RESUMO
BACKGROUND: The prognostic and therapeutic implications of endothelial cells (ECs) heterogeneity in prostate cancer (PCa) are poorly understood. METHODS: We investigated associations of EC heterogeneity with PCa recurrence and castration resistance in 8 bulk transcriptomic and 4 single-cell RNA-seq cohorts. A recurrence-associated EC (RAEC) signature was constructed by comparing 11 machine learning algorithms through nested cross-validation. Functional relevances of RAEC-specific genes were also tested. RESULTS: A subset of ECs was significantly associated with recurrence in primary PCa and named RAECs. RAECs were characteristic of tip and immature cells and were enriched in migration, angiogenesis, and collagen-related pathways. We then developed an 18-gene RAEC signature (RAECsig) representative of RAECs. Higher RAECsig scores independently predicted tumor recurrence and performed better or comparably compared to clinicopathological factors and commercial gene signatures in multiple PCa cohorts. Of the 18 RAECsig genes, FSCN1 was upregulated in ECs from PCa with higher Gleason scores; and the silencing of FSCN1, TMEME255B, or GABRD in ECs either attenuated tube formation or inhibited PCa cell proliferation. Finally, higher RAECsig scores predicted castration resistance in both primary and castration-resistant PCa. CONCLUSION: This study establishes an endothelial signature that links a subset of ECs to prostate cancer recurrence and castration resistance.
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Although cancer diagnosis and treatment have rapidly advanced in recent decades, urological malignancies, which have high morbidity and mortality rates, are among the most difficult diseases to treat. The Hippo signaling is an evolutionarily conserved pathway in organ size control and tissue homeostasis maintenance. Its downstream effectors, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), are key modulators of numerous physiological and pathological processes. Recent work clearly indicates that Hippo signaling is frequently altered in human urological malignancies. In this review, we discuss the disparate viewpoints on the upstream regulators of YAP/TAZ and their downstream targets and systematically summarize the biological implications. More importantly, we highlight the molecular mechanisms involved in Hippo-YAP signaling to improve our understanding of its role in every stage of prostate cancer, bladder cancer and kidney cancer progression. A better understanding of the biological outcomes of YAP/TAZ modulation will contribute to the establishment of future therapeutic approaches.
Assuntos
Via de Sinalização Hippo , Proteínas Serina-Treonina Quinases , Transdução de Sinais , Fatores de Transcrição , Humanos , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Transcrição/metabolismo , Neoplasias Urológicas/metabolismo , Neoplasias Urológicas/etiologia , Neoplasias Urológicas/patologia , Proteínas de Sinalização YAP/metabolismo , Animais , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/genética , MasculinoRESUMO
Combination therapy has emerged as a promising approach for treating tumors, although there is room for improvement. This study introduced a novel strategy that combined the enhancement of apoptosis, ferroptosis, and DNA damage to improve therapeutic outcomes for prostate cancer. Specifically, we have developed a supramolecular oxidative stress nanoamplifier, which was comprised of ß-cyclodextrin, paclitaxel, and ferrocene-poly(ethylene glycol). Paclitaxel within the system disrupted microtubule dynamics, inducing G2/M phase arrest and apoptosis. Concurrently, ferrocene utilized hydrogen peroxide to generate toxic hydroxyl radicals in cells through the Fenton reaction, triggering a cascade of reactive oxygen species expansion, reduction of glutathione levels, lipid peroxidation, and ferroptosis. The increased number of hydroxyl radicals and the inhibitory effect of THZ531 on DNA repair mechanisms exacerbated DNA damage within tumor cells. As expected, the supramolecular nanoparticles demonstrated excellent drug delivery ability to tumor cells or tissues, exhibited favorable biological safety in vivo, and enhanced the killing effect on prostate cancer.
Assuntos
Estresse Oxidativo , Paclitaxel , Neoplasias da Próstata , Paclitaxel/farmacologia , Paclitaxel/química , Humanos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Animais , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Camundongos , Metalocenos/química , Nanopartículas/química , Apoptose/efeitos dos fármacos , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Linhagem Celular Tumoral , beta-Ciclodextrinas/química , Polietilenoglicóis/química , Camundongos Nus , Ferroptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Dano ao DNA/efeitos dos fármacosRESUMO
Drug-based supramolecular self-assembling delivery systems have enhanced the bioavailability of chemotherapeutic drugs and reduced systemic side effects; however, improving the delivery efficiency and responsive release ability of these systems remains challenging. This study focuses primarily on the utilization of per-6-thio-ß-cyclodextrin (CD) to link a significant quantity of paclitaxel (PTX) via ROS-sensitive thioketal (TK) linkages (designated as CDTP), thereby allowing efficiently drug release when exposed to high levels of reactive oxygen species (ROS) in the tumor microenvironment. To construct these supramolecular nanoparticles (NPs) with CDTP, we introduced PEGylated ferrocene (Fc) through host-guest interactions. The intracellular hydrogen peroxide (H2O2) is converted into hydroxyl radicals (â¢OH) through the Fc-catalyzed Fenton reaction. Additionally, the generated Fc+ consumes the antioxidant glutathione (GSH). In both in vivo and in vitro experiments, CDTP@Fc-PEG NPs were absorbed effectively by tumor cells, which increased levels of ROS and decreased levels of GSH, disrupting the redox balance of cancer cells and increasing their sensitivity to chemotherapy. Furthermore, CDTP@Fc-PEG NPs exhibited high tumor accumulation and cytotoxicity without causing significant toxicity to healthy organs. Collectively, our results suggest CDTP@Fc-PEG NPs as a promising supramolecular nano-delivery platform for high drug-loading of PTX and synergistic chemotherapy.
Assuntos
Nanopartículas , Neoplasias , Humanos , Espécies Reativas de Oxigênio , Peróxido de Hidrogênio , Sistemas de Liberação de Medicamentos , Paclitaxel/uso terapêutico , Neoplasias/tratamento farmacológico , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
Chemotherapy remains the most essential treatment for prostate cancer, but multidrug resistance (MDR) contributes to chemotherapy failure and tumor-related deaths. The overexpression of P-glycoprotein (P-gp) is one of the main mechanisms behind MDR. Here, this work reports a multimodal nanoplatform with a reactive oxygen species (ROS) cascade for gas therapy/ferroptosis/chemotherapy in reversing MDR. The nanoplatform disassembles when responding to intracellular ROS and exerts three main functions: First, nitric oxide (NO) targeted delivery can reverse MDR by downregulating P-gp expression and inhibiting mitochondrial function. Second, ferrocene-induced ferroptosis breaks the redox balance in the tumor intracellular microenvironment and synergistically acts against the tumor. Third, the release of paclitaxel (PTX) is precisely controlled in situ in the tumor for chemotherapy that avoids damage to normal tissues. Excitingly, this multimodal nanoplatform is a promising weapon for reversing MDR and may provide a pioneering paradigm for synergetic cancer therapy.
Assuntos
Ferroptose , Neoplasias da Próstata , Masculino , Humanos , Espécies Reativas de Oxigênio/metabolismo , Resistencia a Medicamentos Antineoplásicos , Resistência a Múltiplos Medicamentos , Paclitaxel/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
Messenger RNA (mRNA) vaccine is explored as a promising strategy for cancer immunotherapy, but the side effects, especially the liver-related damage caused by LNP, raise concerns about its safety. In this study, a novel library of 248 ionizable lipids comprising 1,2-diesters is designed via a two-step process involving the epoxide ring-opening reaction with carboxyl group-containing alkyl chains followed by an esterification reaction with the tertiary amines. Owing to the special chemical structure of 1,2-diesters, the top-performing lipids and formulations exhibit a faster clearance rate in the liver, contributing to increased stability and higher safety compared with DLin-MC3-DMA. Moreover, the LNP shows superior intramuscular mRNA delivery and elicits robust antigen-specific immune activation. The vaccinations delivered by the LNP system suppress tumor growth and prolong survival in both model human papillomavirus E7 and ovalbumin antigen-expressing tumor models. Finally, the structure of lipids which enhances the protein expression in the spleen and draining lymph nodes compared with ALC-0315 lipid in Comirnaty is further optimized. In conclusion, the 1, 2-diester-derived lipids exhibit rapid liver clearance and effective anticancer efficiency to different types of antigens-expressing tumor models, which may be a safe and universal platform for mRNA vaccines.
Assuntos
Vacinas Anticâncer , Nanopartículas , Neoplasias , Humanos , Vacinas de mRNA , RNA Mensageiro/metabolismo , Fígado/metabolismo , Vacinação , Lipídeos/química , Nanopartículas/químicaRESUMO
The development of castration-resistant prostate cancer (CRPC) is a significant factor that reduces life expectancy among patients with prostate cancer. Previously, it is reported that CDK4/6 inhibitors can overcome the resistance of CRPC to BET inhibitors by destabilizing BRD4, suggesting that the combination of CDK4/6 inhibitors and BET inhibitors is a promising approach for treating CRPC. In this study, candidates that affect the combined antitumor effect of CDK4/6 inhibitors and BET inhibitors on CRPC is aimed to examine. The data demonstrates that CBX3 is abnormally upregulated in CDK4/6 inhibitors-resistant cells. CBX3 is almost positively correlated with the cell cycle in multiple malignancies and is downregulated by BET inhibitors. Mechanistically, it is showed that CBX3 is transcriptionally upregulated by BRD4 in CRPC cells. Moreover, it is demonstrated that CBX3 modulated the sensitivity of CRPC to CDK4/6 inhibitors by binding with RB1 to release E2F1. Furthermore, it is revealed that PLK1 phosphorylated CBX3 to enhance the interaction between RB1 and CBX3, and desensitize CRPC cells to CDK4/6 inhibitors. Given that BRD4 regulates CBX3 expression and PLK1 affects the binding between RB1 and CBX3, it is proposed that a dual BRD4/PLK1 inhibitor can increase the sensitivity of CRPC cells to CDK4/6 inhibitors partially through CBX3.
Assuntos
Antineoplásicos , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Fatores de Transcrição/metabolismo , Proteínas Nucleares/metabolismo , Proteínas de Ciclo Celular/metabolismo , Antineoplásicos/uso terapêutico , Proteínas que Contêm Bromodomínio , Quinase 4 Dependente de Ciclina/uso terapêutico , Proteínas Cromossômicas não Histona/uso terapêuticoRESUMO
Androgen receptor (AR) inhibition by androgen deprivation and/or antiandrogen administration is the mainstay therapy for advanced prostate cancer. However, most prostate cancers ultimately become resistant to these therapies, indicating the importance of identifying mechanisms driving resistance to improve patient outcomes. Here we demonstrated that acute treatment with the antiandrogen enzalutamide (ENZ) decreased glutathione (GSH) production, increased lipid peroxidation, and induced ferroptosis in prostate cancer cells. Consistently, meta-analysis of transcriptomic data linked the androgen-AR axis to metabolism-related biological processes, including lipid metabolism. The cystine transporter gene SLC7A11 was a key AR target, and full-length AR (AR-FL) transactivated SLC7A11 transcription by directly occupying the SLC7A11 promoter and putative enhancer regions. AR variants (AR-V) preferentially bound the SLC7A11 enhancer and upregulated SLC7A11 expression, thereby conferring resistance to ferroptosis induced by ENZ treatment. However, this effect was abolished following downregulation of AR-Vs using the dual CBP/p300 and BET inhibitor NEO2734. These findings reveal ferroptosis induction as an anticancer mechanism of antiandrogens and SLC7A11 as a direct target gene of AR-FL and AR-Vs. AR-V-mediated SLC7A11 expression represents a mechanism coupling ferroptosis resistance to prostate cancer progression. SIGNIFICANCE: Upregulation of SLC7A11 can be induced by androgen receptor variants to inhibit antiandrogen-induced prostate cancer cell ferroptosis and to drive castration resistance in prostate cancer.
Assuntos
Ferroptose , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Antagonistas de Androgênios/farmacologia , Androgênios/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Nitrilas/farmacologia , Castração , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genéticaRESUMO
Immune checkpoint blockade (ICB) antibody such as anti-PD-L1 (aPD-L1) activates cytotoxic T cells (CTLs) to combat cancer, but they showed poor efficacy in prostate cancer (PCa). Lysosome-dependent autophagy is utilized by cancer cells to degrade their MHC-I and to lower their vulnerability to TNF-α and CTLs. Lysosomal pH-sensitive polymeric nanoparticle as a drug delivery carrier may also be a novel autophagy inhibitor to boost immunotherapy, but such an important effect has not been investigated. Herein, we developed a unique tumor acidity-activatable macromolecular nanodrug (called P-PDL1-CP) with the poly(2-diisopropylaminoethyl methacrylate) (PDPA) core and the conjugations of both aPD-L1 and long-chain polyethylene glycol (PEG) coating. The PDPA core was demonstrated to disturb lysosome to block the autophagic flux, thus elevating the cancer cell's MHC-I expression and vulnerability to the TNF-α and CTLs. Long-chain PEG facilitated a good tumor accumulation of P-PDL1-CP nanodrug. Furthermore, P-PDL1-CP nanodrug inhibited tumor autophagy, which synergized with aPD-L1 to promote the tumor-infiltrating CTLs and DCs maturation, to elevate intratumoral TNF-α and IFN-γ levels, and to elicit an anti-tumor immune memory effect in mice for PCa growth inhibition with low side effects. This study verified the synergistic anti-PCa treatment between autophagy inhibition and PD-L1 blockade and meantime broadened the application of pH-sensitive macromolecular nanodrug. STATEMENT OF SIGNIFICANCE: A macromolecular nanodrug, comprising the PDPA core and the surface conjugation of both aPD-L1 antibodies and long-chain PEG coating via a tumor acidity-labile α-carboxy-dimethylmaleic anhydride amine bond, was developed. Tumoral acidity triggered the release of aPD-L1 for immunotherapy. Meantime, the charge switch of the remanent nanodrug enhanced the cancer cell uptake of PDPA, which disturbed the lysosomes to inhibit autophagy. This advanced nanodrug promoted the tumor-infiltrating CTLs and DCs maturation, elevated the intratumoral TNF-α and IFN-γ levels, and elicited the robust anti-tumor immune memory effect. This study demonstrated that the pH-sensitive PDPA macromolecule could serve as a carrier for the aPD-L1 delivery and as an efficient autophagy inhibitor to boost the immunotherapy of prostate cancer.
Assuntos
Inibidores de Checkpoint Imunológico , Neoplasias da Próstata , Humanos , Masculino , Animais , Camundongos , Fator de Necrose Tumoral alfa/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Linfócitos T Citotóxicos/metabolismo , Imunoterapia , Linhagem Celular Tumoral , Autofagia , Microambiente TumoralRESUMO
Retinoblastoma (RB) protein can exert tumor suppressor functions even when it becomes phosphorylated. It is thus essential to understand how phosphorylated RB (p-RB) expression and function are regulated. Here, we demonstrated that RING finger domain protein TRIM28 bound and promoted ubiquitination and degradation of CDK4/6-phosphorylated RB protein. SETDB1, a known TRIM28 binding partner, protected p-RB from degradation through the binding of methylated RB by its Tudor domain independent of its methyltransferase activity. SETDB1 was found to be frequently overexpressed due to gene amplification and positively correlated with p-RB in prostate cancer patient specimens. Inhibition of SETDB1 expression using a gene-specific antisense oligonucleotide (ASO) reduced tumor growth but accelerated RB protein degradation, limiting the therapeutic efficacy. However, coadministration of the CDK4/6 inhibitor palbociclib blocked ASO-induced RB degradation and resulted in a much greater cancer-inhibitory effect than each inhibitor alone both in vitro and in vivo. This study identified CDK4/6-dependent, TRIM28-mediated proteasomal degradation as a mechanism of RB inactivation and reveals SETDB1 as a key inhibitor of this process. Our findings suggest that combined targeting of SETDB1 and CDK4/6 represents a viable approach for the treatment of cancers with SETDB1 gene amplification or overexpression. SIGNIFICANCE: The identification of a role for TRIM28 and SETDB1 in regulating CDK4/6-phosphorylated RB stability uncovers a combination strategy using CDK4/6 and SETDB1 inhibition to decrease RB degradation and inhibit cancer growth.
Assuntos
Neoplasias , Humanos , Masculino , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Fosforilação , Proteína do Retinoblastoma/genéticaRESUMO
Androgen receptor (AR) is a major survival factor for prostate cancer. Inflammation is implicated in many cancer types, including prostate cancer. Activation of MAP3K7 (also termed TAK1) and downstream IκB kinase ß (IKKß) by proinflammatory cytokines such as TNFα stimulates NF-κB survival pathways. Paradoxically, MAP3K7 is often deleted in human prostate cancer. Here, we demonstrate that AR protein expression is lower in inflammatory tumor areas compared with non-inflammatory tissues in patients with prostate cancer. Map3k7 knockout increased AR protein levels and activity in the mouse prostate, and MAP3K7 and AR protein levels were inversely correlated in prostate cancer patient specimens. TNFα treatment increased AR protein ubiquitination and proteasomal degradation. Mechanistically, activation of IKKß by TNFα induced phosphorylation and TRCP1/2 E3 ligase-mediated polyubiquitination and degradation of AR protein. TNFα suppressed prostate cancer proliferation, which could be rescued by blockade of AR degradation. These findings reveal a previously unrecognized tumor suppressive function of the inflammation-activated MAP3K7-IKKß axis in degrading AR protein. Moreover, they suggest that aberrant elevation of AR protein could be a prognostic biomarker and therapeutic target for MAP3K7-deficient prostate cancer. SIGNIFICANCE: This study identifies that MAP3K7-IKKß signaling plays a tumor-suppressive role in prostate cancer by degrading AR, revealing potential prognostic and therapeutic strategies for MAP3K7-deficient tumors.
Assuntos
Quinase I-kappa B/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Células HEK293 , Humanos , Inflamação , Masculino , Camundongos , Camundongos Knockout , Camundongos SCID , Transplante de Neoplasias , Prognóstico , Complexo de Endopeptidases do Proteassoma/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ubiquitina/metabolismoRESUMO
Molecular mechanisms underlying intratumoral androgenesis and aberrant androgen receptor (AR) activation in prostate cancer remain poorly understood. Here we demonstrate that ectopic expression of the E3 ubiquitin ligase adaptor speckle-type poxvirus and zinc finger domain protein (SPOP) stabilizes 17ßHSD4. SPOP bound a functional substrate-binding consensus (SBC) motif 315RATST319 in 17ßHSD4 and promoted nondegradable K27- and K29-linked polyubiquitination of 17ßHSD4. The effect of SPOP was antagonized by serum- and glucocorticoid kinase-3 (SGK3)-mediated phosphorylation of serine 318 (S318) in the SBC and S318 phosphorylation-dependent binding of SKP2 E3 ligase and subsequent K48-linked polyubiquitination and proteasomal degradation of 17ßHSD4. Prostate cancer-associated SPOP mutations impaired the SPOP-17ßHSD4 interaction, caused 17ßHSD4 protein destruction in prostate cancer cells in culture and patient specimens, and increased testosterone production and prostate cancer cell growth in vitro and in mouse models. Thus, we have identified SPOP and SKP2 as two essential E3 ubiquitin ligases that exert opposite effects on 17ßHSD4 protein degradation and intratumoral androgenesis in prostate cancer cells. We further demonstrate that SPOP mutations or SKP2 overexpression contribute to prostate cancer progression by decreasing 17ßHSD4 expression and increasing intratumoral androgen synthesis. SIGNIFICANCE: This study reveals a novel mechanism of aberrant AR activation in SPOP-mutated prostate cancer and uncovers putative biomarkers for effective treatment by AR-targeted therapies.
Assuntos
Androgênios/metabolismo , Regulação Neoplásica da Expressão Gênica , Mutação , Proteínas Nucleares/metabolismo , Proteína Multifuncional do Peroxissomo-2/metabolismo , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Proteínas Repressoras/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Humanos , Masculino , Camundongos , Camundongos SCID , Proteínas Nucleares/genética , Proteína Multifuncional do Peroxissomo-2/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Proteólise , Receptores Androgênicos/genética , Proteínas Repressoras/genética , Células Tumorais Cultivadas , Ubiquitinação , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
For the treatment of malignant tumors, drug nanocarriers with long blood circulation time and ability to target the tumor microenvironment are promising therapeutic abilities. In this work, to systematically investigate the roles and functions of polysaccharides as drug nanocarriers targeting the tumor microenvironment, different types of polysaccharides (alginic acid (Alg), hyaluronic acid (HA), and dextran (Dex)) were covalently bonded with doxorubicin (DOX) through a Schiff base reaction to form a pH-sensitive polysaccharide-DOX prodrug having an acid-sensitive imine bond. After screening, Dex-DOX exhibited high drug loading content and good stability, while Alg-DOX and HA-DOX may have disadvantages such as low degree of oxidation, limited drug loading capacity, or instability in physiological conditions. Dex-DOX prodrugs were able to self-assemble into stable nanoparticles in phosphate buffered saline (PBS). Then, Dex6k-DOX and Dex150k-DOX were selected for further comparisons since they had similar drug-binding rates and long circulation time. When compared with Dex6k-DOX, the longer main-chain Dex150k-DOX showed a higher drug release rate under simulated acidic conditions in vitro, which significantly inhibited cell proliferation. Further in vivo experiments showed that Dex150k-DOX could more effectively improve the antitumor efficiency and survival rate while reducing side-effects. Overall, the screening and comparisons provided detailed and systematical information about the polysaccharide-DOX prodrug platform as potential antitumor drugs.
Assuntos
Doxorrubicina/farmacologia , Portadores de Fármacos/farmacologia , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Pró-Fármacos/uso terapêutico , Ácido Algínico/química , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dextranos/química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Feminino , Ácido Hialurônico/química , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Microambiente Tumoral/efeitos dos fármacosRESUMO
Previous investigations yielded inconsistent results for association of esophageal cancer (EC) risk and intake of processed food (including pickled food) or pickled food alone. The aim of this study was to perform a systematic review and meta-analysis of data exploring association of EC risk and intake of processed food (including pickled food) or pickled food alone. We systematically searched on PubMed and Web of Science for association of EC risk and intake of processed and pickled food published from 1964 to April 2018. We computed the multivariate odd ratio (OR) or relative risk (RR) and 95% confidence intervals (CI), comparing the highest and the lowest categories of processed or pickled food intake. The present meta-analysis showed that the highest categories of processed food intake were associated with a 78% increase in EC risk compared with the lowest categories. In addition, meta-analysis results indicated that the combined OR/RRs (95%CI) of studies comparing the highest and lowest categories were 2.10 (1.64-2.69) for pickled food. Subgroup study indicated significant positive associations between EC risk and intake of processed food or pickled food in case-control studies (combined ORs: processed food: 1.93 (95%CI: 1.66-2.24), pickled food: 2.28 (95%CI: 1.93-2.70)), whereas no significant associations were detected between them in cohort studies (combined RRs: processed food: 1.24 (95%CI: 0.98-1.58), pickled food: 1.43 (95%CI: 0.85-2.42)). In conclusion, this study suggests that both a high consumption of processed and pickled food may increase the EC risk.
Assuntos
Neoplasias Esofágicas/etiologia , Manipulação de Alimentos , Alimentos/efeitos adversos , Intervalos de Confiança , Humanos , Razão de Chances , RiscoRESUMO
Disruption of the nursery function in Sertoli cells (SCs) by reducing lactate production, a preferred energy substrate for developed germ cells (spermatocytes and spermatids), is tightly associated with spermatogenic failure such as SC-only syndrome (SCOS). However, whether this complicated pathogenesis is regulated by certain miRNAs at the post-transcriptional level remain fascinating but largely unknown. Here we show for the first time that mmu-miR-320-3p was exclusively expressed in murine SCs and this expression was significantly induced in busulphan-treated murine testis. The most efficient stimulatory germ cell types for the induction of apoptosis-elicited mmu-miR-320-3p expression were meiotic spermatocytes and haploid spermatids. Functionally, forced expression of the exogenous mmu-miR-320-3p in SCs compromises male fertility by causing oligozoospermia and defection of sperm mobility. Mechanistically, mmu-miR-320-3p negatively regulates lactate production of SCs by directly inhibiting glucose transporter 3 (GLUT3) expression. Thus, dysregulation of mmu-miR-320-3p/GLUT3 cascade and consequently of lactate deficiency may be a key molecular event contributing the germ cell loss by SC dysfunction. Future endeavor in the continuous investigation of this important circulating miRNA may shed novel insights into epigenetic regulation of SCs nursery function and the etiology of azoospermia, and offers novel therapeutic and prognostic targets for SCOS.
Assuntos
Transportador de Glucose Tipo 3/metabolismo , MicroRNAs/metabolismo , Células de Sertoli/metabolismo , Animais , Epigênese Genética/genética , Epigênese Genética/fisiologia , Perfilação da Expressão Gênica , Transportador de Glucose Tipo 3/genética , Lactatos/metabolismo , Masculino , Camundongos , MicroRNAs/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologiaRESUMO
Type 2 diabetes mellitus (T2DM) promotes a high oxidative stress and hypercoagulable state that drives microvascular injury and multiple-organ abnormality. Elevated thrombin activity underlies T2DM-linked endothelial dysfunction, but the mechanistic links between T2DM/oxidative stress axis and thrombin-associated endothelial pathologies are incompletely understood. In this work, immunohistochemical studies and quantitative analysis using isolated endothelial cells (ECs) identified accumulated Kru¨ppel-like family of transcription factor 14 (KLF14) deposits in ECs from multiple organs as distinct features of T2DM mice. KLF14 upregulation in ECs, which was stimulated by thrombin treatment, was dependent on multiple pathways including calcium mobilization, activation of PKC and AMPK pathways. Functionally, inhibition of endogenous KLF14 expression significantly attenuated thrombin-induced endotheliocyte proliferation, endothelial cell migration and oxidative stress. Molecularly, by directly binding the promoter, KLF14 functions as a transcriptional activator of PLK1, a polo-like kinase whose overexpression induced excessive reactive oxygen species (ROS) production. Transient knockdown of PLK1 was sufficient to suppress KLF14 overexpression-potentiated endothelial dysfunction. Collectively, these data provide proof of concept that deregulation of KLF14/PLK1 cascade plays a key role in thrombin-induced endothelial dysfunction and targeting KLF14 or PLK1 may limit thrombin-associated pathologies in T2DM patients.
Assuntos
Proteínas de Ciclo Celular/genética , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Fatores de Transcrição Kruppel-Like/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Animais , Movimento Celular/genética , Proliferação de Células/genética , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/genética , Células Endoteliais/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Trombina/metabolismo , Quinase 1 Polo-LikeRESUMO
SCOPE: GTPs (green tea polyphenols) exert anti-CRC (colorectal cancer) activity. The intestinal microbiota and intestinal colonization by bacteria of oral origin has been implicated in colorectal carcinogenesis. GT modulates the composition of mouse gut microbiota harmonious with anticancer activity. Therefore, the effect of green tea liquid (GTL) consumption on the gut and oral microbiome is investigated in healthy volunteers (n = 12). METHODS AND RESULTS: 16S sequencing and phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) analysis of both fecal and saliva samples (collected before intervention, after 2 weeks of GTL (400 mL per day) and after a washout period of one week) in healthy volunteers show changes in microbial diversity and core microbiota and difference in clear classification (partial least squares-discriminant analysis [PLS-DA]). An irreversible, increased FIR:BAC (Firmicutes to Bacteroidetes ratio), elevated SCFA producing genera, and reduction of bacterial LPS synthesis in feces are discovered in response to GTL. GTL alters the salivary microbiota and reduces the functional pathways abundance relevance to carcinogenesis. Similar bacterial networks in fecal and salivary microbiota datasets comprising putative oral bacteria are found and GTL reduces the fecal levels of Fusobacterium. Interestingly, both Lachnospiraceae and B/E (Bifidobacterium to Enterobacteriacea ratio-markers of colonization resistance [CR]) are negatively associated with the presence of oral-like bacterial networks in the feces. CONCLUSION: These results suggest that GTL consumption causes both oral and gut microbiome alterations.
Assuntos
Microbioma Gastrointestinal , Microbiota , Saliva/microbiologia , Chá , Adulto , Bifidobacterium/genética , Bifidobacterium/isolamento & purificação , Fezes/microbiologia , Feminino , Fusobacterium/genética , Fusobacterium/isolamento & purificação , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , RNA Ribossômico 16SRESUMO
Although both insulin and estrogen receptor α (ERα) are known to exert inhibitory effects on testicular steroidogenesis, it remains unknown whether these pathways regulate testosterone (T) production under certain pathological conditions [e.g., type 2 diabetes mellitus (T2DM)] in a coordinated manner. Here, we found that the expression of forkhead box protein A3 (Foxa3), an essential transcriptional regulator engaged in adipogenesis and energy metabolism, was significantly down-regulated in the Leydig cells (LCs) from T-deficient T2DM mice. Functionally, upon hCG stimulation, Foxa3 recruits to the Esr1 promoter and suppresses the transactivation of Esr1 gene. Disruption of this recruitment by T2DM-elicited hyperinsulinemia led to abnormal activation of ERα pathway, inhibited steroidogenic enzyme genes expression, and thus caused inadequate T production. Therapeutically, insulin-impaired and Foxa3 ablation-compromised steroidogenesis were effectively rescued by a pharmacological inhibitor of the ERα pathway. These findings reveal an obligatory coregulatory role of Foxa3 in the regulation of ERα expression and of the Foxa3/ERα cascade, at least in part, in the pathogenesis of androgen deficiency caused by T2DM.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Receptor alfa de Estrogênio/metabolismo , Fator 3-gama Nuclear de Hepatócito/metabolismo , Células Intersticiais do Testículo/metabolismo , Transdução de Sinais , Testosterona/metabolismo , Animais , Células Cultivadas , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Regulação para Baixo , Receptor alfa de Estrogênio/genética , Fator 3-gama Nuclear de Hepatócito/genética , Células Intersticiais do Testículo/patologia , Masculino , Camundongos Endogâmicos BALB C , Esteroides/metabolismo , Ativação TranscricionalRESUMO
BAP31 is an evolutionarily conserved polytopic integral protein of the endoplasmic reticulum (ER) membrane implicated in regulating the export of selected membrane proteins from the ER to downstream compartments of the secretory pathway. BAP31 interacts with mIgD, cellubrevin, major histocompatibility complex class I, and BCL-2/BCL-X(L) and plays an important role in regulating the egress of these proteins and in apoptosis. Although BAP31 RNA is ubiquitous, the protein's anatomic localization in rat tissues has not been determined. This is partially because production of high affinity antibodies, especially monoclonal antibodies (MAbs) suitable for immunohistochemical staining, has lagged. To gain further insight into its possible functions, we generated a novel MAb specific for rat BAP31 in immunocytochemistry and immunohistochemistry and localized BAP31 in some rat tissues. Immunoreactivity of BAP31 was prominent in fundic glands, colon, pancreatic acinuses, and liver but not in skeleton muscle and lung. Thus, successful production of rat BAP31 monoclonal antibodies provides a new powerful tool for investigation of BAP31 function in the rat model.