-year survival rate than those with low expression of MTA1 (P<0.05). In conclusion, MTA1 plays a certain role in the occurrence and development of NSCLC in elderly patients and has an association with their prognosis, which can provide references for the treatment and prognosis of NSCLC, with important clinical significance.

Abstract 3466: Can grape powder supplemented diet prevent prostate cancer progression

Abstract Epidemiological and experimental studies suggest a correlation between diet, particularly fat consumption and the risk of developing prostate cancer (PCa). In previous studies, we reported that stilbenes, namely resveratrol and pterostilbene, restrained prostatic intraepithelial neoplasia (PIN) formation and reduced tumor development and progression in mice models of PCa with high expression of metastasis-associated protein 1 (MTA1), an epigenetic modifier involved in the regulation of prostate cancer progression and metastasis. In this report, we evaluated three major aspects: 1) whether altering diet [low fat diet (LFD) versus high fat diet (HFD)] affects PCa progression; 2) whether grape powder (GP) supplementation to the diets protects against PCa progression, and 3) whether MTA1 targeting is the main mechanism of action. We addressed these questions by utilizing the prostate-specific (PB-Cre4) Pten heterozygous transgenic mice (Pten+/f), which mimic slow-growing PCa progression in humans. Upon accumulating 56 mice of desired genotype, we randomized mice in two major groups and fed them ad libitum with either LFD or HFD. Each of these diets contained either 0% GP or 10% GP supplementation. The same groups were assigned for control wild-type (WT) mice (Pten+/f; Cre-). After 33 weeks on corresponding diets, mice were sacrificed and urogenital system was collected for histological and immunochemical analysis. In addition, protein and RNA was isolated from the prostate tissues for molecular analysis. Blood was also collected for cytokines evaluation and pharmacokinetic analysis. The results demonstrated the following beneficial effects of GP supplementation: LFD and HFD - fed Pten+/f mice showed added favorable histopathology (H&amp;E), intact basal layer (SMA) and luminal cells (CK-8); significant reduction of the proliferative rate of prostate epithelial cells (Ki67); non-significant trend for reducing HFD-induced MTA1 expression in Pten+/f and WT mice; protective effects against “bad” genotype and HFD-induced activation of Akt pathway; attenuation of HFD-associated increase in AR levels in both Pten+/f and WT mice; reduction of HFD-provoked increased inflammation marker IL-1β levels; non-significant trend for reducing angiogenesis (CD31; VEGF-C) in Pten+/f mice; and trend towards decreasing inflammatory TGFβ1 expression in Pten+/f mice. Curious results were obtained concerning the effect of GP on apoptosis. There were no significant changes in body weight, food intake or fat intake in GP supplemented diets groups. Citation Format: Tanvi Joshi, Ishani Patel, Avinash Kumar, Virginia Donovan, Anait S. Levenson. Can grape powder supplemented diet prevent prostate cancer progression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3466.

Metastasis-associated protein 1 (MTA1) regulates the catecholamine production homeostasis via transcriptional repression of aromatic l-amino acid decarboxylase (Aadc) in the interstitial cells of Cajal of mouse prostate

Based on the lately identified role for the interstitial cells of Cajal (ICCs) of mouse prostate in catecholamine production, as well as the well-established role for the master coregulator metastasis-associated protein 1 (MTA1) in inflammation, we probed into the functional link between aberrant MTA1 expression and pathogenesis of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) using both a MTA1−/− mouse model of experimental autoimmune prostatitis (EAP) and an in vitro chronic prostatitis model in cultured murine ICCs. EAP-induced MTA1 expression was enriched in ICCs of mouse prostate. EAP resulted in a higher increase in the pelvic pain response in MTA1−/− mice compared to WT mice. Consistently, the ICCs from MTA1−/− mice produced higher levels of catecholamines upon induction of in vitro chronic prostatitis. Mechanistically, MTA1 could directly suppress the transcription of Aadc, a rate-limiting enzyme during catecholamine synthesis, in a HDAC2-depdendent manner. Importantly, treatment with AADC inhibitor NSD-1015 significantly ameliorated EAP-elicited pain response and catecholamine overactivity in MTA1−/− mice. Taken together, our findings reveal an inherent regulatory role of the MTA1/AADC pathway in the maintenance of catecholamine production homeostasis in prostate ICCs, and also point to a potential use of HDAC inhibitors and/or AADC inhibitors to treat CP/CPPS.

MiR-543 promotes tumorigenesis and angiogenesis in non-small cell lung cancer via modulating metastasis associated protein 1

ObjectiveThis study is aimed to explore the role of miR-543 in non-small cell lung cancer (NSCLC), and verify whether miR-543 targets metastasis associated protein 1 (MTA1) to affect tumorigenesis and angiogenesis in NSCLC.MethodsFirstly, miR-543 mimic and inhibitor were transfected into A549 cells and H1299 cells. The cells proliferation was tested by MTT and clone formation. The cells apoptosis was analyzed by cytometry. Tube formation assay was used to measure the vascularization of cells. qRT-PCR and Western Blot were used to measure the MTA1 expression. Dual-luciferase assay was used to analyze whether miR-543 targets MTA1. Secondly, MTA1 mimic and inhibitor were transfected into cells to analyze the effect of MTA1 on proliferation and angiogenesis in NSCLC cells. Lastly, the nude mice were used to verify the effect of miR-543 on tumorigenesis and angiogeneisis in NSCLC via modulating MATA1.ResultsmiR-543 overexpression could apparently promote cells proliferation and angiogeneisis in NSCLC cells. Meanwhile, the MTA1 expression was increased after transfecting miR-543 mimic. Dual luciferase reporter assay revealed MTA1 was a downstream target of miR-543. Further studies showed that inhibition of MTA1 weakened the role of miR-543 overexpression in NSCLC cells. Vivo experiments revealed that miR-543 promoted cells proliferation and angiogenesis in tumor tissues via modulating MTA1.ConclusionmiR-543 could target MTA1 to promote tumorigenesis and angiogenesis in NSCLC via targeting MTA1.

LINC00963 Functions as an Oncogene in Bladder Cancer by Regulating the miR-766-3p/MTA1 Axis.

PurposeLong non-coding RNAs have been found to be involved in bladder cancer development. This article studied LINC00963 effects on bladder cancer progression to provide a novel treatment target.Patients and MethodsTotally 56 bladder cancer patients participated in this research. Bladder cancer cells were transfected. Cell counting kit 8 assay and clone formation experiment were used for cell viability and colony formation detection. Cell migration and invasion were determined by Transwell experiment. LINC00963 distribution was explored by cytoplasmic and nuclear extract isolation and quantitative real-time polymerase chain reaction. Luciferase reporter experiment and RNA pulldown experiment were performed to detect the relationship between these two genes. The cancer genome atlas analysis was used for the detection of metastasis-associated protein 1 (MTA1) expression in bladder cancer.ResultsLINC00963 was seriously up-regulated in bladder cancer patients. High LINC00963 expression indicated high histological grade and low survival. LINC00963 was obviously up-regulated in bladder cancer cells. Knockdown of LINC00963 significantly reduced bladder cancer cells viability, colony formation, migration and invasion. Luciferase reporter experiment and RNA pulldown experiment revealed that LINC00963 promoted MTA1 expression via directly inhibiting miR-766-3p. MTA1 was up-regulated in bladder cancer patients. MTA1 up-regulation reversed the inhibitory effect of LINC00963 knockdown on bladder cancer cell viability, migration and invasion.ConclusionLINC00963 functions as an oncogene in bladder cancer by regulating the miR-766-3p/MTA1 axis.

MTA1 coregulator regulates LDHA expression and function in breast cancer

Metastasis Associated Protein1 (MTA1) is a chromatin modifier and its expression is significantly associated with prognosis of many cancers. However, its role in glucose metabolism remains unexplored. Here, we report that MTA1 has a significant role in glucose metabolism where MTA1 regulates the LDHA expression and activity and subsequently its function in breast cancer motility. The results showed that MTA1 expression is positively correlated with the LDHA expression levels in breast cancer patients. Further, it was found that MTA1 is necessary for the optimal expression of LDHA. The underlying molecular mechanism involves the interaction of MTA1 with c-Myc and recruitment of MTA1-c-Myc complex on to the LDHA promoter to regulate its transcription. Consequently, the LDHA knock down using LDHA specific siRNA in MCF7 cells stably expressing MTA1 reduced the migration of MCF7 cells. Altogether these findings revealed the regulatory role for MTA1 in LDHA expression and its resulting biological function.