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Introduction: Osteosarcoma is a common bone malignant tumor in adolescents with high mortality and poor prognosis. At present, the progress of osteosarcoma and effective treatment strategies are not clear. This study provides a new potential target for the progression and treatment of osteosarcoma. Methods: The relationship between lncRNA PRR7-AS1 and osteosarcoma was analyzed using the osteosarcoma databases and clinical sample testing. Cell function assays and tumor lung metastasis were employed to study the effects of PRR7-AS1 on tumorigenesis in vivo and in vitro. Potential downstream RNF2 of PRR7-AS1 was identified and explored using RNA pulldown and RIP. The GTRD and KnockTF database were used to predict the downstream target gene, MTUS1, and ChIP-qPCR experiments were used to verify the working mechanismy. Rescue experiments were utilized to confirm the role of MTUS1 in the pathway. Results: Deep mining of osteosarcoma databases combined with clinical sample testing revealed a positive correlation between lncRNA PRR7-AS1 and osteosarcoma progression. Knockdown of PRR7-AS1 inhibited osteosarcoma cell proliferation and metastasis in vitro and in vivo. Mechanistically, RNA pulldown and RIP revealed that PRR7-AS1 may bind RNF2 to play a cancer-promoting role. ChIPqPCR experiments were utilized to validate the working mechanism of the downstream target gene MTUS1. RNF2 inhibited the transcription of MTUS1 through histone H2A lysine 119 monoubiquitin. Rescue experiments confirmed MTUS1 as a downstream direct target of PRR7-AS1 and RNF2. Discussion: We identified lncRNA PRR7-AS1 as an important oncogene in osteosarcoma progression, indicating that it may be a potential target for diagnosis and prognosis of osteosarcoma. [ABSTRACT FROM AUTHOR]

Abstract Background The morbidity and mortality of colorectal cancer (CRC) remain high, posing a serious threat to human life and health. The early diagnosis and prognostic evaluation of CRC are two major challenges in clinical practice. MTUS1 is considered a tumour suppressor and can play an important role in inhibiting cell proliferation, migration, and tumour growth. Moreover, the expression of MTUS1 is decreased in different human cancers, including CRC. However, the biological functions and molecular mechanisms of MTUS1 in CRC remain unclear. Methods In the present study, data from The Cancer Genome Atlas (TCGA) database were analysed using R statistical software (version 3.6.3.) to evaluate the expression of MTUS1 in tumour tissues and adjacent normal tissues using public databases such as the TIMER and Oncomine databases. Then, 38 clinical samples were collected, and qPCR was performed to verify MTUS1 expression. We also investigated the relationship between MTUS1 expression and clinicopathological characteristics and elucidated the diagnostic and prognostic value of MTUS1 in CRC. In addition, the correlation between MTUS1 expression and immune infiltration levels was identified using the TIMER and GEPIA databases. Furthermore, we constructed and analysed a PPI network and coexpression modules of MTUS1 to explore its molecular functions and mechanisms. Results CRC tissues exhibited lower levels of MTUS1 than normal tissues. The logistic regression analysis indicated that the expression of MTUS1 was associated with N stage, TNM stage, and neoplasm type. Moreover, CRC patients with low MTUS1 expression had poor overall survival (OS). Multivariate analysis revealed that the downregulation of MTUS1 was an independent prognostic factor and was correlated with poor OS in CRC patients. MTUS1 expression had good diagnostic value based on ROC analysis. Furthermore, we identified a group of potential MTUS1-interacting proteins and coexpressed genes. GO and KEGG enrichment analyses showed that MTUS1 was involved in multiple cancer-related signalling pathways. Moreover, the expression of MTUS1 was significantly related to the infiltration levels of multiple cells. Finally, MTUS1 expression was strongly correlated with various immune marker sets. Conclusions Our results indicated that MTUS1 is a promising biomarker for predicting the diagnosis and prognosis of CRC patients. MTUS1 can also become a new molecular target for tumour immunotherapy.

Background: The morbidity and mortality of colorectal cancer (CRC) remain high, posing a serious threat to human life and health. The early diagnosis and prognostic evaluation of CRC are two major challenges in clinical practice. MTUS1 is considered a tumour suppressor and can play an important role in inhibiting cell proliferation, migration, and tumour growth. Moreover, the expression of MTUS1 is decreased in different human cancers, including CRC. However, the biological functions and molecular mechanisms of MTUS1 in CRC remain unclear. Methods: In the present study, data from The Cancer Genome Atlas (TCGA) database were analysed using R statistical software (version 3.6.3.) to evaluate the expression of MTUS1 in tumour tissues and adjacent normal tissues using public databases such as the TIMER and Oncomine databases. Then, 38 clinical samples were collected, and qPCR was performed to verify MTUS1 expression. We also investigated the relationship between MTUS1 expression and clinicopathological characteristics and elucidated the diagnostic and prognostic value of MTUS1 in CRC. In addition, the correlation between MTUS1 expression and immune infiltration levels was identified using the TIMER and GEPIA databases. Furthermore, we constructed and analysed a PPI network and coexpression modules of MTUS1 to explore its molecular functions and mechanisms. Results: CRC tissues exhibited lower levels of MTUS1 than normal tissues. The logistic regression analysis indicated that the expression of MTUS1 was associated with N stage, TNM stage, and neoplasm type. Moreover, CRC patients with low MTUS1 expression had poor overall survival (OS). Multivariate analysis revealed that the downregulation of MTUS1 was an independent prognostic factor and was correlated with poor OS in CRC patients. MTUS1 expression had good diagnostic value based on ROC analysis. Furthermore, we identified a group of potential MTUS1-interacting proteins and coexpressed genes. GO and KEGG enrichment analyses showed that MTUS1 was involved in multiple cancer-related signalling pathways. Moreover, the expression of MTUS1 was significantly related to the infiltration levels of multiple cells. Finally, MTUS1 expression was strongly correlated with various immune marker sets. Conclusions: Our results indicated that MTUS1 is a promising biomarker for predicting the diagnosis and prognosis of CRC patients. MTUS1 can also become a new molecular target for tumour immunotherapy. [ABSTRACT FROM AUTHOR]

Maintaining the integrity of the mitotic spindle in metaphase is essential to ensure normal cell division. We show here that depletion of microtubule-associated protein ATIP3 reduces metaphase spindle length. Mass spectrometry analyses identified the microtubule minus-end depolymerizing kinesin Kif2A as an ATIP3 binding protein. We show that ATIP3 controls metaphase spindle length by interacting with Kif2A and its partner Dda3 in an Aurora kinase A-dependent manner. In the absence of ATIP3, Kif2A and Dda3 accumulate at spindle poles, which is consistent with reduced poleward microtubule flux and shortening of the spindle. ATIP3 silencing also limits Aurora A localization to the poles. Transfection of GFP-Aurora A, but not kinase-dead mutant, rescues the phenotype, indicating that ATIP3 maintains Aurora A activity on the poles to control Kif2A targeting and spindle size. Collectively, these data emphasize the pivotal role of Aurora kinase A and its mutual regulation with ATIP3 in controlling spindle length. [ABSTRACT FROM AUTHOR]

Aneuploidy, an abnormal chromosome number, is a hallmark of cancer. We recently showed that depletion of microtubule-associated protein ATIP3 (AT2 receptor-interacting protein 3) induces aneuploidy and sensitizes breast cancer cells to taxanes. Combining taxane treatment with ATIP3 depletion cooperates to reach a detrimental level of aneuploidy.

OBJECTIVE: Many studies showed that long non-coding RNAs (lncRNAs) may serve as prospective markers for patients with malignant cancers, including cervical cancer (CC). In this study, we mainly investigate the functions of lncRNA PTENP1 in the progression of human CC. MATERIALS AND METHODS: Quantitative Real Time-Polymerase Chain Reaction (qRTPCR) was performed to detect expression levels of PTENP1, miR-19b and MTUS1 in CC tissues, the adjacent tissues and CC cell lines. The correlations between PTENP1 with miR-19b, miR- 19b with MTUS1 and PTENP1 with MTUS1 were analyzed. Overall survival (OS) of patients was analyzed using Kaplan-Meier method. Proliferation capacity was measured by CCK-8 assay and the invasion ability in CC cell line was detected by transwell assay. Western blot (WB) assay was performed to measure protein levels of tissues and CC cell lines. Finally, Dual-Luciferase reporter assay was performed to prove the potential binding sites between PTENP1 and miR-19b, miR-19b and MTUS1. RESULTS: We found that PTENP1 was reduced in CC tissues and CC cell lines, which predicted the poor diagnosis of CC patients. MiR-19b was increased in CC tissues, which was negatively correlated with PTENP1 in CC tissues. MTUS1 was reduced in CC tissues, which was negatively correlated with miR-19b and positively correlated within PTENP1 CC tissues. Furthermore, PTENP1 overexpression inhibited cell proliferation ability and invasion capacity in HeLa cells, as well as repressed expressions of Cyclin D1, N-cadherin, and Vimentin. Moreover, Luciferase gene reporter assays verified that miR-19b was a direct target miRNA of PTENP1, and MTUS1 was identified as a direct target of miR-19b. In addition, the inhibited cell proliferation and invasion abilities in HeLa cells with p-PTENP1 were eliminated following with miR- 19b mimic transfection. CONCLUSIONS: According to the results, this study showed that PTENP1 was reduced in CC patients and it was a prognostic factor for CC patients. Furthermore, we firstly uncovered that PTENP1 could inhibit cell proliferation and invasion via miR-19b/MTUS1 in CC patients, which uncovered the tumor-suppressive role of PTENP1 in CC and suggested that it might be a potential target for treating human CC. [ABSTRACT FROM AUTHOR]

Predictive biomarkers for tumor response to neoadjuvant chemotherapy are needed in breast cancer. This study investigates the predictive value of 280 genes encoding proteins that regulate microtubule assembly and function. By analyzing 3 independent multicenter randomized cohorts of breast cancer patients, we identified 17 genes that are differentially regulated in tumors achieving pathological complete response (pCR) to neoadjuvant chemotherapy. We focused on the MTUS1 gene, whose major product, ATIP3, is a microtubule-associated protein down-regulated in aggressive breast tumors. We show here that low levels of ATIP3 are associated with an increased pCR rate, pointing to ATIP3 as a predictive biomarker of breast tumor chemosensitivity. Using preclinical models of patient-derived xenografts and 3-dimensional models of breast cancer cell lines, we show that low ATIP3 levels sensitize tumors to the effects of taxanes but not DNA-damaging agents. ATIP3 silencing improves the proapoptotic effects of paclitaxel and induces mitotic abnormalities, including centrosome amplification and multipolar spindle formation, which results in chromosome missegregation leading to aneuploidy. As shown by time-lapse video microscopy, ATIP3 depletion exacerbates cytokinesis failure and mitotic death induced by low doses of paclitaxel. Our results favor a mechanism by which the combination of ATIP3 deficiency and paclitaxel treatment induces excessive aneuploidy,which in turn results in elevated cell death. Together, these studies highlight ATIP3 as an important regulator of mitotic integrity and a useful predictive bio-marker for a population of chemoresistant breast cancer patients. [ABSTRACT FROM AUTHOR]

Microtubule-associated tumor suppressor 1 (MTUS1) is thought to be downregulated in arious human cancers, which suggests its role as a tumor suppressor. This study investigated the clinicopathological significance of MTUS1 expression in lung adenocarcinoma. Tissue microarray blocks consisting of 161 cases were constructed, and immunohistochemical staining was used to assess MTUS1 expression. Correlations of MTUS1 expression and clinicopathological parameters were analyzed. In addition, we used public databases and performed bioinformatics analysis. Low level of MTUS1 was significantly associated with higher clinical stage (p = 0.006), higher tumor stage (p = 0.044), lymph node metastasis (p = 0.01), worse histologic grade (p = 0.007), lymphovascular invasion (p = 0.014), and higher Ki-67 proliferation index (p < 0.001). Patients with low MTUS1 expression also showed shorter disease-free survival (p = 0.002) and cancer-specific survival (p = 0.006). Analysis of data from the Cancer Genome Atlas confirmed that the mRNA expression of MTUS1 in lung adenocarcinoma was significantly lower than that of normal lung tissue (p = 0.02), and patients with decreased MTUS1 expression showed significantly shorter overall survival (p = 0.008). These results suggest that MTUS1 may be a potential biomarker for predicting clinical outcomes in lung adenocarcinoma patients.

Breast cancer is the leading cause of death by malignancy among women worldwide. Clinical data and molecular characteristics of breast tumors are essential to guide clinician’s therapeutic decisions. In the new era of precision medicine, that aims at personalizing the treatment for each patient, there is urgent need to identify robust companion biomarkers for new targeted therapies. This review focuses on ATIP3, a potent anti-cancer protein encoded by candidate tumor suppressor gene MTUS1, whose expression levels are markedly down-regulated in breast cancer. ATIP3 is a microtubule-associated protein identified both as a prognostic biomarker of patient survival and a predictive biomarker of breast tumors response to taxane-based chemotherapy. We present here recent studies pointing out ATIP3 as an emerging anti-cancer protein and a potential companion biomarker to be combined with future personalized therapy against ATIP3-deficient breast cancer.

ABSTRACT MTUS1 (microtubule-associated tumor suppressor 1) has been identified that can function as a tumor suppressor gene in many malignant tumors. However, the function and mechanisms underlying the regulation of MTUS1 are unclear. In the present study, we reported that miR-19a and miR-19b (miR-19a/b) promote proliferation and migration of lung cancer cells by targeting MTUS1. First, MTUS1 was proved to function as a tumor suppressor in lung cancer and was linked to cell proliferation and migration promotion. Second, an inverse correlation between miR-19a/b expression and MTUS1 mRNA/protein expression was noted in human lung cancer tissues. Third, MTUS1 was appraised as a direct target of miR-19a/b by bioinformatics analysis. Fourth, direct MTUS1 regulation by miR-19a/b in lung cancer cells was experimentally affirmed by cell transfection assay and luciferase reporter assay. Finally, miR-19a/b were shown to cooperatively repress MTUS1 expression and synergistically regulate MTUS1 expression to promote lung cancer cell proliferation and migration. In conclusion, our findings have provided the first clues regarding the roles of miR-19a/b, which appear to function as oncomirs in lung cancer by downregulating MTUS1.

Background: The MTUS1 gene encodes a microtubule-associated protein involved in multiple processes including cell polarity and microtubule balance during myocardial development.Aims: To investigate the association between a de novo c. 2617A->C mutation in MTUS1 (NM_001001924.2) and non-compaction of ventricular myocardium (NVM) and explore the potential mechanisms.Methods: A de novo mutation in MTUS1 was identified for a familial pedigree with NVM. Lentiviral vectors containing MTUS1 wild type or the mutation MTUS1 were constructed and co-infected into HEK-293 cells. MTUS1, Rac1/Cdc42, α-tubulin, α/β-tubulin, polarity protein (PAR6), and the morphology of daughter cells were measured by real-time PCR, Western blot, and immunofluorescence assays, respectively.Results: The lentiviral vectors were constructed successfully. Immunofluorescence assays revealed the fluorescence intensity of α-tubulin to be decreased and α/β-tubulin to be increased in the mutation MTUS1 group. The fluorescence intensity of PAR6 was higher and morphology of the daughter cells in the mutation group was different from the wild type group. The phosphorylation of Rac1/Cdc42 in the mutation group was significantly lower than in the wild type group.Conclusions: A de novo mutation in MTUS1 decreased the stability of microtubules and increased cell polarity via the Rac1/Cdc42 pathway, which may partly elucidate the mechanism underlying cellular protection in NVM.

Introduction: Osteosarcoma is a common bone malignant tumor in adolescents with high mortality and poor prognosis. At present, the progress of osteosarcoma and effective treatment strategies are not clear. This study provides a new potential target for the progression and treatment of osteosarcoma., Methods: The relationship between lncRNA PRR7-AS1 and osteosarcoma was analyzed using the osteosarcoma databases and clinical sample testing. Cell function assays and tumor lung metastasis were employed to study the effects of PRR7-AS1 on tumorigenesis in vivo and in vitro . Potential downstream RNF2 of PRR7-AS1 was identified and explored using RNA pulldown and RIP. The GTRD and KnockTF database were used to predict the downstream target gene, MTUS1, and ChIP-qPCR experiments were used to verify the working mechanismy. Rescue experiments were utilized to confirm the role of MTUS1 in the pathway., Results: Deep mining of osteosarcoma databases combined with clinical sample testing revealed a positive correlation between lncRNA PRR7-AS1 and osteosarcoma progression. Knockdown of PRR7-AS1 inhibited osteosarcoma cell proliferation and metastasis in vitro and in vivo. Mechanistically, RNA pulldown and RIP revealed that PRR7-AS1 may bind RNF2 to play a cancer-promoting role. ChIP-qPCR experiments were utilized to validate the working mechanism of the downstream target gene MTUS1. RNF2 inhibited the transcription of MTUS1 through histone H2A lysine 119 monoubiquitin. Rescue experiments confirmed MTUS1 as a downstream direct target of PRR7-AS1 and RNF2., Discussion: We identified lncRNA PRR7-AS1 as an important oncogene in osteosarcoma progression, indicating that it may be a potential target for diagnosis and prognosis of osteosarcoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen-Xi, Jin-Fu, An-Quan, Xiao, Ying-Hui, Suo-Yuan, Cong, Tian-Ming and Jun.)

OBJECTIVE: Previous studies have shown that microRNA-765 (miR-765) is involved in certain biological behaviors of human cancers. However, abnormal expression and function of miR-765 have not been reported in osteosarcoma (OS). PATIENTS AND METHODS: Changes in the expression of miR-765 and MTUS1 (Microtubule-associated tumor suppressor 1) were examined via Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. The function of miR-765 was investigated through Cell Counting Kit-8 (CCK-8) and transwell assays in OS. The target of miR-765 was identified using a Dual-Luciferase reporter assay. RESULTS: MiR-765 was upregulated in OS tissues. And upregulation of miR-765 promoted cell proliferation, migration and invasion in OS. In addition, MTUS1 was confirmed as a direct target gene of miR-765. Moreover, miR-765 promoted the progression of OS through targeting MTUS1. Furthermore, miR-765 was involved in tumorigenesis of OS through activating extracellular- signal-regulated kinase/ epithelial-mesenchymal transition (ERK/EMT) pathway. CONCLUSIONS: MiR-765 targets MTUS1 to promote the progression of OS via mediating the ERK/EMT pathway. Therefore, miR-765 may be used as a novel biomarker for the diagnosis of OS. [ABSTRACT FROM AUTHOR]

Purpose: The identification of molecular biomarkers for classification of breast cancer is needed to better stratify the patients and guide therapeutic decisions. The aim of this study was to investigate the value of MAPRE1 gene encoding microtubule-end binding proteins EB1 as a biomarker in breast cancer and evaluate whether combinatorial expression of MAPRE1 and MTUS1 gene encoding EB1-negative regulator ATIP3 may improve breast cancer diagnosis and prognosis.Methods: Probeset intensities for MAPRE1 and MTUS1 genes were retrieved from Exonhit splice array analyses of 45 benign and 120 malignant breast tumors for diagnostic purposes. Transcriptomic analyses (U133 Affymetrix array) of one exploratory cohort of 150 invasive breast cancer patients and two independent series of 130 and 155 samples were compared with clinical data of the patients for prognostic studies. A tissue microarray from an independent cohort of 212 invasive breast tumors was immunostained with anti-EB1 and anti-ATIP3 antibodies.Results: We show that MAPRE1 gene is a diagnostic and prognostic biomarker in breast cancer. High MAPRE1 levels correlate with tumor malignancy, high histological grade and poor clinical outcome. Combination of high-MAPRE1 and low-MTUS1 levels in tumors is significantly associated with tumor aggressiveness and reduced patient survival. IHC studies of combined EB1/ATIP3 protein expression confirmed these results.Conclusions: These studies emphasize the importance of studying combinatorial expression of EB1 and ATIP3 genes and proteins rather than each biomarker alone. A population of highly aggressive breast tumors expressing high-EB1/low-ATIP3 may be considered for the development of new molecular therapies. [ABSTRACT FROM AUTHOR]

Mitochondria are dynamic organelles that are able to change their morphology and cellular distribution by either fission or fusion. However, the molecular mechanisms controlling mitochondrial dynamics in vascular endothelial cells (ECs) remain largely unknown. In this study, we observed that knockdown of microtubule-associated tumor suppressor 1 (MTUS1) in ECs inhibited tube formation and migration, accompanied with decreased promigratory signalings. We showed that MTUS1 was localized in the outer membrane of mitochondria in ECs. Knockdown of MTUS1 disturbed the elongated mitochondrial network and induced the formation of perinuclear clusters of mitochondria. Importantly, mitochondrial motility and fusion were suppressed, whereas generation of reactive oxygen species was increased in MTUS1 knockdown ECs. Mechanistically, we showed that the N-terminal coiled-coil domain of MTUS1 interacted with the mitochondrial membrane proteins, mitofusin-1 and mitofusin-2, to maintain mitochondrial morphology in ECs. This study illustrated a novel role of MTUS1 in mitochondrial morphology and EC angiogenic responses. [ABSTRACT FROM AUTHOR]

Loss of tumor suppressor activity is a frequent event in the formation and progression of tumors and has been listed as an important hallmark of cancers. Microtubule - Associated Scaffold Protein 1 ( MTUS1 ) is a candidate tumor suppressor gene which is reported to be frequently down-regulated in a variety of human cancers including pancreas, colon, bladder, head-and-neck, ovarian, breast cancers, gastric, lung cancers. It is also reported to be implicated in several types of pathologies such as cardiac hypertrophy, atherosclerosis, and SLE-like lymphoproliferative diseases. Moreover, MTUS1 -encoded proteins are shown to be involved in the regulation of vital cellular processes such as proliferation, differentiation, DNA repair, inflammation, vascular remodeling and senescence. However, the current knowledge is very limited about the role of this gene in human cancers as well as other type diseases. Besides, there is no literature report which summarizes and criticizes the importance of MTUS1 in the cellular processes, especially in the processes of carcinogenesis. Accordingly, in this comprehensive review, we tried to shed light on the role of tumor suppressor MTUS1 /ATIP in health and disease, putting special emphasis on its role in the development and progression of human cancers as well as associated molecular mechanisms and the reasons behind MTUS1 /ATIP deficiency, which have been not well documented previously. [ABSTRACT FROM AUTHOR]

Background Endothelial cell activation is thought to be a key event in atherosclerosis. p38 mitogen-activated protein kinase (p38 MAPK) plays an important role in regulating pro-inflammatory cytokine production in endothelial cells (ECs), however, how p38 MAPK is controlled in EC activation remain unclear. In this study, we investigated the effect of mitochondrial tumor suppressor 1 (MTUS1) on p38 MAPK activation, cytokine induction and the underlying molecular mechanisms in ECs. Methods and results Using qPCR and ELISA methods, we found that knockdown of MTUS1 led to a marked increase in the mRNA and protein expression of E -selectin (SELE) and monocyte chemotactic protein-1 in ECs, which is accompanied with increased phosphorylation of p38 MAPK (Thr180/Tyr182), MKK3/6 (Ser 189) and IκBα (Ser 32). Using luciferase reporter assay, we found that MTUS1 silencing also activated NF-κB transcriptional activity. The inhibition of p38 MAPK and NF-κB pathway was shown to abrogate MTUS1 silencing-induced cytokine expression in ECs. Furthermore, MTUS1 silencing induced p38 MAPK-dependent ubiquitination of cAMP-response element binding protein (CREB) which potentiated CREB-binding protein-mediated NF-κB p65 acetylation and binding to the promoter of the SELE gene. Conversely, adenovirus-mediated overexpression of MTUS1 inhibited p38 MAPK activation in ECs in vitro and in vivo . Importantly, decreased expression of MTUS1 and CREB, accompanied with induced activation of p38 MAPK were observed in aortas of apoE −/− mice after high-fat diet challenge. Conclusions Our findings showed that MTUS1 regulates the p38 MAPK-mediated cytokine production in ECs. MTUS1 gene probably plays a protective role against pro-inflammatory response of ECs. [ABSTRACT FROM AUTHOR]

Breast cancer is major public health problem predominantly effects female population. Current therapeutic approaches to deal with breast cancer are still lack of effectiveness. Thus, identifying/developing novel strategies to fight against breast cancer is very important. The frequent deletions at 8p21.3-22 chromosomal location nearby D8S254 marker enabled the discovery of a novel tumor suppressor gene, MTUS1 . Subsequently, MTUS1 was demonstrated to be less expressed in a variety cancer types including breast cancer. Also, it is obvious that gene expression is widely regulated by miRNAs. Here, we aimed to report differential expression of MTUS1 and its regulatory miRNAs in breast cancer and fibroadenoma tissues. Dynamic analysis of MTUS1 expression levels and its miRNAs regulators were attained by Fluidigm 96 × 96 Dynamic Array Expression chips and reactions were performed in Fluidigm BioMark™ HD System qPCR. Consequently, MTUS1 mRNA levels were significantly diminished in breast cancer tissues and elevated in fibroadenoma tissues. Also, among MTUS1 targeting miRNAs, miR-183-5p was identified to be overexpressed in breast cancer and down-regulated in fibroadenoma tissues. Also, expression levels of MTUS1 and miR-183-5p were well correlated with clinical parameters. In particular, MTUS1 expression was found to be diminished and miR-183-5p expression was elevated with the advancing stage. In conclusion, as a potential therapeutic target, miR-183-5p can be a chief regulator of MTUS1 and MTUS1 -miR-183-5p axis may have significant influence in the pathology of breast cancer. [ABSTRACT FROM AUTHOR]

Deregulated microRNA (miRNA) expression has been shown to be involved in the pathogenesis of several types of cancers including colorectal cancer (CRC). Thus, determining miRNA targets of genes that play critical role in the malignant transformation is very important. Here, expression levels of tumor suppressor microtubule-associated tumor suppressor 1 ( MTUS1) and its regulatory miRNAs were reported. Predicted and validated targets of MTUS1 gene was determined by a computational approach. Expressions of MTUS1 and miRNAs were determined by using 96.96 Dynamic Array™ integrated fluidic circuit (Fluidigm). As a result, MTUS1 levels were found to be diminished in formalin-fixed, paraffin-embedded (FFPE) tissue samples of CRC patients compared to controls. Also, several of MTUS1 targeting miRNAs were found to be upregulated in CRC samples (miR-373-3p, 183-5p, 142-5p, 200c-3p, 19a-3p, -20a-5p, -181a-5p, -184, -181d-5p, -372-3p, 27b-3p, 98-5p, -let-7i-5p, -let-7d-5p, -let-7g-5p, -let-7b-5p, and -let-7c-5p). Of these miRNAs, miR-135b-5p, -373-3p, 183-5p, 142-5p, 200c-3p, 19a-3p showed marked expression levels. In contrast, expression levels of let-7a-5p, 7e-5p, 7f-5p, hsa-miR-125a-5p, and 125b-5p were found to be downregulated in CRC tissues. Accordingly, some of the overexpressed miRNAs especially the miR-135b-5p, -373-3p, 183-5p, 142-5p, 200c-3p, and 19a-3p may play key roles in CRC pathophysiology through MTUS1. In contrast, let-7a-5p, 7e-5p, 7f-5p, miR-125a-5p, and 125b-5p may play important roles in CRC carcinogenesis independent from the MTUS1. In conclusion, MTUS1 targeting miRNAs may play key roles in the development of CRC by downregulating tumor suppressor MTUS1. [ABSTRACT FROM AUTHOR]

Background: Microtubule-associated tumor suppressor gene (MTUS1) has been identified as tumor suppressor gene in many malignant tumors. In this study, we investigated the role of MTUS1 in the development of salivary adenoid cystic carcinoma (SACC) and its functional effect on the migration and invasion of SACC. Methods: Archival clinical samples including 49 primary SACC were examined for MTUS1 expression by immunohistochemistry. Statistical analyses were performed to evaluate the correlation between MTUS1 with histopathological features and survival. The expression of MTUS1/ATIP (AT2 receptor-interacting protein) isoforms was determined in SACC tissue samples and cell lines using quantitative RT-PCR assays. Then we investigated whether the migration and invasion of SACC were mediated by MTUS1/ATIP3a using in vitro cell migration and invasion assay. Results: We confirmed that the down-regulation of MTUS1 was a frequent event in SACC, and was correlated with distant metastasis and associated with reduced overall survival and disease free survival. Isoform specific quantitative RT-PCR assays revealed that ATIP1, ATIP3a and ATIP3b were the major isoforms of the MTUS1 gene products in SACC, and were significant down-regulation in SACC as compared to matching normal tissues. For functional analyses, we found that SACC-LM cells (SACC cell line with higher migration and invasion ability) possessed a lower expression level of ATIP3a compared to SACC-83 cells (lower migration and invasion ability). Restoration of ATIP3a expression in SACC-LM cells induced anti-proliferative activity and inhibited the migration and invasion ability. Knockdown of ATIP3a promoted the proliferation, migration and invasion ability of SACC-83 cells. Restoration of ATIP3a inhibited the phosphorylation of ERK (extracellular-regulated kinase) 1/2, the expression of Slug and Vimentin in SACC-LM cells, while knockdown of ATIP3a increased the phosphorylation of ERK1/2, the expression of Slug and Vimentin in SACC-83 cells. Conclusions: Our studies confirm that MTUS1 plays an important role in the progression of SACC, and may serve as a biomarker or therapeutic target for patients with SACC. MTUS1/ATIP3a down-regulation contributes to the proliferation, migration and the invasion abilities of SACC. [ABSTRACT FROM AUTHOR]

Background: Seventy percent of all bladder tumours tend to recur and need intensive surveillance, and a subset of tumours progress to muscle-invasive and metastatic disease. However, it is still difficult to find the adequate treatment for every individual patient as it is a very heterogeneous disease and reliable biomarkers are still missing. In our study we searched for new target genes in the critical chromosomal region 8p and investigated the potential tumour suppressor gene candidate MTUS1/ATIP in bladder cancer. Methods: MTUS1 was identified to be the most promising deleted target gene at 8p in aCGH analysis with 19 papillary bladder tumours. A correlation with bladder cancer was further validated using immunohistochemistry of 85 papillary and 236 advanced bladder tumours and in functional experiments. Kaplan-Meier analysis and multivariate Cox-regression addressed overall survival (OS) and disease-specific survival (DSS) as a function of MTUS1/ATIP expression. Bivariate correlations investigated associations between MTUS1/ATIP expression, patient characteristics and histopathology. MTUS1 expression was analysed in cell lines and overexpressed in RT112, where impact on viability, proliferation and migration was measured. Results: MTUS1 protein expression was lost in almost 50% of all papillary and advanced bladder cancers. Survival, however, was only influenced in advanced carcinomas, where loss of MTUS1 was associated with adverse OS and DSS. In this cohort, there was also a significant correlation of MTUS1 expression and histological subtype: positive expression was detected in all micropapillary tumours and aberrant nuclear staining was detected in a subset of plasmocytoid urothelial carcinomas. MTUS1 was expressed in all investigated bladder cell lines and overexpression in RT112 led to significantly decreased viability. Conclusions: MTUS1 is a tumour suppressor gene in cultured bladder cancer cells and in advanced bladder tumours. It might represent one new target gene at chromosome 8p and can be used as an independent prognostic factor for advanced bladder cancer patients. The limitation of the study is the retrospective data analysis. Thus, findings should be validated with a prospective advanced bladder tumour cohort. [ABSTRACT FROM AUTHOR]

Abstract: Microtubule-associated tumor suppressor gene (MTUS1, also known as mitochondrial tumor suppressor) is a recently identified tumor suppressor gene that has been implicated in several cancer types. The expression of MTUS1 gene leads to 5 known transcript variants and codes for 5 isoforms of Angiotensin II AT2 receptor interacting protein (ATIP). In this study, we first confirmed that the down-regulation of MTUS1/ATIP was a frequent event in oral tongue squamous cell carcinoma (OTSCC) and the premalignant lesion (leukoplakia). We further demonstrated that the down-regulation of MTUS1/ATIP was correlated with poor differentiation and enhanced proliferation (Ki67 proliferation index). Statistical analysis suggests that the down-regulation of MTUS1/ATIP was associated with reduced overall survival. Isoform specific quantitative RT-PCR assays revealed that ATIP1, ATIP3a and ATIP3b were the major isoforms of the MTUS1 gene products in oral tongue epithelial cells. Significant down-regulations were observed for all 3 ATIP isoforms in OTSCC as compared to matching normal tissues. In vitro functional study showed that the restoration of ATIP1 expression led to G1 arrest, apoptosis and reduction of cell proliferation in OTSCC cell lines. These ATIP1-induced cellular changes were accompanied by reduced phosphorylation of ERK1/2 and up-regulation of p53. Taken together, these data suggest that MTUS1 plays major roles in the progression of OTSCC, and may serve as a biomarker or therapeutic target for patients with OTSCC. [Copyright &y& Elsevier]

Abstract: A high frequency of allelic loss affecting chromosome 8p and a minimal region of deletion at p21-22 have been previously reported in hepatocellular carcinoma (HCC), suggesting that at least one tumor suppressor gene is present in this region. In this study, we assessed whether the angiotensin II AT2 receptor interacting protein (ATIP)/mitochondrial tumor suppressor gene (MTUS1), a gene newly identified at position 8p22, may be a candidate tumor suppressor gene mutated in HCC. We searched for alterations in the 17 coding exons of ATIP/MTUS1 by means of denaturating high-performance liquid chromatography and sequencing, in 51 HCC tumors and 58 cell lines for which loss of heterozygosity status was known. Five major nucleotide substitutions were identified, all located in exons used by the ATIP3 transcript which is the only ATIP transcript variant expressed in liver. These nucleotide variations result in amino-acid substitution or deletion of conserved structural motifs (nuclear localisation signal, polyproline motif, leucine zipper) and also affect exonic splicing enhancer motifs and physiological splice sites, suggesting potential deleterious effects on ATIP3 function and/or expression. [Copyright &y& Elsevier]

Microtubule-associated tumor suppressor 1 (MTUS1) is thought to be downregulated in arious human cancers, which suggests its role as a tumor suppressor. This study investigated the clinicopathological significance of MTUS1 expression in lung adenocarcinoma. Tissue microarray blocks consisting of 161 cases were constructed, and immunohistochemical staining was used to assess MTUS1 expression. Correlations of MTUS1 expression and clinicopathological parameters were analyzed. In addition, we used public databases and performed bioinformatics analysis. Low level of MTUS1 was significantly associated with higher clinical stage (p = 0.006), higher tumor stage (p = 0.044), lymph node metastasis (p = 0.01), worse histologic grade (p = 0.007), lymphovascular invasion (p = 0.014), and higher Ki-67 proliferation index (p < 0.001). Patients with low MTUS1 expression also showed shorter disease-free survival (p = 0.002) and cancer-specific survival (p = 0.006). Analysis of data from the Cancer Genome Atlas confirmed that the mRNA expression of MTUS1 in lung adenocarcinoma was significantly lower than that of normal lung tissue (p = 0.02), and patients with decreased MTUS1 expression showed significantly shorter overall survival (p = 0.008). These results suggest that MTUS1 may be a potential biomarker for predicting clinical outcomes in lung adenocarcinoma patients. [ABSTRACT FROM AUTHOR]

Breast cancer is the leading cause of death by malignancy among women worldwide. Clinical data and molecular characteristics of breast tumors are essential to guide clinician's therapeutic decisions. In the new era of precision medicine, that aims at personalizing the treatment for each patient, there is urgent need to identify robust companion biomarkers for new targeted therapies. This review focuses on ATIP3, a potent anti-cancer protein encoded by candidate tumor suppressor gene MTUS1, whose expression levels are markedly down-regulated in breast cancer. ATIP3 is a microtubule-associated protein identified both as a prognostic biomarker of patient survival and a predictive biomarker of breast tumors response to taxane-based chemotherapy. We present here recent studies pointing out ATIP3 as an emerging anti-cancer protein and a potential companion biomarker to be combined with future personalized therapy against ATIP3-deficient breast cancer. [ABSTRACT FROM AUTHOR]

Background/aim: Microtubule-associated tumor suppressor 1 (MTUS1) is a novel tumor suppressor involved in proliferation and migration, and down-regulation of MTUS1 is associated with the poor prognosis of several cancers. We evaluated the clinicopathological significance of MTUS1 expression in renal cell carcinoma (RCC)., Patients and Methods: We assessed MTUS1 expression by immunohistochemical staining of tissue microarrays from 249 cases of RCC. We analyzed the correlation of MTUS1 expression and clinicopathological characteristics. Additionally, we used public databases and performed bioinformatics analysis., Results: We investigated The Cancer Genome Atlas databases and identified that MTUS1 mRNA expression was significantly lower in RCC tissues than in normal tissues. Loss of MTUS1 expression was correlated with high WHO/ISUP nuclear grade, lymphovascular invasion, renal vein thrombus, and high pT stage in patients with RCC. Although there was no statistically significant correlation between MTUS1 expression and patients' prognosis in our cohort, MTUS1 overexpression was significantly correlated with a favorable prognosis in public data., Conclusion: Loss of MTUS1 expression in RCC might be a potential biomarker for predicting clinical outcome., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aneuploidy, an abnormal chromosome number, is a hallmark of cancer. We recently showed that depletion of microtubule-associated protein ATIP3 (AT2 receptor-interacting protein 3) induces aneuploidy and sensitizes breast cancer cells to taxanes. Combining taxane treatment with ATIP3 depletion cooperates to reach a detrimental level of aneuploidy., (© 2019 Taylor & Francis Group, LLC.)

Background: The MTUS1 gene encodes a microtubule-associated protein involved in multiple processes including cell polarity and microtubule balance during myocardial development. Aims: To investigate the association between a de novo c. 2617A->C mutation in MTUS1 (NM&#95;001001924.2) and non-compaction of ventricular myocardium (NVM) and explore the potential mechanisms. Methods: A de novo mutation in MTUS1 was identified for a familial pedigree with NVM. Lentiviral vectors containing MTUS1 wild type or the mutation MTUS1 were constructed and co-infected into HEK-293 cells. MTUS1 , Rac1/Cdc42, α-tubulin, α/β-tubulin, polarity protein (PAR6), and the morphology of daughter cells were measured by real-time PCR, Western blot, and immunofluorescence assays, respectively. Results: The lentiviral vectors were constructed successfully. Immunofluorescence assays revealed the fluorescence intensity of α-tubulin to be decreased and α/β-tubulin to be increased in the mutation MTUS1 group. The fluorescence intensity of PAR6 was higher and morphology of the daughter cells in the mutation group was different from the wild type group. The phosphorylation of Rac1/Cdc42 in the mutation group was significantly lower than in the wild type group. Conclusions: A de novo mutation in MTUS1 decreased the stability of microtubules and increased cell polarity via the Rac1/Cdc42 pathway, which may partly elucidate the mechanism underlying cellular protection in NVM.

Mitochondria are dynamic organelles that are able to change their morphology and cellular distribution by either fission or fusion. However, the molecular mechanisms controlling mitochondrial dynamics in vascular endothelial cells (ECs) remain largely unknown. In this study, we observed that knockdown of microtubule-associated tumor suppressor 1 (MTUS1) in ECs inhibited tube formation and migration, accompanied with decreased promigratory signalings. We showed that MTUS1 was localized in the outer membrane of mitochondria in ECs. Knockdown of MTUS1 disturbed the elongated mitochondrial network and induced the formation of perinuclear clusters of mitochondria. Importantly, mitochondrial motility and fusion were suppressed, whereas generation of reactive oxygen species was increased in MTUS1 knockdown ECs. Mechanistically, we showed that the N-terminal coiled-coil domain of MTUS1 interacted with the mitochondrial membrane proteins, mitofusin-1 and mitofusin-2, to maintain mitochondrial morphology in ECs. This study illustrated a novel role of MTUS1 in mitochondrial morphology and EC angiogenic responses.-Wang, Y., Huang, Y., Liu, Y., Li, J., Hao, Y., Yin, P., Liu, Z., Chen, J., Wang, Y., Wang, N., Zhang, P. Microtubule associated tumor suppressor 1 interacts with mitofusins to regulate mitochondrial morphology in endothelial cells.

Deregulated microRNA (miRNA) expression has been shown to be involved in the pathogenesis of several types of cancers including colorectal cancer (CRC). Thus, determining miRNA targets of genes that play critical role in the malignant transformation is very important. Here, expression levels of tumor suppressor microtubule-associated tumor suppressor 1 (MTUS1) and its regulatory miRNAs were reported. Predicted and validated targets of MTUS1 gene was determined by a computational approach. Expressions of MTUS1 and miRNAs were determined by using 96.96 Dynamic Array™ integrated fluidic circuit (Fluidigm). As a result, MTUS1 levels were found to be diminished in formalin-fixed, paraffin-embedded (FFPE) tissue samples of CRC patients compared to controls. Also, several of MTUS1 targeting miRNAs were found to be upregulated in CRC samples (miR-373-3p, 183-5p, 142-5p, 200c-3p, 19a-3p, -20a-5p, -181a-5p, -184, -181d-5p, -372-3p, 27b-3p, 98-5p, -let-7i-5p, -let-7d-5p, -let-7g-5p, -let-7b-5p, and -let-7c-5p). Of these miRNAs, miR-135b-5p, -373-3p, 183-5p, 142-5p, 200c-3p, 19a-3p showed marked expression levels. In contrast, expression levels of let-7a-5p, 7e-5p, 7f-5p, hsa-miR-125a-5p, and 125b-5p were found to be downregulated in CRC tissues. Accordingly, some of the overexpressed miRNAs especially the miR-135b-5p, -373-3p, 183-5p, 142-5p, 200c-3p, and 19a-3p may play key roles in CRC pathophysiology through MTUS1. In contrast, let-7a-5p, 7e-5p, 7f-5p, miR-125a-5p, and 125b-5p may play important roles in CRC carcinogenesis independent from the MTUS1. In conclusion, MTUS1 targeting miRNAs may play key roles in the development of CRC by downregulating tumor suppressor MTUS1.

The regulation of microtubule dynamics is critical to ensure essential cell functions. End binding protein 1 (EB1) is a master regulator of microtubule dynamics that autonomously binds an extended GTP/GDP-Pi structure at growing microtubule ends and recruits regulatory proteins at this location. However, negative regulation of EB1 association with growing microtubule ends remains poorly understood. We show here that microtubule-associated tumor suppressor ATIP3 interacts with EB1 through direct binding of a non-canonical proline-rich motif. Results indicate that ATIP3 does not localize at growing microtubule ends and that in situ ATIP3-EB1 molecular complexes are mostly detected in the cytosol. We present evidence that a minimal EB1-interacting sequence of ATIP3 is both necessary and sufficient to prevent EB1 accumulation at growing microtubule ends in living cells and that EB1-interaction is involved in reducing cell polarity. By fluorescence recovery of EB1-GFP after photobleaching, we show that ATIP3 silencing accelerates EB1 turnover at microtubule ends with no modification of EB1 diffusion in the cytosol. We propose a novel mechanism by which ATIP3-EB1 interaction indirectly reduces the kinetics of EB1 exchange on its recognition site, thereby accounting for negative regulation of microtubule dynamic instability. Our findings provide a unique example of decreased EB1 turnover at growing microtubule ends by cytosolic interaction with a tumor suppressor.