RESUMEN
PURPOSE: STK3 has a central role in maintaining cell homeostasis, proliferation, growth, and apoptosis. Previously, we investigated the functional link between STK3/MST2, and estrogen receptor in MCF-7 breast cancer cells. To expand the investigation, this study evaluated STK3's higher expression and associated genes in breast cancer intrinsic subtypes using publicly available data. METHODS: The relationship between clinical pathologic features and STK3 high expression was analyzed using descriptive and multivariate analysis. RESULTS: Increased STK3 expression in breast cancer was significantly associated with higher pathological cancer stages, and a different expression level was observed in the intrinsic subtypes of breast cancer. Kaplan-Meier analysis showed that breast cancer with high STK3 had a lower survival rate in IDC patients than that with low STK3 expression (p < 0.05). The multivariate analysis unveiled a strong correlation between STK3 expression and the survival rate among IDC patients, demonstrating hazard ratios for lower expression. In the TCGA dataset, the hazard ratio was 0.56 (95% CI 0.34-0.94, p = 0.029) for patients deceased with tumor, and 0.62 (95% CI 0.42-0.92, p = 0.017) for all deceased patients. Additionally, in the METABRIC dataset, the hazard ratio was 0.76 (95% CI 0.64-0.91, p = 0.003) for those deceased with tumor. From GSEA outcomes 7 gene sets were selected based on statistical significance (FDR < 0.25 and p < 0.05). Weighted Sum model (WSM) derived top 5% genes also have higher expression in basal and lower in luminal A in association with STK3. CONCLUSION: By introducing a novel bioinformatics approach that combines GSEA and WSM, the study successfully identified the top 5% of genes associated with higher expression of STK3.
Asunto(s)
Biomarcadores de Tumor , Neoplasias de la Mama , Carcinoma Ductal de Mama , Regulación Neoplásica de la Expresión Génica , Serina-Treonina Quinasa 3 , Anciano , Femenino , Humanos , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/metabolismo , Perfilación de la Expresión Génica , Estimación de Kaplan-Meier , Estadificación de Neoplasias , Pronóstico , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Serina-Treonina Quinasa 3/análisis , Serina-Treonina Quinasa 3/genéticaRESUMEN
Mitophagy induction upon mitochondrial stress is critical for maintaining mitochondrial homeostasis and cellular function. Here, we found that Mst1/2 (Stk3/4), key regulators of the Hippo pathway, are required for the induction of mitophagy under various mitochondrial stress conditions. Knockdown of Mst1/2 or pharmacological inhibition by XMU-MP-1 treatment led to impaired mitophagy induction upon CCCP and DFP treatment. Mechanistically, Mst1/2 induces mitophagy independently of the PINK1-Parkin pathway and the canonical Hippo pathway. Moreover, our results suggest the essential involvement of BNIP3 in Mst1/2-mediated mitophagy induction upon mitochondrial stress. Notably, Mst1/2 knockdown diminishes mitophagy induction, exacerbates mitochondrial dysfunction, and reduces cellular survival upon neurotoxic stress in both SH-SY5Y cells and Drosophila models. Conversely, Mst1 and Mst2 expression enhances mitophagy induction and cell survival. In addition, AAV-mediated Mst1 expression reduced the loss of TH-positive neurons, ameliorated behavioral deficits, and improved mitochondrial function in an MPTP-induced Parkinson's disease mouse model. Our findings reveal the Mst1/2-BNIP3 regulatory axis as a novel mediator of mitophagy induction under conditions of mitochondrial stress and suggest that Mst1/2 play a pivotal role in maintaining mitochondrial function and neuronal viability in response to neurotoxic treatment.
Asunto(s)
Mitofagia , Neuroblastoma , Proteínas Serina-Treonina Quinasas , Serina-Treonina Quinasa 3 , Animales , Humanos , Ratones , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Mitocondrias/metabolismo , Mitofagia/genética , Mitofagia/fisiología , Neuronas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Serina-Treonina Quinasa 3/genética , Serina-Treonina Quinasa 3/metabolismo , Drosophila/genéticaAsunto(s)
Transformación Celular Neoplásica/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Serina-Treonina Quinasa 3/metabolismo , Neoplasias Gástricas/etiología , Neoplasias Gástricas/metabolismo , Proteínas ras/metabolismo , Biomarcadores de Tumor , Ciclo Celular/genética , Transformación Celular Neoplásica/genética , Susceptibilidad a Enfermedades , Regulación Neoplásica de la Expresión Génica , Humanos , Oncogenes , Pronóstico , Serina-Treonina Quinasa 3/genética , Transducción de Señal , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/mortalidadRESUMEN
[Figure: see text].
Asunto(s)
Leucotrieno B4/metabolismo , Macrófagos/metabolismo , Infarto del Miocardio/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Serina-Treonina Quinasa 3/metabolismo , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/genética , Antígenos de Diferenciación Mielomonocítica/metabolismo , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocina CCL4/genética , Quimiocina CCL4/metabolismo , Quimiocina CXCL2/metabolismo , Femenino , Lipooxigenasa/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Miocardio/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Receptores de Leucotrieno B4/antagonistas & inhibidores , Receptores de Leucotrieno B4/metabolismo , Serina-Treonina Quinasa 3/genéticaRESUMEN
Three elements of the Hippo tumor suppressor pathway - MST1/2, SAV1, and RASSF1-6 - share in common a C-terminal interaction motif termed the SARAH domain. Proteins containing this domain are capable of self-association as homodimers and also of trans-association with other SARAH domain containing proteins as well as selected additional proteins that lack this domain. Recently, the association of MST1/2 with itself or with other proteins has been shown to be regulated by phosphorylation at sites near or within the SARAH domain. In this review, we focus on recent findings regarding the regulation of such MST1/2 interactions, with an emphasis on the effects of these events on Hippo pathway activity.