RESUMEN
This study investigates the role of USP47, a deubiquitinating enzyme, in the tumor microenvironment and its impact on antitumor immune responses. Analysis of TCGA database revealed distinct expression patterns of USP47 in various tumor tissues and normal tissues. Prostate adenocarcinoma showed significant downregulation of USP47 compared to normal tissue. Correlation analysis demonstrated a positive association between USP47 expression levels and infiltrating CD8+ T cells, neutrophils, and macrophages, while showing a negative correlation with NKT cells. Furthermore, using Usp47 knockout mice, we observed a slower tumor growth rate and reduced tumor burden. The absence of USP47 led to increased infiltration of immune cells, including neutrophils, macrophages, NK cells, NKT cells, and T cells. Additionally, USP47 deficiency resulted in enhanced activation of cytotoxic T lymphocytes (CTLs) and altered T cell subsets within the tumor microenvironment. These findings suggest that USP47 plays a critical role in modulating the tumor microenvironment and promoting antitumor immune responses, highlighting its potential as a therapeutic target in prostate cancer.
Asunto(s)
Linfocitos Infiltrantes de Tumor , Neoplasias de la Próstata , Animales , Humanos , Masculino , Ratones , Línea Celular Tumoral , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Microambiente TumoralRESUMEN
The world of RNAs is much more complex than previously thought, and has rapidly emerged as one of the most actively researched topics in the life sciences. Recently, two findings in this field were reported and given special attention: promoter-associated RNAs (paRNAs), a novel class of RNAs with numerous potential functions; and promoter-targeted RNA-induced transcriptional gene regulation, a new regulatory mechanism to control transcription. In this review, we summarize the studies in these two areas, and outline the current understanding with respect to the potential biological functions of paRNAs, and the molecular mechanisms of promoter-targeted RNA-induced transcriptional gene silencing and activation. Additionally, we seek to integrate these two areas, as paRNAs may have potential biological links with promoter-targeted RNA-induced transcriptional gene regulation. Finally, we will discuss the significance of identifying paRNAs and the possible use of promoter-targeted RNAs in gene regulation and therapy.
Asunto(s)
Regulación de la Expresión Génica , Regiones Promotoras Genéticas/genética , ARN/genética , Transcripción Genética , Animales , HumanosRESUMEN
Serine-threonine kinase 10 (STK10) is a member of the STE20/p21-activated kinase (PAK) family and is predominantly expressed in immune organs. Our previous reports suggested that STK10 participates in the growth and metastasis of prostate cancer via in vitro and in vivo data. However, the correlation between STK10 and the tumor microenvironment (TME) remains unclear. In this study, we assessed the relationship between STK10 and the immune cells in the tumor microenvironment of prostate cancer through bioinformatic analysis, and investigated the role of Stk10 in tumor growth using an Stk10 knockout mouse model. The results showed that STK10 is significantly associated with the tumor-infiltrating immune cells including lymphocytes, neutrophils, macrophages and dendritic cells. The target deletion of host Stk10 results in increased tumor growth, due to decreased activated/effector cytotoxic T lymphocytes (CTLs) and increased vessel density in the TME. In conclusion, we demonstrate that host Stk10 is involved in the host anti-tumor response by modulating the activated tumor-infiltrated CTLs and angiogenesis.
RESUMEN
Studies have indicated that RIG-I may act as a tumor suppressor and participate in the tumorigenesis of some malignant diseases. However, RIG-I induces distinct cellular responses via different downstream signaling pathways depending on the cell type. To investigate the biological function and underlying molecular mechanism of RIG-I in the tumorigenesis of melanoma, we constructed RIG-I knockout, RIG-I-overexpressing B16-F10 and RIG-I knockdown A375 melanoma cell lines, and analyzed the RIG-I-mediated change in the biological behavior of tumor cells in spontaneous and poly (I:C)-induced RIG-I activation. Cell proliferation, cell cycling, apoptosis and migration were detected by CCK-8 assay, BrdU incorporation assay, Annexin V-PI staining assay and Transwell assay, respectively. In vivo tumorigenicity was evaluated by tumor xenograft growth in nude mice and subsequently by Ki67 staining and TUNEL assays. Furthermore, Western blotting was utilized to explore the underlying mechanism of RIG-I in melanoma cells. Our data showed that RIG-I promotes apoptosis and inhibits proliferation by G1 phase cell cycle arrest in the melanoma cell lines. Mechanistically, RIG-I induced the phosphorylation of p38 MAPK and MAPK kinases MKK3 and MKK4. In conclusion, the current study demonstrated that RIG-I suppressed the development of melanoma by regulating the activity of the MKK/p38 MAPK signaling pathway, which is relevant to research on novel therapeutic targets for this malignant disease.
Asunto(s)
Proteína 58 DEAD Box , Melanoma , Quinasas de Proteína Quinasa Activadas por Mitógenos , Receptores Inmunológicos , Neoplasias Cutáneas , Animales , Apoptosis/genética , Carcinogénesis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Proteína 58 DEAD Box/genética , Proteína 58 DEAD Box/metabolismo , Humanos , Melanoma/genética , Ratones , Ratones Desnudos , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Receptores Inmunológicos/genética , Transducción de Señal/genética , Neoplasias Cutáneas/genética , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Prostate cancer (PCa) is one of the most common types of cancer and is a serious threat to men's health due to the high rate of incidence and metastasis. However, the exact underlying pathology of this malignant disease has yet to be fully elucidated. The ezrin-radixin-moesin (ERM) family of proteins are associated with the development and metastasis of various types of cancer. Serine threonine kinase 10 (STK10) is an ERM kinase that is involved in the activation of ERM proteins and serves essential roles in the aggregation and adhesion of lymphocytes. To evaluate the functional roles of STK10 in the pathogenesis of PCa, a STK10-knockout (KO) DU145 PCa cell line was generated using the CRISPR-Cas9 gene editing system, and the effects of STK10 deletion on tumor biological behaviors were further analyzed. The present data suggested that STK10 KO promoted PCa cell proliferation by inhibiting p38 MAPK activation and suppressed migration primarily via the inhibition of p38 MAPK signaling and ERM protein activation. To the best of our knowledge, this is the first study to provide evidence that STK10 plays important roles in the proliferation and migration of PCa cells, which will be useful for further investigation into the pathogenesis of this disease.
RESUMEN
BACKGROUND: Serine threonine kinase 10 (STK10) is an ERM kinase involved in the activation of ERM proteins and plays an essential role in the aggregation and adhesion of lymphocytes. STK10 is expressed in about 17 cancer types, including cervical cancer. Cervical cancer is the fourth most common cancer that seriously threatens women's health worldwide. Previous studies have shown that STK10 may affect LFA-1-mediated cell adhesion. Other studies reported a mutation (R634H) of STK10 detected in peripheral T-cell lymphoma. This study aimed to evaluate the functional roles of STK10 in the pathogenesis of cervical cancer. METHODS: We generated STK10 knockout cervical cancer cell lines using the CRISPR-Cas9 gene-editing system, and further analyzed the effects of STK10 deficiency on tumor biological behaviors. The proliferation, apoptosis, migration and invasive activity of these cells were respectively detected by BrdU incorporation, AnnexinV/propidium iodide (PI) staining, wound healing assay and Transwell assays without and with Matrigel. The phosphorylation and expression level of indicated proteins were analyzed by Western blot. The differential expression genes between STK10 knockout and control cells were identified by RNA-seq analysis and further confirmed using qRT-PCR. RESULTS: Our data revealed that target deletion of STK10 does not affect cell proliferation and apoptosis, but promotes the adhesion, migration, and invasion of cervical cancer cells. Most strikingly, the phosphorylation and expression level of ezrin and other ERM proteins in STK10 knockout cells was comparable with that in the control cells. Further, RNA-seq analysis indicated that the knockout of STK10 resulted in a profound alteration of gene expression in cervical cancer cells. CONCLUSIONS: This is the first study to provide evidence that STK10 executes various physiological functions in addition to phosphorylation of ERM proteins, and plays a vital role in the migration and invasion of cervical cancer cells.
RESUMEN
OBJECTIVES: To study the effect of cryopreservative period on the cryosurvival of human spermatozoa and find out the optimal recovery time of cryopreservation. METHODS: Eighty-eight semen samples were collected from normal donors and divided randomly into 5 groups according to the period of cryopreservative storage (1 d, 7 d, 30 d, 180 d, 300 d) in liquid nitrogen after being frozen by the programized, three-step freezing method. Fresh and frozen-thawed semen were examined by the routine analysis of semen and then the sperm recovery rate were calculated. RESULTS: There were no significant differences in sperm recovery rate between group I and the others (P > 0.05). The period of cryopreservative storage in liquid nitrogen had no correlation with the cryosurvival of human spermatozoa (r = 0.05, P > 0.05). CONCLUSIONS: It was indicated that freezing-thawing after 24 h would be helpful to the screening of semen donors in batches for donor insemination of human sperm bank.