RESUMEN
BACKGROUND: The maintenance of mitochondrial homeostasis is critical for tumor initiation and malignant progression because it increases tumor cell survival and growth. The molecular events controlling mitochondrial integrity that facilitate the development of hepatocellular carcinoma (HCC) remain unclear. Here, we report that UBX domain-containing protein 1 (UBXN1) hyperactivation is essential for mitochondrial homeostasis and liver tumorigenesis. METHODS: Oncogene-induced mouse liver tumor models were generated with the Sleeping Beauty (SB) transposon delivery system. Assessment of HCC cell growth in vivo and in vitro, including tumour formation, colony formation, TUNEL and FACS assays, was conducted to determine the effects of UBXN1 on HCC cells, as well as the involvement of the UBXN1-prohibitin (PHB) interaction in mitochondrial function. Coimmunoprecipitation (Co-IP) was used to assess the interaction between UBXN1 and PHB. Liver hepatocellular carcinoma (LIHC) datasets and HCC patient samples were used to assess the expression of UBXN1. RESULTS: UBXN1 expression is commonly upregulated in human HCCs and mouse liver tumors and is associated with poor overall survival in HCC patients. UBXN1 facilitates the growth of human HCC cells and promotes mouse liver tumorigenesis driven by the NRas/c-Myc or c-Myc/shp53 combination. UBXN1 interacts with the inner mitochondrial membrane protein PHB and sustains PHB expression. UBXN1 inhibition triggers mitochondrial damage and liver tumor cell apoptosis. CONCLUSIONS: UBXN1 interacts with PHB and promotes mitochondrial homeostasis during liver tumorigenesis.
Asunto(s)
Carcinogénesis , Carcinoma Hepatocelular , Homeostasis , Neoplasias Hepáticas , Mitocondrias , Prohibitinas , Animales , Humanos , Ratones , Apoptosis , Carcinogénesis/patología , Carcinogénesis/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Mitocondrias/metabolismo , Unión Proteica , Proteínas Represoras/metabolismoRESUMEN
BACKGROUND AND AIMS: Liver tumorigenesis encompasses oncogenic activation and self-adaptation of various biological processes in premalignant hepatocytes to circumvent the pressure of cellular stress and host immune control. Ubiquitin regulatory X domain-containing proteins (UBXNs) participate in the regulation of certain signaling pathways. However, whether UBXN proteins function in the development of liver cancer remains unclear. APPROACH AND RESULTS: Here, we demonstrated that UBXN9 (Alveolar Soft Part Sarcoma Chromosomal Region Candidate Gene 1 Protein/Alveolar Soft Part Sarcoma Locus) expression was decreased in autochthonous oncogene-induced mouse liver tumors and ~47.7% of human HCCs, and associated with poor prognosis in patients with HCC. UBXN9 attenuated liver tumorigenesis induced by different oncogenic factors and tumor growth of transplanted liver tumor cells in immuno-competent mice. Mechanistically, UBXN9 significantly inhibited the function of the RNA exosome, resulting in increased expression of RLR-stimulatory RNAs and activation of the retinoic acid-inducible gene-I-IFN-Ι signaling in tumor cells, and hence potentiated T cell recruitment and immune control of tumor growth. Abrogation of the CD8 + T cell response or inhibition of tumor cell retinoic acid-inducible gene-I signaling efficiently counteracted the UBXN9-mediated suppression of liver tumor growth. CONCLUSIONS: Our results reveal a modality in which UBXN9 promotes the stimulatory RNA-induced retinoic acid-inducible gene-I-interferon signaling that induces anti-tumor T cell response in liver tumorigenesis. Targeted manipulation of the UBXN9-RNA exosome circuit may have the potential to reinstate the immune control of liver tumor growth.
RESUMEN
We previously identified the mouse dynein axonemal intermediate chain 2 (Dnaic2) gene. This gene expresses a component of the axonemal dynein complex that functions in cilia or flagella. We found that overexpression of Dnaic2 results in female subfertility and male infertility. In this study, we generated Dnaic2 knockdown (KD) mice and identified the potential regulatory mechanisms involved in Dnaic2 function. For phenotype analysis, we found that body weight was lighter and size was smaller in Dnaic2 KD mice than in wild-type mice. A total of 45% of these Dnaic2 KD mice were infertile due to sperm abnormalities in males, or had oocyte abnormalities and pathological changes in the tunica mucosa in the oviduct of females. Moreover, Dnaic2 overexpression enhanced the expression of proliferating cell nuclear antigen (PCNA) in the ovaries, which suggested that Dnaic2 stimulated proliferation of cells in the ovaries. However, PCNA expression in the testis of Dnaic2-overexpressed mice was lower than that in controls. Additionally, the ratio of Bax/B-cell lymphoma-2(Bcl-2) in the testis of Dnaic2-overexpressed mice was higher than that in controls, which suggested that Dnaic2 inhibited cellular proliferation in the testis. To examine the molecular action of Dnaic2, immunoprecipitation analysis was used and showed that Dnaic2 protein interacted with signal transducer and activator of transcription 3 (Stat3). Molecular modelling analysis showed that Dnaic2 bound with the linker and SH2 domains of Stat3. Furthermore, overexpression of Dnaic2 promoted phosphorylation of Stat3. In conclusion, our study suggests that Dnaic2 plays a role in oogenesis and spermatogenesis by activation of Stat3.
Asunto(s)
Dineínas Axonemales/metabolismo , Gametogénesis/fisiología , Factor de Transcripción STAT3/metabolismo , Animales , Línea Celular , Proliferación Celular/fisiología , Cilios/metabolismo , Cilios/fisiología , Femenino , Células HEK293 , Humanos , Infertilidad Masculina/metabolismo , Infertilidad Masculina/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Células 3T3 NIH , Ovario/metabolismo , Ovario/fisiología , Espermatogénesis/fisiología , Testículo/metabolismoRESUMEN
BACKGROUND: POH1, a member of the JAMM domain containing deubiquitinases, functions in malignant progression of certain types of cancer. However, the role of POH1 in prostate cancer (PCa) remains unclear. METHODS: We performed RNA interference against the JAMM members in PC3 cells and analyzed cell proliferation. POH1 knockdown was established to evaluate the effects of POH1 on cell growth in vitro and in vivo. RNA-sequencing was utilized to explore the molecular details underlying the biological function of POH1 in PCa. The expression of POH1 in PCa tissues was detected by immunohistochemistry. The POH1 inhibitor capzimin was evaluated to explore whether pharmacologically inhibiting POH1 significantly affected PCa cell proliferation alone or enhanced the inhibitory efficacy of docetaxel and androgen deprivation. RESULTS: Functional analyses identified POH1 as a JAMM deubiquitinase that is required for PCa proliferation. Importantly, expression of POH1 was higher in human PCa tissues (PCas) than that in normal prostate tissues, and a positive correlation was detected between elevated POH1 expression and higher pathological grades in PCas. In vivo experiments further demonstrated that depleting POH1 significantly suppressed the growth of PCa cell xenografts. POH1 deficiency profoundly inhibited the expression of a set of genes involving the cell cycle and caused G0/G1 phase arrest. Furthermore, the POH1 inhibitor capzimin phenotypically recapitulated the effects of POH1 knockdown and improved the efficacy of docetaxel and androgen deprivation in PCa cells. CONCLUSIONS: POH1 was overexpressed in PCas and was correlated with pathological grades in human PCas. Inhibiting POH1 by gene silencing or pharmacological inhibition with capzimin suppressed PCa cell growth. Exploring the inhibition of POH1 in combination with other drugs may provide a strategy to benefit patients with PCa.
Asunto(s)
Antagonistas de Andrógenos/farmacología , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Docetaxel/farmacología , Neoplasias de la Próstata/genética , Complejo de la Endopetidasa Proteasomal/genética , Transactivadores/genética , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Desnudos , Próstata/diagnóstico por imagen , Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Complejo de la Endopetidasa Proteasomal/metabolismo , Interferencia de ARN , Transactivadores/metabolismoRESUMEN
UNLABELLED: Growth arrest and DNA damage 45G (GADD45G), a stress sensor with multiple implications in various biological processes, is down-regulated in a broad spectrum of cancers. However, little is known about the biological effects of GADD45G on hepatocellular carcinoma (HCC) cells and the related mechanisms. In the present study, we found that GADD45G was commonly down-regulated in oncogene-transformed mouse liver cells and in human and mouse HCC. Ectopic expression of GADD45G robustly elicited senescence in HCC cells and suppressed tumor growth in vivo. Furthermore, GADD45G-induced senescence occurred in HCC cells independently of p53, p16(INK4a) (p16), and retinoblastoma (Rb). Instead, the prompt inhibition of Janus kinase 2 (Jak2), tyrosine kinase 2 (Tyk2), and signal transducer and activator of transcription 3 (Stat3) activation was observed in cells undergoing senescence. Impairment of Jak-Stat3 activation caused by GADD45G expression was associated with activation of SH2 domain-containing protein tyrosine phosphatase-2 (Shp2). Expression of constitutively activated Stat3 or human telomerase reverse transcriptase (hTERT), as well as knockdown of Shp2f, efficiently counteracted GADD45G-induced senescence. More important, in clinical HCC specimens, we found that GADD45G expression was inversely correlated with phosphorylated Stat3 expression in tumor cells and disease progression. CONCLUSION: GADD45G functions as a negative regulator of the Jak-Stat3 pathway and inhibits HCC by inducing cellular senescence. The decrease or absence of GADD45G expression may be a key event for tumor cells or premalignant liver cells to bypass cellular senescence.
Asunto(s)
Carcinoma Hepatocelular/metabolismo , Proteínas Portadoras/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Quinasas Janus/metabolismo , Neoplasias Hepáticas Experimentales/metabolismo , Factor de Transcripción STAT3/metabolismo , Animales , Línea Celular Tumoral , Senescencia Celular , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Regulación hacia Abajo , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Fosforilación , Proteína de Retinoblastoma/metabolismo , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
BACKGROUND: Kruppel-like factors (KLFs) are involved in various biological processes; emerging studies have indicated that KLF9 plays a critical role in regulating tumorigenesis. The role of KLF9 in prostate cancer (PCa), however, has not yet been investigated. METHODS: The expression of KLF members, AKT- and apoptosis-related proteins were analyzed by Western blot or qRT-PCR. Tet-On inducible KLF9 expression was established for the evaluation of the effects of KLF9 on cell proliferation, apoptosis, and xenograft tumor growth in nude mice. Cell cycle and apoptosis were determined by flow cytometry. RESULTS: KLF9 was induced in a time-dependent manner in flutamide-caused apoptosis, and knockdown of KLF9 significantly decreased flutamide-induced growth inhibition and apoptosis in LNCaP cells. The levels of KLF9 were relatively lower in PCa cell lines, particularly in androgen-independent cell lines compared with those in nontumorous prostate epithelial cell lines. Overexpression of KLF9 dramatically suppressed cell proliferation and caused cell cycle arrest in the G2/M phase and cell apoptosis in the androgen-independent cell lines, PC3 and DU145. Intriguingly, KLF9 expression severely suppressed the activation of AKT and its downstream targets. AKT reactivation partially rescued the KLF9-mediated inhibitory effects on the proliferation of PCa cells. More importantly, we found that KLF9 overexpression efficiently inhibited the xenograft tumor growth of PCa cells. CONCLUSIONS: These data collectively showing that KLF9 substantially inhibits AKT activation and abrogates tumor growth of PCa cells, suggest the potential of either genetic or pharmacological activation of KLF9 in the therapeutic treatment of castration-resistant PCa.
Asunto(s)
Apoptosis/efectos de los fármacos , Flutamida/farmacología , Factores de Transcripción de Tipo Kruppel/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Animales , Apoptosis/fisiología , Western Blotting , Procesos de Crecimiento Celular/efectos de los fármacos , Procesos de Crecimiento Celular/fisiología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Citometría de Flujo , Xenoinjertos , Humanos , Etiquetado Corte-Fin in Situ , Estimación de Kaplan-Meier , Factores de Transcripción de Tipo Kruppel/biosíntesis , Factores de Transcripción de Tipo Kruppel/genética , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Neoplásico/química , ARN Neoplásico/genética , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Myeloid cells have a critical role in maintaining intestinal homeostasis and regulating the development of inflammatory bowel disease and colitis-associated cancer (CAC). However, the signaling pathways that control the function of colonic myeloid cells in these pathological processes are still poorly defined. In this study, we demonstrate that transforming growth factor-ß (TGF-ß) signaling in colonic myeloid cells is significantly involved in the development of CAC. Myeloid TGF-ß receptor II (Tgfbr2)-deficient mice showed reduced susceptibility to chemically induced colitis-associated tumorigenesis, as evidenced by decreases in number and size of tumors. Myeloid Tgfbr2 deficiency markedly decreased the production of interleukin-6 and tumor necrosis factor-α, two proinflammatory cytokines that are essential for colonic tumorigenesis; in addition, a marked increase in the proportions of Foxp3+CD4+ regulatory T cells was observed in the colonic lamina propria in the initial stage of CAC. Loss of myeloid Tgfbr2 was associated with a decrease in the presence of F4/80 positive macrophages and a downregulation of phosphorylated STAT3, proliferative cell nuclear antigen and cyclin D1 expression in colonic adenoma tissues. TGF-ß enhanced macrophage recruitment, at least in part, through modulating the expression of the chemokine (C-C motif) receptor 2 (CCR2) ligands in tumor environment and the CCR2 signaling in macrophages. Collectively, these results suggest that myeloid TGF-ß signaling modulates intestinal inflammation and significantly promotes tumorigenesis in the development of colitis-associated colon cancer.
Asunto(s)
Carcinogénesis , Colitis/patología , Células Mieloides/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/genética , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Colitis/inducido químicamente , Colitis/genética , Colon/metabolismo , Colon/patología , Humanos , Inflamación/metabolismo , Inflamación/patología , Mucosa Intestinal/citología , Mucosa Intestinal/metabolismo , Ratones , Células Mieloides/patología , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transducción de SeñalRESUMEN
Dysregulation of the Hippo pathway that promotes cell survival, proliferation and tumorigenesis, relays on the coordinated interactions of YAP with the factors that determine YAP translocation and the related transcriptional programming. Here, we demonstrate that ETV4, a transcriptional factor participating in various protumorigenic processes, enhances YAP-mediated transactivation and hepatocellular carcinoma (HCC) progression. Mechanistically, the enhancement of YAP activities is mediated by the interaction between ETV4 and YAP, which not only increases nuclear YAP accumulation but also directly augments the YAP/TEAD4-mediated transcriptional activation in tumor cells. Functionally, the interplay of ETV4 and YAP promotes growth of liver tumor cells, and activates the genes related to myeloid cell recruitment, including CXCL1 and CXCL5, leading to an enriched presence of myeloid-derived suppressive cells and macrophages but a decreased infiltration of T cells and NK cells in transplanted tumors. More importantly, the correlations between YAP activation, the altered immune cell distribution and ETV4 expression are observed in human HCCs. Therefore, our study reveals a functional interaction between ETV4 and YAP that contributes to HCC progression, and provides mechanistic insights into the regulation of nuclear YAP retention and transactivation.
Asunto(s)
Carcinoma Hepatocelular , Proteínas de Ciclo Celular/metabolismo , Neoplasias Hepáticas , Factores de Transcripción/metabolismo , Carcinogénesis/genética , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/patología , Proteínas Musculares/metabolismo , Proteínas Proto-Oncogénicas c-ets/genética , Factores de Transcripción de Dominio TEA , Factores de Transcripción/genéticaRESUMEN
Biofilm formation on the surface of materials has brought great troubles to various industries. Designing surfaces with long-lasting antibiofouling properties can help restrain primary bacterial and protein attachment and subsequent biofilm formation for a long time, which is also of great significance for industrial applications. In this work, we successfully prepared fluorinated carbon nanotubes through a one-step fluorination method using fluorosilane and fabricated a superamphiphobic coating using a simple spray method. This coating with ultralow surface free energy and stable micro/nano structures achieved highly efficient and long-term underwater antibiofouling properties. Tea, milk, BSA, and bacterial solution can bounce highly on this surface without wetting the surface in air. The long-term existence of the underwater air-bubble layer on the surface of the superamphiphobic coating was observed. Thus, this surface can effectively resist BSA and bacterial attachment (E. coli), and the efficiency, respectively, reaches 97.5 and 98.2%. Even if it is fully soaked in BSA and BS solution for 120 h, the whole surface is still able to repel water, BSA, and BS solution very well. In addition, the coating possessed excellent wear resistance, the CAs of BSA and BS solution just decreased slightly (higher than 158°), and the sliding angles increased slightly (lower than 4°) after 50 tape abrasion cycles. Therefore, this superamphiphobic coating may have promising applications for marine devices, biomedical materials, protective clothing, and chemical shielding.
Asunto(s)
Nanotubos de Carbono , Escherichia coli , Agua/químicaRESUMEN
Dysregulated ubiquitination of tumor-related proteins plays a critical role in tumor development and progression. The deubiquitinase USP22 is aberrantly expressed in certain types of cancer and contributes to aggressive tumor progression. However, the precise mechanism underlying the pro-tumorigenic function of USP22 in hepatocellular carcinoma (HCC) remains unclear. Here, we report that E2F6, a pocket protein-independent transcription repressor, is essential for HCC cell growth, and that its activities are controlled by USP22-mediated deubiquitination. USP22 interacts with and stabilizes E2F6, resulting in the transcriptional repression of phosphatase DUSP1. Moreover, the process involving DUSP1 repression by E2F6 strengthens AKT activation in HCC cells. Therefore, these findings provide mechanistic insights into the USP22-mediated control of oncogenic AKT signaling, emphasizing the importance of USP22-E2F6 regulation in HCC development.
Asunto(s)
Carcinoma Hepatocelular/genética , Proliferación Celular/genética , Factor de Transcripción E2F6/genética , Neoplasias Hepáticas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Ubiquitina Tiolesterasa/genética , Ubiquitinación/genética , Animales , Carcinoma Hepatocelular/patología , Línea Celular , Línea Celular Tumoral , Expresión Génica/genética , Células HEK293 , Células Hep G2 , Humanos , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Desnudos , Monoéster Fosfórico Hidrolasas/genética , Transducción de Señal/genética , Transcripción Genética/genéticaRESUMEN
Oncogenic activation of KRAS and its surrogates is essential for tumour cell proliferation and survival, as well as for the development of protumourigenic microenvironments. Here, we show that the deubiquitinase USP12 is commonly downregulated in the KrasG12D-driven mouse lung tumour and human non-small cell lung cancer owing to the activation of AKT-mTOR signalling. Downregulation of USP12 promotes lung tumour growth and fosters an immunosuppressive microenvironment with increased macrophage recruitment, hypervascularization, and reduced T cell activation. Mechanistically, USP12 downregulation creates a tumour-promoting secretome resulting from insufficient PPM1B deubiquitination that causes NF-κB hyperactivation in tumour cells. Furthermore, USP12 inhibition desensitizes mouse lung tumour cells to anti-PD-1 immunotherapy. Thus, our findings propose a critical component downstream of the oncogenic signalling pathways in the modulation of tumour-immune cell interactions and tumour response to immune checkpoint blockade therapy.
Asunto(s)
Resistencia a Antineoplásicos , Neoplasias Pulmonares/terapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Microambiente Tumoral/inmunología , Ubiquitina Tiolesterasa/metabolismo , Animales , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Quimiocinas/metabolismo , Regulación hacia Abajo , Humanos , Tolerancia Inmunológica , Inmunoterapia , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Proteína Fosfatasa 2C/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Ubiquitina Tiolesterasa/antagonistas & inhibidoresRESUMEN
K-RAS mutation and molecular alterations of its surrogates function essentially in lung tumorigenesis and malignant progression. However, it remains elusive how tumor-promoting and deleterious events downstream of K-RAS signaling are coordinated in lung tumorigenesis. Here, we show that USP16, a deubiquitinase involved in various biological processes, functions as a promoter for the development of K-RAS-driven lung tumor. Usp16 deletion significantly attenuates K-rasG12D-mutation-induced lung tumorigenesis in mice. USP16 upregulation upon RAS activation averts reactive oxygen species (ROS)-induced p38 activation that would otherwise detrimentally influence the survival and proliferation of tumor cells. In addition, USP16 interacts with and deubiquitinates JAK1, and thereby promoting lung tumor growth by augmenting JAK1 signaling. Therefore, our results reveal that USP16 functions critically in the K-RAS-driven lung tumorigenesis through modulating the strength of p38 and JAK1 signaling.
Asunto(s)
Carcinogénesis , Neoplasias Pulmonares , Animales , Transformación Celular Neoplásica , Humanos , Janus Quinasa 1 , RatonesRESUMEN
BACKGROUND: Spermatogenesis is a complex process involving cell development, differentiation and apoptosis. This process is governed by a series of genes whose expressions are highly regulated. Male infertility can be attributed to multiple genetic defects or alterations that are related to spermatogenesis. The discovery, cloning and further functional study of genes related to spermatogenesis is of great importance to the elucidation of the molecular mechanism of spermatogenesis. It is also physiologically and pathologically significant to the therapy of male infertility. METHODS: GON-SJTU1 was identified and cloned from rat testis by cDNA library screening and 3'-and 5'-RACE. The products of GON-SJTU1 were assessed by Northern and Western blotting. The expression of GON-SJTU1 was also examined by In situ hybridization and immunohistochemistry. RESULTS: Here we identified and cloned a new gene, GON-SJTU1, with the biological process of spermatogenesis. GON-SJTU1 is highly expressed in the testis from day 1 to 15 and then decreased, suggesting that GON-SJTU1 might be a time-related gene and involved in the early stage of spermatogenesis. And the expression of GON-SJTU1 in the testis occurred in some male germ cells, particularly in gonocytes and spermatogonial stem cells. CONCLUSION: GON-SJTU1 may play a role in the biological process of spermatogenesis.
Asunto(s)
Fosfoproteínas/genética , Proteínas de Plasma Seminal/genética , Espermatogénesis/genética , Testículo/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Clonación Molecular , Expresión Génica , Biblioteca de Genes , Genes , Masculino , Datos de Secuencia Molecular , Ratas , Proteínas de Plasma Seminal/aislamiento & purificación , Proteínas de Plasma Seminal/metabolismo , Distribución TisularRESUMEN
BACKGROUND: Hyper-activation of TGF-ß signaling is critically involved in progression of hepatocellular carcinoma (HCC). However, the events that contribute to the dysregulation of TGF-ß pathway in HCC, especially at the post-translational level, are not well understood. METHODS: Associations of deubiquitinase POH1 with TGF-ß signaling activity and the outcomes of HCC patients were examined by data mining of online HCC datasets, immunohistochemistry analyses using human HCC specimens, spearman correlation and survival analyses. The effects of POH1 on the ubiquitination and stability of the TGF-ß receptors (TGFBR1 and TGFBR2) and the activation of downstream effectors were tested by western blotting. Primary mouse liver tissues from polyinosinic:polycytidylic acid (poly I:C)- treated Mx-Cre+, poh1f/f mice and control mice were used to detect the TGF-ß receptors. The metastatic-related capabilities of HCC cells were studied in vitro and in mice. FINDINGS: Here we show that POH1 is a critical regulator of TGF-ß signaling and promotes tumor metastasis. Integrative analyses of HCC subgroups classified with unsupervised transcriptome clustering of the TGF-ß response, metastatic potential and outcomes, reveal that POH1 expression positively correlates with activities of TGF-ß signaling in tumors and with malignant disease progression. Functionally, POH1 intensifies TGF-ß signaling delivery and, as a consequence, promotes HCC cell metastatic properties both in vitro and in vivo. The expression of the TGF-ß receptors was severely downregulated in POH1-deficient mouse hepatocytes. Mechanistically, POH1 deubiquitinates the TGF-ß receptors and CAV1, therefore negatively regulates lysosome pathway-mediated turnover of TGF-ß receptors. CONCLUSION: Our study highlights the pathological significance of aberrantly expressed POH1 in TGF-ß signaling hyperactivation and aggressive progression in HCC.
Asunto(s)
Carcinoma Hepatocelular/patología , Caveolina 1/metabolismo , Neoplasias Hepáticas/patología , Complejo de la Endopetidasa Proteasomal/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transactivadores/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Regulación hacia Abajo , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Pronóstico , Complejo de la Endopetidasa Proteasomal/genética , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Transactivadores/antagonistas & inhibidores , Transactivadores/genética , UbiquitinaciónRESUMEN
Metastatic progression is the main cause of mortality in breast cancer, necessitating the determination of the molecular events driving this process for the development of new therapeutic approaches. Here, we demonstrate that hyperactivation of the deubiquitinase USP1 contributes to breast cancer metastasis. Upregulated USP1 expression in primary breast cancer specimens correlates with metastatic progression and poor prognosis in breast cancer patients. USP1 enhances the expression of a number of pro-metastatic genes in breast cancer cells, promotes cell migration and invasion in vitro, and facilitates lung metastasis of breast cancer cells. Moreover, USP1-mediated deubiquitination and stabilization of KPNA2 are revealed as the downstream events crucial for USP1-pro-metastatic function. Most importantly, pharmacological intervention of USP1 function by pimozide or ML323 significantly represses breast cancer metastasis in mice, suggesting a rationale for using USP1 inhibitors for treatment of patients with breast cancer. Taken together, our results establish USP1 as a promoter of breast cancer metastasis and provide evidence for the potential practice of USP1 targeting in the treatment of breast cancer.
Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Metástasis de la Neoplasia/patología , Proteasas Ubiquitina-Específicas/antagonistas & inhibidores , alfa Carioferinas/metabolismo , Animales , Línea Celular , Línea Celular Tumoral , Movimiento Celular/fisiología , Progresión de la Enfermedad , Femenino , Células HEK293 , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Invasividad Neoplásica/patología , Pronóstico , Regiones Promotoras Genéticas/fisiologíaRESUMEN
Foxp3-expressing regulatory T (Treg) cells are essential for averting autoimmune diseases and maintaining immune homeostasis. However, the molecular mechanisms underlying the development and maintenance of Treg cells are still unclear. Here, we found that T cell-specific deletion of the gene encoding the deubiquitinase POH1 compromised the development of mature T cells, especially CD4+Foxp3+ Treg cells. Moreover, POH1 deficiency significantly attenuated the transition of CD25+ Treg cell precursors into Foxp3+ Treg cells accompanied by downregulation of interleukin 2 (IL-2)-STAT5 signaling. Deletion of POH1 in generated CD4+Foxp3+ Treg cells led to an early onset of fetal autoimmune disorders and a decrease in the pool size of peripheral Treg cells in mice, which were mostly due to decreased expansion of these cells. Thus, these results revealed that POH1 has a pivotal role in the development and maintenance of CD4+Foxp3+ Treg cells and contributes to immune tolerance.
Asunto(s)
Autoinmunidad/genética , Diferenciación Celular/genética , Factores de Transcripción Forkhead/metabolismo , Tolerancia Inmunológica/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Linfocitos T Reguladores/metabolismo , Transactivadores/metabolismo , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Diferenciación Celular/inmunología , Proliferación Celular/genética , Factores de Transcripción Forkhead/inmunología , Interleucina-2/metabolismo , Subunidad alfa del Receptor de Interleucina-2/inmunología , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Complejo de la Endopetidasa Proteasomal/genética , RNA-Seq , Factor de Transcripción STAT5/metabolismo , Bazo/inmunología , Bazo/metabolismo , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , Timo/inmunología , Timo/metabolismo , Transactivadores/genéticaRESUMEN
Inflammasome activation is essential for host defence against invading pathogens, but is also involved in various forms of inflammatory diseases. The processes that control inflammasome activity are thus important for averting excessive immune responses and tissue damage. Here we show that the deubiquitinase POH1 negatively regulates the immune response triggered by inflammasome activation. POH1 deficiency in macrophages enhances mature IL-1ß production without significant alterations in inflammasome priming and ASC-caspase-1 activation. In WT macrophages, POH1 interacts with and deubiquitinates pro-IL-1ß by decreasing the K63-linked polyubiquitin chains, as well as decreases the efficacy of pro-IL-1ß cleavage. Furthermore, myeloid cell-specific deletion of POH1 aggravates lipopolysaccharide-induced systemic inflammation and alum-induced peritonitis inflammatory responses in vivo. Our study thereby reveals that POH1-mediated deubiquitination of pro-IL-1ß is an important regulatory event that restrains inflammatory responses for the maintenance of immune homeostasis.
Asunto(s)
Inflamasomas/metabolismo , Inflamación/metabolismo , Interleucina-1beta/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Transactivadores/metabolismo , Animales , Caspasa 1/genética , Caspasa 1/metabolismo , Sistemas de Computación , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Células HEK293 , Humanos , Inmunoprecipitación , Inflamasomas/efectos de los fármacos , Inflamación/inducido químicamente , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Plásmidos/genética , Poliubiquitina/metabolismo , Complejo de la Endopetidasa Proteasomal/genética , Transactivadores/genéticaRESUMEN
The mammalian preimplantation embryo is a critical and unique stage in embryonic development. This stage includes a series of crucial events: the transition from oocyte to embryo, the first cell divisions, and the establishment of cellular contacts. These events are regulated by multiple signal-transduction pathways. In this article we describe patterns of stage-specific expression in several signal-transduction pathways and try to give a profile of the signaling transduction network in preimplantation development of mammalian embryo.
Asunto(s)
Blastocisto , Mamíferos/embriología , Transducción de Señal , Animales , Mamíferos/fisiologíaRESUMEN
MicroRNAs, identified only relatively recently, are regulators of gene expression with potential medical benefits. The combination of microRNAs and regenerative medicine is an emerging interdisciplinary medical field that can yield exciting new possibilities for clinical medicine. In this paper, we review the prospects of microRNAs as future therapies in regenerative medicine. Recently, researchers have demonstrated the crucial roles of microRNAs, not only in the differentiation and proliferation of stem cells, which have a key function in the regeneration and transplantation of organs, but also in oncogenesis. Several lines of indirect evidence show that the initiation and maintenance of cancer stem cells might also be under the control of microRNAs. Further, microRNAs have been indicated to be involved in diverse biological processes, suggesting the potential role of these molecules in the treatment of diseases.