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BACKGROUND: Acute myeloid leukemia (AML) is a hematological malignancy with a heterogeneous prognosis. Novel markers are required to accurately assess the prognosis and formulate treatment plans. METHODS: The association of ARHGAP family genes with prognostic value in acute myeloid leukemia (AML) was assessed using public databases (CCLE, GEPIA, TCGA, and GEO). RESULTS: Elevated expression of ARHGAP43 (SH3BP1) was associated with poor prognosis in patients with acute myeloid leukemia. ARHGAP43 (SH3BP1) expression was higher in the poor/adverse prognosis (P < 0.001) and TP53 mutation groups (P = 0.0093). Higher ARHGAP43 (SH3BP1) expression was found to be an independent prognostic predictor in multivariate COX regression analysis (HR = 1.317, 95% CI: 1.008-1.720, P = 0.044). Higher ARHGAP43 (SH3BP1) expression who did not receive hematopoietic stem cell transplantation (HSCT) had shorter overall survival (OS) and progression-free survival (PFS) (OS: median: 7.60 vs. 24.90 months; P = 0.006; PFS: median: 11.40 vs. 27.22 months; P = 0.0096), whereas OS and PFS of patients who received HSCT were unaffected, suggesting that HSCT is a better treatment option for patients with higher ARHGAP43 (SH3BP1) expression. KEGG and GSEA analyses revealed that high-expression ARHGAP43 (SH3BP1) was related to inflammation and immune response. Additionally, down-regulation of ARHGAP43 (SH3BP1) expression inhibited AML cell proliferation. CONCLUSION: These findings highlight the clinical potential of ARHGAP43 (SH3BP1) as a novel biomarker of AML, with higher levels indicating a poor prognosis.
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Prostate cancer is a very common malignant disease and a leading cause of death for men in the Western world. Tumorigenesis and progression of prostate cancer involves multiple signaling pathways, including the Hippo pathway. Yes-associated protein (YAP) is the downstream transcriptional co-activator of the Hippo pathway, is overexpressed in prostate cancer, and plays a vital role in the tumorigenesis and progression of prostate cancer. However, the role of the YAP paralog and another downstream effector of the Hippo pathway, transcriptional co-activator with PDZ-binding motif (TAZ), in prostate cancer has not been fully elucidated. Here, we show that TAZ is a basal cell marker for the prostate epithelium. We found that overexpression of TAZ promotes the epithelial-mesenchymal transition (EMT), cell migration, and anchorage-independent growth in the RWPE1 prostate epithelial cells. Of note, knock down of TAZ in the DU145 prostate cancer cells inhibited cell migration and metastasis. We also found that SH3 domain binding protein 1 (SH3BP1), a RhoGAP protein that drives cell motility, is a direct target gene of TAZ in the prostate cancer cells, mediating TAZ function in enhancing cell migration. Moreover, the prostate cancer-related oncogenic E26 transformation-specific (ETS) transcription factors, ETV1, ETV4, and ETV5, were required for TAZ gene transcription in PC3 prostate cancer cells. MAPK inhibitor U0126 treatment decreased TAZ expression in RWPE1 cells, and ETV4 overexpression rescued TAZ expression in RWPE1 cells with U0126 treatment. Our results show a regulatory mechanism of TAZ transcription and suggest a significant role for TAZ in the progression of prostate cancer.
Assuntos
Proteínas E1A de Adenovirus/metabolismo , Movimento Celular , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Fatores de Transcrição/metabolismo , Aciltransferases , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas E1A de Adenovirus/genética , Animais , Adesão Celular , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Humanos , Masculino , Camundongos , Camundongos Nus , Metástase Neoplásica , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Neoplasias da Próstata/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-ets , Fatores de Transcrição/genética , Proteínas de Sinalização YAPRESUMO
Cervical cancer still remains the fourth most common cancer, affecting women worldwide with large geographic variations in cervical cancer incidence and mortality rates. SH3-domain binding protein-1 (SH3BP1) specifically inactivating Rac1 and its target Wave2 is required for cell motility, thus regarded as an essential regulator of cancer cell metastasis. However, the exact effects and molecular mechanisms of SH3BP1 in cervical cancer progression are still unknown. The present study is aimed to investigate the mechanism of SH3BP1 in regulation of cervical cancer cell metastasis and chemoresistance. In the present study, we demonstrated a high SH3BP1 expression in cervical cancer tissues; a higher SH3BP1 expression is also correlated with a shorter overall survival of patients with cervical cancer. Further, we revealed that SH3BP1 overexpression promoted the invasion, migration, and chemoresistance of cervical cancer cell through increasing Rac1 activity and Wave2 protein level. The promotive effect of SH3BP1 could be partially reversed by a Rac1 inhibitor, NSC 23766. In cisplatin-resistant cervical cancer tissues, SH3BP1, Rac1, and Wave2 mRNA expression was significantly up-regulated compared to that of the cisplatin-sensitive cervical cancer tissues. Taken together, SH3BP1/Rac1/Wave2 pathway may potentially act as an effective therapeutic target combined with traditional cisplatin-based chemotherapy for cervical cancer.
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Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Proteínas Ativadoras de GTPase/genética , Neoplasias do Colo do Útero/genética , Família de Proteínas da Síndrome de Wiskott-Aldrich/genética , Proteínas rac1 de Ligação ao GTP/genética , Linhagem Celular Tumoral , Movimento Celular , Progressão da Doença , Feminino , Proteínas Ativadoras de GTPase/metabolismo , Regulação Neoplásica da Expressão Gênica , Células HeLa , Humanos , Invasividade Neoplásica , Transdução de Sinais , Análise de Sobrevida , Regulação para Cima , Neoplasias do Colo do Útero/metabolismo , Família de Proteínas da Síndrome de Wiskott-Aldrich/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
Background: SH3-domain binding protein-1 (SH3BP1), which specifically inactivates Rac1 and its target protein Wave2, has been shown to be an important regulator of cancer metastasis. However, the effects of SH3BP1 in melanoma progression remain unclear. The current study aimed to explore the function of SH3BP1 in melanoma and its possible molecular mechanism. Methods: TCGA database was used to analyze the expression of SH3BP1 in melanoma. Then, reverse transcription-quantitative polymerase chain reaction was performed to detect the expression of SH3BP1 in melanoma tissues and cells. Next, genes related to SH3BP1 were analyzed by LinkedOmics database, and protein interactions were analyzed by STRING database. These genes were further subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. In addition, the signaling pathway of SH3BP1 action was screened by bioinformatics analysis. Finally, the function of SH3BP1 and its mediated signaling pathway in melanoma progression were investigated in vitro and in vivo. Results: SH3BP1 was significantly upregulated in melanoma tissues and cells. The pathways regulated by SH3BP1 are closely related to the occurrence and development of tumors. And we found that overexpression of SH3BP1 promoted the proliferation, migration, and invasion of melanoma cells by increasing Rac1 activity and Wave2 protein levels in vitro. Similarly, overexpression of SH3BP1 facilitated melanoma progression by upregulating Wave2 protein expression in vivo. Conclusion: In summary, this study revealed for the first time that SH3BP1 promoted melanoma progression through Rac1/Wave2 signaling pathway, providing a new therapeutic target for melanoma.
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Cobll1 affects blast crisis (BC) progression and tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML). PACSIN2, a novel Cobll1 binding protein, activates TKI-induced apoptosis in K562 cells, and this activation is suppressed by Cobll1 through the interaction between PACSIN2 and Cobll1. PACSIN2 also binds and inhibits SH3BP1 which activates the downstream Rac1 pathway and induces TKI resistance. PACSIN2 competitively interacts with Cobll1 or SH3BP1 with a higher affinity for Cobll1. Cobll1 preferentially binds to PACSIN2, releasing SH3BP1 to promote the SH3BP1/Rac1 pathway and suppress TKI-mediated apoptosis and eventually leading to TKI resistance. Similar interactions among Cobll1, PACSIN2, and SH3BP1 control hematopoiesis during vertebrate embryogenesis. Clinical analysis showed that most patients with CML have Cobll1 and SH3BP1 expression at the BC phase and BC patients with Cobll1 and SH3BP1 expression showed severe progression with a higher blast percentage than those without any Cobll1, PACSIN2, or SH3BP1 expression. Our study details the molecular mechanism of the Cobll1/PACSIN2/SH3BP1 pathway in regulating drug resistance and BC progression in CML.
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Proteínas Adaptadoras de Transdução de Sinal , Proteínas Ativadoras de GTPase , Leucemia Mielogênica Crônica BCR-ABL Positiva , Fatores de Transcrição , Humanos , Proteínas Adaptadoras de Transdução de Sinal/genética , Apoptose , Crise Blástica , Resistência a Medicamentos , Resistencia a Medicamentos Antineoplásicos , Proteínas Ativadoras de GTPase/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Inibidores de Proteínas Quinases/farmacologia , Fatores de Transcrição/genéticaRESUMO
Signaling via the Rho GTPases provides crucial regulation of numerous cell polarization events, including apicobasal (AB) polarity, polarized cell migration, polarized cell division and neuronal polarity. Here we review the relationships between the Rho family GTPases and epithelial AB polarization events, focusing on the 3 best-characterized members: Rho, Rac and Cdc42. We discuss a multitude of processes that are important for AB polarization, including lumen formation, apical membrane specification, cell-cell junction assembly and maintenance, as well as tissue polarity. Our discussions aim to highlight the immensely complex regulatory mechanisms that encompass Rho GTPase signaling during AB polarization. More specifically, in this review we discuss several emerging common themes, that include: 1) the need for Rho GTPase activities to be carefully balanced in both a spatial and temporal manner through a multitude of mechanisms; 2) the existence of signaling feedback loops and crosstalk to create robust cellular responses; and 3) the frequent multifunctionality that exists among AB polarity regulators. Regarding this latter theme, we provide further discussion of the potential plasticity of the cell polarity machinery and as a result the possible implications for human disease.
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Polaridade Celular , Proteína cdc42 de Ligação ao GTP/metabolismo , Proteínas rac de Ligação ao GTP/metabolismo , Animais , Diferenciação Celular , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Células Epiteliais/fisiologia , Humanos , Junções Intercelulares/metabolismo , Proteína cdc42 de Ligação ao GTP/genética , Proteínas rac de Ligação ao GTP/genéticaRESUMO
The establishment and maintenance of epithelial cell-cell junctions is crucially important to regulate adhesion, apico-basal polarity and motility of epithelial cells, and ultimately controls the architecture and physiology of epithelial organs. Junctions are supported, shaped and regulated by cytoskeletal filaments, whose dynamic organization and contractility are finely tuned by GTPases of the Rho family, primarily RhoA, Rac1 and Cdc42. Recent research has identified new molecular mechanisms underlying the cross-talk between these GTPases and epithelial junctions. Here we briefly summarize the current knowledge about the organization, molecular evolution and cytoskeletal anchoring of cell-cell junctions, and we comment on the most recent advances in the characterization of the interactions between Rho GTPases and junctional proteins, and their consequences with regards to junction assembly and regulation of cell behavior in vertebrate model systems. The concept of "zonular signalosome" is proposed, which highlights the close functional relationship between proteins of zonular junctions (zonulae occludentes and adhaerentes) and the control of cytoskeletal organization and signaling through Rho GTPases, transcription factors, and their effectors.