Research IndicatorsGraph generated 31 August 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (3)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: MTA1 (cancer-related)
Triple‑negative breast cancer (TNBC) is a subtype of breast cancer. MicroRNA (miR)‑214 is closely associated with controlling the development of tumor cells; therefore, in the present study, the target gene and effects of miR‑214 on TNBC cells were explored. Luciferase activity was examined by luciferase reporter assay. The viability, invasion and migration of MDA‑MB‑231 TNBC cells were measured using Cell Counting kit‑8, Transwell and wound‑healing assays, respectively. The expression levels of various factors were determined using reverse transcription‑quantitative polymerase chain reaction and western blotting. The results demonstrated that the expression levels of miR‑214 were higher and the levels of α1‑antitrypsin (α1‑AT) were lower in TNBC tissues compared with in normal tissues. Subsequently, α1‑AT was revealed to be a target of miR‑214. Furthermore, inhibition of miR‑214 decreased cell viability, invasion and migration, enhanced the expression of E‑cadherin and tissue inhibitor of metalloproteinases‑2, and reduced the expression of metastatic tumour antigen 1 and matrix metalloproteinase‑2. Inhibition of miR‑214 also significantly downregulated the phosphorylation of protein kinase B (Akt) and mammalian target of rapamycin (mTOR), and markedly downregulated that of phosphoinositide 3‑kinase (PI3K); however, the expression levels of total PI3K, Akt and mTOR remained stable in all groups. Taken together, these findings indicated that α1‑AT may be a target of miR‑214. Downregulation of miR‑214 markedly suppressed the viability, migration and invasion of MDA‑MB‑231 cells, and inhibited the PI3K/Akt/mTOR pathway. These findings suggested that miR‑214 targeting α1‑AT may be a potential mechanism underlying TNBC development.
Hannafon BN, Gin AL, Xu YF, et al.Metastasis-associated protein 1 (MTA1) is transferred by exosomes and contributes to the regulation of hypoxia and estrogen signaling in breast cancer cells.
Cell Commun Signal. 2019; 17(1):13 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Exosomes are small membrane-bound vesicles that contribute to tumor progression and metastasis by mediating cell-to-cell communication and modifying the tumor microenvironment at both local and distant sites. However, little is known about the predominant factors in exosomes that contribute to breast cancer (BC) progression. MTA1 is a transcriptional co-regulator that can act as both a co-activator and co-repressor to regulate pathways that contribute to cancer development. MTA1 is also one of the most up-regulated proteins in cancer, whose expression correlates with cancer progression, poor prognosis and increased metastatic potential.
METHODS: We identified MTA1 in BC exosomes by antibody array and confirmed expression of exosome-MTA1 across five breast cancer cells lines. Ectopic expression of tdTomato-tagged MTA1 and exosome transfer were examined by fluorescent microscopy. CRISPR/Cas9 genetic engineering was implemented to knockout MTA1 in MCF7 and MDA-MB-231 breast cancer cells. Reporter assays were used to monitor hypoxia and estrogen receptor signaling regulation by exosome-MTA1 transfer.
RESULTS: Ectopic overexpression of tdTomato-MTA1 in BC cell lines demonstrated exosome transfer of MTA1 to BC and vascular endothelial cells. MTA1 knockout in BC cells reduced cell proliferation and attenuated the hypoxic response in these cells, presumably through its co-repressor function, which could be rescued by the addition of exosomes containing MTA1. On the other hand, consistent with its co-activator function, estrogen receptor signaling was enhanced in MTA1 knockout cells and could be reversed by addition of MTA1-exosomes. Importantly, MTA1 knockout sensitized hormone receptor negative cells to 4-hydroxy tamoxifen treatment, which could be reversed by the addition of MTA1-exosomes.
CONCLUSIONS: This is the first report showing that BC exosomes contain MTA1 and can transfer it to other cells resulting in changes to hypoxia and estrogen receptor signaling in the tumor microenvironment. These results, collectively, provide evidence suggesting that exosome-mediated transfer of MTA1 contributes to BC progression by modifying cellular responses to important signaling pathways and that exosome-MTA1 may be developed as a biomarker and therapeutic target for BC.
BACKGROUND This study aimed to investigate the effects of metastasis-associated 1 (MTA1) gene expression and gene silencing in human non-small cell lung cancer (NSCLC) cells in vitro and on angiogenesis in tumor xenografts in vivo in nude mice. MATERIAL AND METHODS Human H460 and H1299 NSCLC cell lines underwent transfection with lentiviral transfer plasmids (lenti) and short-interfering RNA (si-RNA) and included a control group, a lenti-MTA1 group, a lenti-si-MTA1 group, a lenti control group, and a si-RNA control group. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect MTA1 gene expression after cell transfection. MTA1 transfection was more effective in H460 cells, which were selected for further in vivo studies. Sixty Balb/c nude mice, containing human H460 cell tumor xenografts, included a control group (N=20), a lenti-MTA1 group (N=20), and a lenti-si-MTA1 group (N=20). Tumor tissue immunohistochemistry was used to detect the expression of MTA1 protein and microvessel density (MVD) using CD31. Western blot was used to quantify the expression of cyclooxygenase-2 (COX-2), angiopoietin 1/2 (Ang1/2), hypoxia-inducible factor 1-a (HIF-1a), and vascular endothelial growth factor (VEGF). RESULTS MTA1 silencing with si-RNA significantly reduced the tumor growth rate in nude mice (p<0.01), reduced tumor MVD, and 70% of mice survived for more than 30 days. MTA1 overexpression resulted in the death of all mice at 30 days after tumor inoculation and upregulated the expression of COX-2, Ang1/2, HIF-1a and VEGF, which were down-regulated by MTA1 silencing. CONCLUSIONS MTA1 gene expression promoted angiogenesis in mouse xenografts from human NSCLC cells.
Xue L, Yang DMiR-421 inhibited proliferation and metastasis of colorectal cancer by targeting MTA1.
J BUON. 2018 Nov-Dec; 23(6):1633-1639 [PubMed
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PURPOSE: To investigate the role and molecular mechanism of miR-421 in the development of colorectal cancer (CRC), providing a theoretical basis for the search for new CRC therapeutic targets.
METHODS: 30 pairs of human CRC and cancer-adjacent normal tissue samples were collected. The expression of miR-421 was detected in CRC tissues and cells. On-line target gene prediction software was applied to screen metastasis-associated protein 1 (MTA1), the potential downstream target gene of miR-421. The role of miR-421 in regulating MTA1 and its effect on the expression of epithelial-mesenchymal transition (EMT) markers (E-cadherinand Vimentin) were detected.
RESULTS: Compared with that in adjacent normal tissues and normal human intestinal epithelial cells, the miR-421expression level in CRC tissues and cells was significantly reduced. The potential target of miR-421 was analyzed by three public databases, in which we found that MTA1 was a direct target of miR-421, and miR-421 inhibited the proliferation, invasion, migration and EMT of CRC cells through the targeted regulation of the expression of target gene MTA1, thus effectively suppressing the ability of CRC cells.
CONCLUSIONS: This research demonstrated the suppressive function of miR-421 in CRC. Therefore, the miR-421/MAT1 axis is expected to be one of the targets of CRC targeted therapy.
Bian W, Zhang H, Tang M, et al.Potential Role of microRNA-183 as a Tumor Suppressor in Hepatocellular Carcinoma.
Cell Physiol Biochem. 2018; 51(5):2065-2072 [PubMed
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BACKGROUND/AIMS: Disseminated tumors, known as metastases, are responsible for ninety-percent of mortality due to cancer. Epithelial to mesenchymal transition, a phenomenon required for morphological conversion of non-motile discoid shaped epithelial cells to highly motile spindle-shaped mesenchymal cells, is thought to be a pre-requisite for metastatic progression. Metastasis-associated 1 (MTA1) protein is a prime inducer of EMT and metastatic progression in all solid tumors including hepatocellular carcinoma (HCC). However, the molecular mechanisms that regulate the expression and function of MTA1 in HCC have not been elucidated.
METHODS: In silico prediction algorithms were used to find microRNAs (miRNAs) that may target MTA1. We examined the relationship between the expression of MTA1 and miR-183 using quantitative real time PCR. We also determined the levels of the MTA1 protein using immunohistochemistry. Reporter assays, in the presence and absence of the miR-183 mimic, were used to confirm MTA1 as a bona fide target of miR183. The effect of miR-183 on HCC pathogenesis was determined using a combination of in vitro migration and invasion assay, together with in vivo xenograft experiments. The correlation between miR-183 and MTA1 expression was also studied in samples from HCC patients, and in The Cancer Genome Atlas dataset.
RESULTS: Analysis of the sequence database revealed that MTA1 is a putative target of miR-183. MTA1 protein and RNA expression showed opposite trends to miR-183 expression in breast, renal, prostate, and testicular tissue samples from cancer patients, and in the metastatic HCC cell line HepG2. An inverse correlation was also observed between MTA1 (high) and miR-183 (low) expression within samples from HHC patients and in the TCGA dataset. Reporter assays in HepG2 cells showed that miR-183 could inhibit translation of a reporter harboring the wild-type, but not the mutant miR-183 3'-untranslated region (UTR). In addition, miR-183 significantly inhibited in vitro migration and invasion in HepG2 cells, and in vivo hepatic metastasis.
CONCLUSION: Our results reveal a novel post-transcriptional regulatory mechanism for MTA1 expression via miR-183, which is suppressed during HCC pathogenesis.
Sun X, Zhang Y, Li B, Yang HMTA1 promotes the invasion and migration of pancreatic cancer cells potentially through the HIF-α/VEGF pathway.
J Recept Signal Transduct Res. 2018; 38(4):352-358 [PubMed
] Related Publications
The metastasis-associated gene 1 (MTA1) has previously been recognized as an oncogene, and abnormal MTA1 expression has been related to progression of numerous cancer types to the metastasis stage. However, the function of MTA1 in the regulation of pancreatic cancer progression and metastasis remains unclear. Western blot analysis was adopted to determine the expression of MTA1 in pancreatic cancer tissues and corresponding near normal tissues. Steady clone with MTA1-overexpression and MTA1-inhibitionweregenerated via lentivirus technology in BxPc-3 cells. Transwell assay was carried out for detecting the invasion of pancreatic cancer cells. The migration activity was assessed using the wound scratch assay. The effect of MTA1 in pancreatic cancer was evaluated in the mice xenografts. Western blot analysis was employed to determine the expression of hypoxia inducible factor-α (HIF-α) and vascular endothelial growth factor (VEGF) in vitro and in vivo. We observed that MTA1 overexpression enhanced migration and invasion ability of pancreatic cancer cells in vitro and increased HIF-α and VEGF protein levels in vitro and in vivo. MTA1 inhibition had the opposite effects. MTA1 protein level was positively related to HIF-α and VEGF protein levels. These results indicated that MTA1 potentially promoted pancreatic cancer metastasis via HIF-α/VEGF pathway. This research supplies a new molecular mechanism for MTA1 in the pancreatic cancer progression and metastasis. MTA1 may be an effective therapy target in pancreatic cancer.
In this study, we aimed to assess the independent prognostic value of miR-361-3p in terms of overall survival (OS) and recurrence-free survival (RFS) in cervical cancer, as well as its possible regulative network. A retrospective analysis was performed by using data from the Cancer Genome Atlas-Cervical Cancer (TCGA-CESC). Results showed that decreased miR-361-3p expression was associated with lymphovascular invasion and poor responses to primary therapy. The patients with recurrence and the deceased cases had substantially lower miR-361-3p expression compared to their respective controls. By generating Kaplan-Meier curves of OS and RFS, we found that high miR-361-3p expression was associated with better survival outcome. More importantly, univariate and multivariate analysis confirmed that high miR-361-3p expression was an independent indicator of favorable OS (HR: 0.377, 95% CI: 0.233-0.608,
BACKGROUND: In the past 2 decades, metastasis-associated gene 1 (MTA1) has attracted attention for its close association with cancer progression and its roles in chromatin remodeling processes, making it a central gene in cancer. The present meta-analysis was performed to assess MTA1 expression in solid tumors.
MATERIALS AND METHODS: This analysis identified studies that evaluated the relationship between MTA1 expression and clinical characteristics or prognosis of patients with solid tumors via the PubMed, Cochrane Library, and Embase electronic databases. Fixed-effect and random-effect meta-analytical techniques were used to correlate MTA1 expression with outcome measures. The outcome variables are shown as odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI).
RESULTS: Analysis of 40 cohort studies involving 4564 cancer patients revealed a significant association of MTA1 overexpression with tumor patient age (>50 vs. <50 years: combined OR 0.73, 95% CI 0.57-0.94), tumor grade (G3/4 vs. G1/2: combined OR 1.94, 95% CI 1.48-2.53), tumor size (>3 cm vs. <3 cm: combined OR 2.35, 95% CI 1.73-3.19), T stage (T3/4 vs. T1/2: combined OR 2.11, 95% CI 1.74-2.56), lymph node metastasis (yes vs. no: combined OR 2.92, 95% CI 2.26-3.75), distant metastasis (yes vs. no: combined OR 2.26, 95% CI 1.42-3.59), TNM stage (III/IV vs. I/II: combined OR 2.50, 95% CI 1.84-3.38), vascular invasion (yes vs. no: combined OR 2.26, 95% CI 1.92-3.56), and poor overall survival time (HR 1.83; 95% CI: 1.53-2.20; P = .000).
CONCLUSIONS: Our analyses demonstrate that MTA1 was an effective predictor of a worse prognosis in tumor patients. Moreover, MTA1 may play important role in tumor progression and outcome, and targeting MTA1 may be a new strategy for anti-cancer therapy.
BACKGROUND/AIMS: Atrophic gastritis (AG), intestinal metaplasia (IM), and Helicobacter pylori (HP) are the risk factors for the development of gastric cancer (GC). Chromatin remodeling is one of the epigenetic mechanisms involved in the carcinogenesis of GC. The purpose of this study was to investigate the expression profiles of defined chromatin remodeling genes in gastric mucosal samples and their values as gastric carcinogenesis biomarkers.
MATERIALS AND METHODS: In total, 95 patients were included in the study. Patients were divided into 3 groups as: GC group (n=34), AG group (n=36), and control group (n=25). AG group was further divided into subgroups based on the presence of HP and IM in gastric mucosa. Chromatin remodeling gene expressions were analyzed using real-time PCR (RT-PCR) array in all groups. Data were evaluated using the RT-qPCR primer assay data analysis software.
RESULTS: EED, CBX3, and MTA1 were more overexpressed, whereas ARID1A, ING5, and CBX7 were more underexpressed in the AG and GC groups compared with the controls. No significant differences were observed between the AG and GC groups concerning the expression of these 6 genes, although the fold change levels of these genes in the GC group were well above than in the AG group. EED, CBX3, and MTA1 were significantly more overexpressed in HP- and IM-positive AG subgroup compared with the HP- or IM-negative AG subgroup.
CONCLUSION: In conclusion, our results provide an evidence of epigenetic alterations in AG. Expressions of EED, CBX3, MTA1, ARID1A, ING5, and CBX7 may be considered as promising markers to be used in GC screening for patients with AG.
Metastasis-associated gene 1 (MTA1) is correlated with prognosis of many tumors. However, little is known about the role of MAT1 in endometriosis and its relationship with the recurrence of endometriosis.The expression of MTA1 in normal, eutopic and ectopic endometrium was detected by immunohistochemistry and RT-PCR, respectively. The relationship of MTA1 expression with the recurrence of endometriosis was evaluated.In the normal endometrium, eutopic endometrium and ectopic endometrium, the positive rates of MTA1 expression showed a gradually increasing trend. In addition, the MTA1 expression difference between each two groups was significant (P < .0125). However, there was no significant difference between proliferative phase and secretory phase in each group (P > .05). In the ectopic endometrium, MTA1 expression in the severe phases (III-IV) was significantly higher than that in mild phases (I-II) (P < .05), indicating the expression of MTA1 correlates with r-AFS staging (P < .05). Additionally, the MTA1 mRNA level was also closely related to the stages of r-AFS, but not to the proliferative phase or secretory phase of endometrium. Logistic regression analysis showed that r-AFS stage and MTA1 overexpression were risk factors for the recurrence of endometriosis. While, postoperative pregnancy was a protective factor for its relapse.MTA1 is closely associated with the occurrence and development of Ems. Thus, MTA1 level may be used as a new indicator to predict the progression of endometriosis.
Prostate cancer often metastasizes to the bone, leading to morbidity and mortality. While metastasis-associated protein 1 (MTA1) is highly overexpressed in metastatic tumors and bone metastatic lesions, its exact role in the development of metastasis is unknown. Here, we report the role of MTA1 in prostate cancer progression and bone metastasis in vitro and in vivo. We found that MTA1 silencing diminished formation of bone metastases and impaired tumor growth in intracardiac and subcutaneous prostate cancer xenografts, respectively. This was attributed to reduced colony formation, invasion, and migration capabilities of MTA1 knockdown cells. Mechanistic studies revealed that MTA1 silencing led to a significant decrease in the expression of cathepsin B (CTSB), a cysteine protease critical for bone metastasis, with an expected increase in the levels of E-cadherin in both cells and xenograft tumors. Moreover, meta-analysis of clinical samples indicated a positive correlation between MTA1 and CTSB. Together, these results demonstrate the critical role of MTA1 as an upstream regulator of CTSB-mediated events associated with cell invasiveness and raise the possibility that targeting MTA1/CTSB signaling in the tumor may prevent the development of bone metastasis in prostate cancer.
Chen WH, Cai MY, Zhang JX, et al.FMNL1 mediates nasopharyngeal carcinoma cell aggressiveness by epigenetically upregulating MTA1.
Oncogene. 2018; 37(48):6243-6258 [PubMed
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It has been suggested that formin-like protein 1 (FMNL1) plays an important role in the pathogenic process of several hematopoietic malignancies. In this study, we performed a series of in vivo and in vitro assays to elucidate the biological functions of FMNL1 and underlying mechanisms in human nasopharyngeal carcinoma (NPC) pathogenesis. Herein, we report that high expression of FMNL1 in NPC is positively associated with an aggressive disease and/or poor patient survival. Ectopic overexpression of FMNL1 in NPC cells substantially promoted cell invadopodia formation, epithelial-mesenchymal transition (EMT) and invasiveness, whereas depletion of FMNL1 potently suppressed NPC cells invadopodia formation, EMT, and invasive/metastatic capacities. We further show that FMNL1 could enhance NPC cell aggressiveness by increasing a key downstream target, the metastasis-associated protein 1 (MTA1) gene. Importantly, ectopic overexpression of FMNL1 in NPC cells markedly improved the binding of HDAC1 with Profilin2 in the cytoplasm and suppressed the enrichment of HDAC1 on the promoter of MTA1 and thereby, leading to an increased MTA1 transcription and expression. Furthermore, in addition to the amplification of FMNL1 gene, decreased level of miR-16 in NPCs is another critical mechanism to upregulate FMNL1 expression. These results, collectively, provide first-line of evidences that high expression of FMNL1, resulted from decreased miR-16 and/or MTA1 amplification, has a potent oncogenic role to drive the development and aggressive process of NPC by upregulating MTA1, and FMNL1 might be employed as a new prognostic biomarker and therapeutic target for human NPC.
Epstein-Barr virus (EBV)-associated Burkitt's lymphoma is characterised by the deregulation of c-Myc expression and a restricted viral gene expression pattern in which the EBV nuclear antigen-1 (EBNA1) is the only viral protein to be consistently expressed. EBNA1 is required for viral genome propagation and segregation during latency. However, it has been much debated whether the protein plays a role in viral-associated tumourigenesis. We show that the lymphomas which arise in EµEBNA1 transgenic mice are unequivocally linked to EBNA1 expression and that both C-Myc and Mdm2 deregulation are central to this process. Tumour cell survival is supported by IL-2 and there is a skew towards CD8-positive T cells in the tumour environment, while the immune check-point protein PD-L1 is upregulated in the tumours. Additionally, several isoforms of Mdm2 are upregulated in the EµEBNA1 tumours, with increased phosphorylation at ser166, an expression pattern not seen in Eµc-Myc transgenic tumours. Concomitantly, E2F1, Xiap, Mta1, C-Fos and Stat1 are upregulated in the tumours. Using four independent inhibitors of Mdm2 we demonstrate that the EµEBNA1 tumour cells are dependant upon Mdm2 for survival (as they are upon c-Myc) and that Mdm2 inhibition is not accompanied by upregulation of p53, instead cell death is linked to loss of E2F1 expression, providing new insight into the underlying tumourigenic mechanism. This opens a new path to combat EBV-associated disease.
Li YH, Zhong M, Zang HL, Tian XFThe E3 ligase for metastasis associated 1 protein, TRIM25, is targeted by microRNA-873 in hepatocellular carcinoma.
Exp Cell Res. 2018; 368(1):37-41 [PubMed
] Related Publications
Tumor metastasis accounts for 90% of all cancer-related deaths. Epithelial to mesenchymal transition (EMT) considered to be centrally important in acquired resistance to chemotherapy and in progression of tumors to secondary organs. One of the important mediators of metastatic progression in hepatocellular carcinoma (HCC) is the metastasis associated protein 1 (MTA-1). We have earlier shown that in the context of HCC and normal liver cell lines, MTA-1 protein is actively stabilized in HCC cell lines and actively degraded in normal liver cells. We have also shown that TRIM25 is the E3 ligase that interacts with and degrades MTA-1 protein. The identity of the factor regulating expression of TRIM25 in normal liver cells and HCC is unknown. In the current work we elucidate that microRNA (miR)- 873 targets TRIM25 in HCC cells. Both metagenomic analysis and quantification of miR-873 and TRIM25 in 25 HCC patients revealed an inverse correlation between the two in HCC patients with high miR-873 and low TRIM25 expression, respectively. The expression pattern was mimicked in the normal liver cells THLE-2 and the HCC cell line, HuH6. In vitro luciferase reporter assays confirmed TRIM25 as the target of miR-873. Transient transfection of HuH6 cells with an anti-miR-873 antagomir significantly decreased both transwell motility in these cells. Furthermore, in in vivo xenograft assays treatment with anti-miR-873 antagomir significantly decreased hepatic nodules formation. Cumulatively, our data indicate that suppression of TRIM25 expression by high levels of miR-873 dictates MTA1 protein upregulation in HCC.
Qian YY, Liu ZS, Yan HJ, et al.Pterostilbene inhibits MTA1/HDAC1 complex leading to PTEN acetylation in hepatocellular carcinoma.
Biomed Pharmacother. 2018; 101:852-859 [PubMed
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PURPOSE: The aim of this study is to investigate the inhibition of cancer growth by pterostilbene through Metastasis-Associated Protein 1 (MTA1) and the histone deacetylase 1 (HDAC1) complex in hepatocellular carcinoma (HCC).
METHODS: We investigate the antitumor effects of pterostilbene (PTER) in HCC. The SMMC-7721 hepatoma cell line was cultured and treated with PTER for different time depending on the experiment. After treatment, we tested the cellular expression of proteins by Western blot and the expression of MTA1 mRNA by real-time PCR. And the immunoprecipitation was performed to confirm the acetylation in PTEN. Animal models have been established to confirm the anti-cancer effects of PTER.
RESULTS: PTER treatment could downregulate the expression of MTA1, and HDAC1 and elevates the Ac-PTEN ratio in tumors. The results suggest that PTER can decrease the expression of MTA1 and destabilize the MTA1/HDAC1 complex allowing acetylation/activation of PTEN on Lys
CONCLUSION: We demonstrated that PTER suppressed the growth, and invasion of HCC and was effective in regulating the levels of the MTA1/HDAC1/NuRD complex, promoting PTEN acetylation and apoptosis in HCC. Our findings suggest that the novel epigenetic nature of PTER anticancer activity opens up new avenues for primary chemoprevention, as well as anticancer and antimetastatic treatment.
Yang CL, Zheng XL, Ye K, et al.MicroRNA-183 Acts as a Tumor Suppressor in Human Non-Small Cell Lung Cancer by Down-Regulating MTA1.
Cell Physiol Biochem. 2018; 46(1):93-106 [PubMed
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BACKGROUNDS/AIMS: MicroRNAs (miRs) often contribute to the progression of non-small cell lung cancer (NSCLC) via regulation of mRNAs that are involved in lung homeostasis. We conducted a study aimed at exploring the roles of miR-183 in the proliferation, epithelial-mesenchymal transition (EMT), invasion and migration of human NSCLC cells via targeting MTA1.
METHODS: NSCLC and adjacent normal tissues were collected from 194 patients with NSCLC. Positive expression of MTA1 protein was detected by immunohistochemistry. The highest levels of expression of miR-183 were detected using RT-qPCR in SPC-A-1 cells, which were selected and assigned to the following groups: blank, negative control (NC), miR-183 mimic, miR-183 inhibitor, siRNA-MTA1, and miR-183 inhibitor + siRNA-MTA1. The expression of miR-183 and the mRNA and protein expression of MTA1, E-cadherin, Vimentin, Snail, PCNA, Bax and Bcl-2 in tissues and transfected cells were measured using RT-qPCR and western blot analysis. Cell proliferation, apoptosis, migration and invasion were evaluated by CCK-8, flow cytometry, scratch tests and Transwell assays. Tumor xenografts were conducted in nude mice to determine tumor growth.
RESULTS: SPC-A-1 cells with the highest levels of miR-183 expression were selected. Compared with adjacent normal tissues, the expression of miR-183 and the mRNA and protein expression of E-cadherin and Bax were decreased in NSCLC tissues, while mRNA and protein expression of MTA1, Vimentin, snail, PCNA and Bcl-2 were increased. MiR-183 was over-expressed in the miR-183 mimic group and under-expressed in the miR-183 inhibitor and miR-183 inhibitor + siRNA-MTA1 groups. In the miR-183 mimic and siRNA-MTA1 groups, the mRNA and protein expression of E-cadherin and Bax, as well as cell apoptosis, were enhanced, while the expression levels of MTA1, Vimentin, snail, PCNA and Bcl-2 mRNA and protein, cell proliferation, migration, invasion and tumor growth were reduced relative to the blank and NC groups. The miR-183 inhibitor group exhibited an opposite trend.
CONCLUSION: Our study indicates that miR-183 down-regulates MTA1 to inhibit the proliferation, EMT, migration and invasion of human NSCLC cells.
BACKGROUND: Cancer progression and metastasis is profoundly influenced by protein kinase D1 (PKD1) and metastasis-associated protein 1 (MTA1) in addition to other pathways. However, the nature of regulatory relationship between the PKD1 and MTA1, and its resulting impact on cancer metastasis remains unknown. Here we present evidence to establish that PKD1 is an upstream regulatory kinase of MTA1.
METHODS: Protein and mRNA expression of MTA1 in PKD1-overexpressing cells were determined using western blotting and reverse-transcription quantitative real-time PCR. Immunoprecipitation and proximity ligation assay (PLA) were used to determine the interaction between PKD1 and MTA1. PKD1-mediated nucleo-cytoplasmic export and polyubiquitin-dependent proteosomal degradation was determined using immunostaining. The correlation between PKD1 and MTA1 was determined using intra-tibial, subcutaneous xenograft, PTEN-knockout (PTEN-KO) and transgenic adenocarcinoma of mouse prostate (TRAMP) mouse models, as well as human cancer tissues.
RESULTS: We found that MTA1 is a PKD1-interacting substrate, and that PKD1 phosphorylates MTA1, supports its nucleus-to-cytoplasmic redistribution and utilises its N-terminal and kinase domains to effectively inhibit the levels of MTA1 via polyubiquitin-dependent proteosomal degradation. PKD1-mediated downregulation of MTA1 was accompanied by a significant suppression of prostate cancer progression and metastasis in physiologically relevant spontaneous tumour models. Accordingly, progression of human prostate tumours to increased invasiveness was also accompanied by decreased and increased levels of PKD1 and MTA1, respectively.
CONCLUSIONS: Overall, this study, for the first time, establishes that PKD1 is an upstream regulatory kinase of MTA1 status and its associated metastatic activity, and that the PKD1-MTA1 axis could be targeted for anti-cancer strategies.
The homeodomain transcription factor SIX3 was recently reported to be a negative regulator of the Wnt pathway and has an emerging role in cancer. However, how SIX3 contributes to tumorigenesis and metastasis is poorly understood.
METHODS: We employed affinity purification and mass spectrometry (MS) to identify the proteins physically associated with SIX3. Genome-wide analysis of the SIX3/LSD1/NuRD(MTA3) complex using a chromatin immunoprecipitation-on-chip approach identified a cohort of target genes including
RESULTS: We demonstrate that the SIX3/LSD1/NuRD(MTA3) complex inhibits carcinogenesis in breast cancer cells and suppresses metastasis in breast cancer. SIX3 expression is downregulated in various human cancers and high SIX3 is correlated with improved prognosis.
CONCLUSION: Our study revealed an important mechanistic link between the loss of function of SIX3 and tumor progression, identified a molecular basis for the opposing actions of MTA1 and MTA3, and may provide new potential prognostic indicators and targets for cancer therapy.
Hypermethylated-in-Cancer 1 (Hic1) is a tumor suppressor gene frequently inactivated by epigenetic silencing and loss-of-heterozygosity in a broad range of cancers. Loss of HIC1, a sequence-specific zinc finger transcriptional repressor, results in deregulation of genes that promote a malignant phenotype in a lineage-specific manner. In particular, upregulation of the HIC1 target gene SIRT1, a histone deacetylase, can promote tumor growth by inactivating TP53. An alternate line of evidence suggests that HIC1 can promote the repair of DNA double strand breaks through an interaction with MTA1, a component of the nucleosome remodeling and deacetylase (NuRD) complex. Using a conditional knockout mouse model of tumor initiation, we now show that inactivation of Hic1 results in cell cycle arrest, premature senescence, chromosomal instability and spontaneous transformation in vitro. This phenocopies the effects of deleting Brca1, a component of the homologous recombination DNA repair pathway, in mouse embryonic fibroblasts. These effects did not appear to be mediated by deregulation of Hic1 target gene expression or loss of Tp53 function, and rather support a role for Hic1 in maintaining genome integrity during sustained replicative stress. Loss of Hic1 function also cooperated with activation of oncogenic KRas in the adult airway epithelium of mice, resulting in the formation of highly pleomorphic adenocarcinomas with a micropapillary phenotype in vivo. These results suggest that loss of Hic1 expression in the early stages of tumor formation may contribute to malignant transformation through the acquisition of chromosomal instability.
Zhang Z, Liu T, Yu M, et al.The plant alkaloid tetrandrine inhibits metastasis via autophagy-dependent Wnt/β-catenin and metastatic tumor antigen 1 signaling in human liver cancer cells.
J Exp Clin Cancer Res. 2018; 37(1):7 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Tetrandrine is a bisbenzylisoquinoline alkaloid isolated from the Chinese medicinal herb Stephania tetrandra S. Moore. We previously demonstrated that tetrandrine exhibits potent antitumor effects in many types of cancer cells. In this study, we investigated the effects of tetrandrine on human hepatocellular carcinoma (HCC) metastasis.
METHODS: The invasion and migration effects were evaluated via wound healing and transwell assays. Immunofluorescence and western blotting analyses were used to investigate the levels of epithelial-mesenchymal transition (EMT)-related protein. A metastasis model was established to investigate the inhibitory effect of tetrandrine on hepatocellular carcinoma metastasis in vivo.
RESULTS: Tetrandrine inhibits HCC invasion and migration by preventing cell EMT. The underlying mechanism was closely associated with tetrandrine-induced human liver cell autophagy, which inhibits Wnt/β-catenin pathway activity and decreases metastatic tumor antigen 1 (MTA1) expression to modulate cancer cell metastasis.
CONCLUSION: Our findings demonstrate, for the first time, that tetrandrine plays a significant role in the inhibition of human hepatocellular carcinoma metastasis and provide novel insights into the application of tetrandrine in clinical HCC treatment.
Butt G, Attar R, Tabassum S, et al.Regulation of signal transduction cascades by Pterostilbenes in different cancers: Is it a death knell for oncogenic pathways.
Cell Mol Biol (Noisy-le-grand). 2017; 63(12):5-10 [PubMed
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Interdisciplinary research has revolutionized the field of medicine and we have witnessed exponential increase in the high-impact research in past few decades. However, the road to this burgeoning research field is obstacle-ridden because of intratumor heterogeneity, loss of apoptosis and dysregulation of spatio-temporally controlled signaling pathways. Ground-breaking findings obtained through genetic, genomic and proteomic studies have considerably improved our concepts related to the complexity of protein network and excitingly, discovery of miRNAs has added another layer of intricacy to quantitatively regulated gene networks. In this review, we chronicle the milestone achievements and discuss how Pterostilbenes effectively regulated different cellular pathways. We have provided detailed mechanistic insights related to regulation of JAK-STAT signaling, Notch pathway, Wnt mediated intracellular signaling by pterostilbene. Underlying mechanisms about regulation of PI3K/AKT and MAPK pathways by pterostilbene in different cancers. Regulation of Metastasis-associated protein 1 (MTA1) proteins and Human telomerase reverse transcriptase (hTERT) in cancer cells by pterostilbene. Pterostilbene has also been reported to modulate the expression of various oncogenic and tumor suppressor microRNAs in cancer cells. Better and sharper comprehension of the concepts associated with the modes of action of pterostilbene in different cancers will be useful in identification of cancers which can be efficiently targeted by pterostilbene.
Lu B, Lian R, Wu Z, et al.MTA1 promotes viability and motility in nasopharyngeal carcinoma by modulating IQGAP1 expression.
J Cell Biochem. 2018; 119(5):3864-3872 [PubMed
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Nasopharyngeal carcinoma (NPC) is frequently seen in Chinese, especially the population that resides in southeast China. Metastasis-associated protein 1 (MTA1) is a chromatin modifier and plays a role in tumor cell metastasis. IQGAP1 is a ubiquitously expressed protein that contributes to cytoskeleton remodeling. This study aimed to investigate the role of MTA1 and IQGAP1 in NPC malignant transformation. MTA1 and IQGAP1 expression in NPC (n = 43) and control tissues (n = 31) were detected using qRT-PCR, immunoblot, and immunohistochemistry. MTA1 was overexpressed in CNE-1 and CNE-2 cell line by pcDNA3.1/MTA1 transfection. Dominant-negative p53 was transfected to inhibit p53 activity. si-IQGAP1 or dominant-negative IQGAP1 (IQGAP1ΔGRD) was used to suppress IQGAP1 activity. Cell proliferation was measured by CKK-8 assay. Cell migration was evaluated by Transwell assay. The results showed that MTA1 and IQGAP1 were highly expressed in NPC tissues compared with the controls. Forced expression of MTA1 accelerated cell proliferation and migration and upregulated IQGAP1 expression in a p53-independent way. Knockdown of IQGAP1 or transfection of dominant-negative IQGAP1 impeded tumor cell proliferation and migration as well as PI3K/Akt signaling induced by MTA1. In conclusion, MTA1 participates in NPC malignant transformation via regulating IQGAP1 expression and PI3K/Akt signaling pathway.
Malisetty VL, Penugurti V, Panta P, et al.MTA1 expression in human cancers - Clinical and pharmacological significance.
Biomed Pharmacother. 2017; 95:956-964 [PubMed
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Remarkably, majority of the cancer deaths are due to metastasis, not because of primary tumors. Metastasis is one of the important hallmarks of cancer. During metastasis invasion of primary tumor cells from the site of origin to a new organ occurs. Metastasis associated proteins (MTAs) are a small family of transcriptional coregulators that are closely associated with tumor metastasis. These proteins are integral components of nuclear remodeling and deacetylation complex (NuRD). By virtue of being integral components of NuRD, these proteins regulate the gene expression by altering the epigenetic changes such as acetylation and methylation on the target gene chromatin. Among the MTA proteins, MTA1 expression is very closely correlated with the aggressiveness of several cancers that includes breast, liver, colon, pancreas, prostate, blood, esophageal, gastro-intestinal etc. Considering its close association with aggressiveness in human cancers, MTA1 may be considered as a potential therapeutic target for cancer treatment. The recent developments in its crystal structure further strengthened the idea of developing small molecule inhibitors for MTA1. In this review, we discuss the recent trends on the diverse functions of MTA1 and its role in various cancers, with the focus to consider MTA1 as a 'druggable' target in the control of human cancers.
Wang X, Qiu LW, Peng C, et al.MicroRNA-30c inhibits metastasis of ovarian cancer by targeting metastasis-associated gene 1.
J Cancer Res Ther. 2017; 13(4):676-682 [PubMed
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BACKGROUND: It is important to find reliable molecular markers or biological targets that associate with ovarian cancer (OC) metastasis for diagnosis and treatment. In this study, researchers investigated the regulated chain of microRNA-30c (miR-30c) and metastasis-associated gene 1 (MTA1) in OC tissues and cells.
MATERIALS AND METHODS: Expression of miR-30c and MTA1 was detected with quantitative real-time polymerase chain reaction and immunohistochemistry in 33 OC and matched adjacent tissues. MiR-30c mimics were synthetized and transfected into SKOV3 cells to target MTA1. The wound healing and transwell assays were detected to observe migration and invasion of transfected OC cells.
RESULTS: Compared with matching normal ovarian tissues, the MTA1 expression was upregulated and localized in the cytoplasm, and the expression of miR-30c was significantly reduced. The expression intensity of MTA1 was correlated with the Federation of Gynecology and Obstetrics stage, tumor grade, and metastasis of OC. Transfecting miR-30c mimics could significantly reduce the expression of MTA1 in SKOV3 cells and obviously inhibit the migration and invasion of SKOV3 cells.
CONCLUSION: MiR-30c and MTA1 abnormally expressed in OC, which may be related to metastasis of OC. In MiR-30c as a tumor suppressor gene, its expression in OC could lead to reduced expression of MTA1, which may be one of the mechanisms of metastasis of OC cells.
Jiang L, Wang WJ, Li ZW, Wang XZDownregulation of Piwil3 suppresses cell proliferation, migration and invasion in gastric cancer.
Cancer Biomark. 2017; 20(4):499-509 [PubMed
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BACKGROUND: Gastric cancer is one of the most common malignancies worldwide. Recent studies reported that Piwil3 was overexpressed in various cancers, including gastric cancer (GC). This study was intended to investigate its function and mechanism in GC progress.
METHODS: Quantitative real time PCR(RT-PCR) and western blotting assays were utilized to measure mRNA and protein expression levels, respectively. SiRNA transfection was performed to suppress the expression of Piwil3. CCK-8 assay, cell invasion and migration assays were used to determine the cell proliferative, cell invasive and migratory ability.
RESULTS: The expression of Piwil3 was significantly increased in GC tissues compared with matched normal tissues. The specific siRNA significantly inhibited the protein and mRNA expressions of Piwil3, and effectively inhibited the proliferation and induced G0/G1 phase arrest in GC cells. Downregulation of Piwil3 significantly suppressed the migration and invasion of GC cells. Moreover, the downregulation of Piwil3 also significantly suppressed the tumor volumes in nude mice. Mechanism investigation showed that the downregulation of Piwil3 significantly decreased the mRNA and protein expressions of metastasis-related genes, including RhoC, MTA1, MMP2 and MMP9, and also modulated the phosphorylation levels of JAK2 and STAT3 but not their protein levels.
CONCLUSIONS: These findings indicate that overexpression of Piwil3 promotes the proliferation, migration and invasion of GC cells partially through JAK2/STAT3 signal pathway.
Zang HL, Ren SN, Cao H, Tian XFThe ubiquitin ligase TRIM25 inhibits hepatocellular carcinoma progression by targeting metastasis associated 1 protein.
IUBMB Life. 2017; 69(10):795-801 [PubMed
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Metastasis associated 1 protein (MTA1) is one of the prime facilitators of metastatic progression in all solid tumors including hepatocellular carcinoma (HCC). However, the underlying regulatory mechanism of MTA1 expression in HCC is not clear. In this study, we evaluated MTA1 transcript and protein expression in HCC and normal hepatic cell lines. The results revealed that MTA1 protein expression had a significantly increase in HCC cell line, HuH6, compared with that in normal hepatic cell line, THLE-2. Determination of protein half-life using cycloheximide (CHX) treatment did not reveal any statistically significant difference in protein turn-over rates between THLE-2 (3.3 ± 0.25 h) and HuH6 (3.6 ± 0.15 h) cell lines. MTA1 protein level was stabilized in THLE-2 cells after treatment with MG-132 to levels similar to those observed in HuH6 cells. Mass spectrometric analysis of FLAG immunoprecipitates of FLAG-MTA1 transfected THLE-2 cells after MG-132 treated revealed candidate ubiquitin ligases that were interacting with MTA1. RNAi-mediated silencing of each prospective ubiquitin ligase in THLE-2 cells indicated that knockdown of TRIM25 resulted in stabilization of MTA1 protein, indicating TRIM25 as a putative E3 ligase for MTA1. Coimmunoprecipitation of FLAG-tagged MTA1, but not IgG, in MG-132 treated and untreated THLE-2 cells cotransfected with either FLAG-MTA1 or Myc-TRIM25 revealed robust polyubiquitinated MTA1, confirming that the TRIM25 is the ubiquitin ligase for MTA1 degradation. Overexpression of TRIM25 in HuH6 and RNAi mediated silencing of TRIM25 in THLE-2 cells inhibited and increased the cell migration and invasion, respectively. Analysis of The Cancer Genome Atlas data for assessment of TRIM25 transcript level and MTA1 protein expression in 25 HCC patients confirmed an inverse correlation between the expression of TRIM25 and MTA1. Cumulatively, our data reveal a novel mechanism of post-translational to regulate MTA1 expression in normal hepatic cells, which is repressed in HCC. © 2017 IUBMB Life, 69(10):795-801, 2017.
Colorectal cancer (CRC) is one of the most common human cancers and the cause of about 700000 deaths per year worldwide. Deregulation of the WNT/β-catenin pathway is a key event in CRC initiation. This pathway interacts with other nuclear signaling pathways, including members of the nuclear receptor superfamily and their transcription coregulators. In this review, we provide an overview of the literature dealing with the main coactivators (NCoA-1 to 3, NCoA-6, PGC1-α, p300, CREBBP and MED1) and corepressors (N-CoR1 and 2, NRIP1 and MTA1) of nuclear receptors and summarize their links with the WNT/β-catenin signaling cascade, their expression in CRC and their role in intestinal physiopathology.
Honjo H, Toh Y, Sohda M, et al.Clinical Significance and Phenotype of MTA1 Expression in Esophageal Squamous Cell Carcinoma.
Anticancer Res. 2017; 37(8):4147-4155 [PubMed
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BACKGROUND/AIM: Metastasis-associated gene 1 (MTA1) is considered a potential prognostic factor in esophageal cancer. We investigated the clinical relationship between MTA1, LAT1, and tumor metabolism, as evaluated by positron emission tomography (PET) in esophageal squamous cell carcinoma.
MATERIALS AND METHODS: We analyzed 142 esophageal squamous cell carcinoma patients who underwent curative resection without preoperative treatment. MTA1 expression was assessed by immuno-zahistochemistry, and tested against standardized uptake values from preoperative PET-CT. The association among MTA1, LAT1, and
RESULTS: MTA1 staining was observed in 82 of 142 cancer tissues. Five-year overall survival was 69.9 % in the absence of MTA1, but 50.7% otherwise (p=0.021), while disease-free survival was 66.5% and 49.0% (p=0.071), respectively. Abnormal
CONCLUSION: MTA1 shows promise as a diagnostic and prognostic marker in esophageal cancer, and we anticipate that the gene will also prove to be a good therapeutic target.
Cao JM, Li GZ, Han M, et al.MiR-30c-5p suppresses migration, invasion and epithelial to mesenchymal transition of gastric cancer via targeting MTA1.
Biomed Pharmacother. 2017; 93:554-560 [PubMed
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BACKGROUND: In China, gastric cancer (GC) is an ordinary malignant tumor. Recent literatures have shown that microRNA is critical during tumorigenesis. This study focuses on the influence of miR-30c-5p on the metastasis of GC and further explores its underlying mechanism.
METHODS: Before the study, expression level of miR-30c-5p and targeted protein was detected in 40 GC tissue samples and 5 GC cells by RT-qPCR. Meanwhile, correlation analysis was conducted between miR-30c-5p expression level and clinicopathological features. In addition, wound healing assay and cell invasion assay were utilized to identify whether miR-30c-5p could affect the migrated and invaded ability of GC cells. Western blotting assay and luciferase assay were used to explore the potential mechanism.
RESULTS: In GC tissues, miR-30c-5p expression level was significantly lower and was remarkably related with clinical features such as tumor node metastasis(TNM) stage and lymphatic metastasis. Moreover, the migrated and invaded ability of GC cells was enhanced through knockdown of miR-30c-5p, while overexpression of miR-30c-5p presented with reversed effect. Further study showed that miR-30c-5p inhibited the expression of its target spot, metastasis-associated protein 1(MTA1), and then suppressed the process of epithelial to mesenchymal transition(EMT) which was important in the metastasis of GC.
CONCLUSION: The results indicate that miR-30c-5p, a novel suppressor in tumorigenesis, could inhibit the metastasis and EMT via MTA1, which may offer a possible therapeutic target in GC.
Huang S, Qin J, Chen J, et al.Impact of laparoscopy on the biological behavior and gene expression of endometrial adenocarcinoma cells.
Gynecol Endocrinol. 2017; 33(11):899-903 [PubMed
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The current study investigated the effect of laparoscopy on the biological behavior and gene expression of endometrial adenocarcinoma cells. Totally, 40 patients with stage I endometrial adenocarcinoma and 20 patients with benign uterine diseases were enrolled in this study. For patients with endometrial adenocarcinoma, laparoscopy was performed in 20 cases and laparotomy was carried out in the other 20 cases. Total laparoscopic hysterectomy was performed in patients with benign diseases. Cell apoptotic rate and the gene expression of N-myc, Fas, metastasis-associated protein 1 (MTA1), and nm23-H1 were determined in the normal and cancerous endometrial tissues both preoperatively and postoperatively. For endometrial adenocarcinoma cells, laparoscopy, instead of laparotomy, promoted the apoptosis of endometrial adenocarcinoma cells, down-regulated the expression of apoptosis suppressor gene N-myc and metastasis-promoting gene MTA1, up-regulated the expression of apoptosis-promoting gene Fas and metastasis suppressor gene nm23-H1. However, laparoscopy did not affect the apoptotic rate and gene expression in normal endometrial cells. Laparoscopy may be used as a safe and effective intervention for endometrial cancer.