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1.
Immunity ; 54(6): 1168-1185.e8, 2021 06 08.
Artículo en Inglés | MEDLINE | ID: mdl-34038747

RESUMEN

Chronic inflammation plays a central role in hepatocellular carcinoma (HCC), but the contribution of hepatocytes to tumor-associated inflammation is not clear. Here, we report that the zinc finger transcription factor Miz1 restricted hepatocyte-driven inflammation to suppress HCC, independently of its transcriptional activity. Miz1 was downregulated in HCC mouse models and a substantial fraction of HCC patients. Hepatocyte-specific Miz1 deletion in mice generated a distinct sub-group of hepatocytes that produced pro-inflammatory cytokines and chemokines, which skewed the polarization of the tumor-infiltrating macrophages toward pro-inflammatory phenotypes to promote HCC. Mechanistically, Miz1 sequestrated the oncoprotein metadherin (MTDH), preventing MTDH from promoting transcription factor nuclear factor κB (NF-κB) activation. A distinct sub-group of pro-inflammatory cytokine-producing hepatocytes was also seen in a subset of HCC patients. In addition, Miz1 expression inversely correated with disease recurrence and poor prognosis in HCC patients. Our findings identify Miz1 as a tumor suppressor that prevents hepatocytes from driving inflammation in HCC.


Asunto(s)
Carcinogénesis/metabolismo , Carcinoma Hepatocelular/metabolismo , Hepatocitos/metabolismo , Inflamación/metabolismo , Neoplasias Hepáticas/metabolismo , Activación de Macrófagos/fisiología , Proteínas Inhibidoras de STAT Activados/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Carcinogénesis/patología , Carcinoma Hepatocelular/patología , Línea Celular , Línea Celular Tumoral , Quimiocinas/metabolismo , Regulación hacia Abajo/fisiología , Femenino , Células HEK293 , Hepatocitos/patología , Humanos , Inflamación/patología , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Transducción de Señal/fisiología , Factores de Transcripción/metabolismo , Dedos de Zinc/fisiología
2.
Nano Lett ; 24(17): 5361-5370, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38630986

RESUMEN

Size plays a crucial role in chemistry and material science. Subnanometer polyoxometalate (POM) clusters have gained attention in various fields, but their use in thermoelectrics is still limited. To address this issue, we propose the POM clusters as an effective second phase to enhance the thermoelectric properties of Bi0.4Sb1.6Te3. Thanks to their subnanometer size, POM clusters improve electrical transport behavior through the superposition of atomic orbitals and the interfacial scattering effect. Furthermore, their ultrasmall size strongly reduces thermal conductivity. Consequently, the introduction of a mere 0.1 mol % of POM into the Bi0.4Sb1.6Te3 matrix realizes a state-of-the-art zT value of 1.46 at 348 K, a 45% enhancement over Bi0.4Sb1.6Te3 (1.01), along with a maximum thermoelectric-conversion efficiency of the integrated module of 6.0%. The enhancement of carrier mobility and the suppression of thermal conduction achieved by introducing the subnanometer clusters hold promise for various applications, such as electronic devices and thermal management.

3.
Small ; : e2406179, 2024 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-39221682

RESUMEN

For BixSb2- xTe3 (BST) in thermoelectric field, the element ratio is easily influenced by the chemical environment, deviating from the stoichiometric ratio and giving rise to various intrinsic defects. In P-type polycrystalline BST, SbTe and BiTe are the primary forms of defects. Defect engineering is a crucial strategy for optimizing the electrical transport performance of Bi2Te3-based materials, but achieving synchronous improvement of thermal performance is challenging. In this study, mesoporous SiO2 is utilized to successfully mitigate the adverse impacts of vacancy defects, resulting in an enhancement of the electrical transport performance and a pronounced reduction in thermal conductivity. Crystal and the microstructure of the continuous modulation contribute to the effective phonon-electronic decoupling. Ultimately, the peak zT of Bi0.4Sb1.6Te3/0.8 wt% SiO2 (with a pore size of 4 nm) nanocomposites reaches as high as 1.5 at 348 K, and a thermoelectric conversion efficiency of 6.6% is achieved at ΔT = 222.7 K. These results present exciting possibilities for the realization of defect regulation in porous materials and hold reference significance for other material systems.

4.
J Hepatol ; 79(2): 403-416, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37040844

RESUMEN

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is a chronic inflammatory disease that can further progress to cirrhosis and hepatocellular carcinoma. However, the key molecular mechanisms behind this process have not been clarified. METHODS: We analyzed human NASH and normal liver tissue samples by RNA-sequencing and liquid chromatography-mass spectrometry, identifying hepatocyte cytosolic protein Myc-interacting zinc-finger protein 1 (Miz1) as a potential target in NASH progression. We established a Western diet+fructose-induced NASH model in hepatocyte-specific Miz1 knockout and adeno-associated virus type 8-overexpressing mice. Human NASH liver organoids were used to confirm the mechanism, and immunoprecipitation and mass spectrometry were used to detect proteins that could interact with Miz1. RESULTS: We demonstrate that Miz1 is reduced in hepatocytes in human NASH. Miz1 is shown to bind to peroxiredoxin 6 (PRDX6), retaining it in the cytosol, blocking its interaction with mitochondrial Parkin at Cys431, and inhibiting Parkin-mediated mitophagy. In NASH livers, loss of hepatocyte Miz1 results in PRDX6-mediated inhibition of mitophagy, increased dysfunctional mitochondria in hepatocytes, and production of proinflammatory cytokines, including TNFα, by hepatic macrophages. Crucially, the increased production of TNFα results in a further reduction in hepatocyte Miz1 by E3-ubiquitination. This produces a positive feedback loop of TNFα-mediated hepatocyte Miz1 degradation, resulting in PRDX6-mediated inhibition of hepatocyte mitophagy, with the accumulation of dysfunctional mitochondria in hepatocytes and increased macrophage TNFα production. CONCLUSIONS: Our study identified hepatocyte Miz1 as a suppressor of NASH progression via its role in mitophagy; we also identified a positive feedback loop by which TNFα production induces degradation of cytosolic Miz1, which inhibits mitophagy and thus leads to increased macrophage TNFα production. Interruption of this positive feedback loop could be a strategy to inhibit the progression of NASH. IMPACT AND IMPLICATIONS: Non-alcoholic steatohepatitis (NASH) is a chronic inflammatory disease that can further develop into cirrhosis and hepatocellular carcinoma. However, the key molecular mechanism of this process has not been fully clarified. Herein, we identified a positive feedback loop of macrophage TNFα-mediated hepatocyte Miz1 degradation, resulting in PRDX6-mediated inhibition of hepatocyte mitophagy, aggravation of mitochondrial damage and increased macrophage TNFα production. Our findings not only provide mechanistic insight into NASH progression but also provide potential therapeutic targets for patients with NASH. Our human NASH liver organoid culture is therefore a useful platform for exploring treatment strategies for NASH development.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Humanos , Animales , Ratones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Carcinoma Hepatocelular/patología , Factor de Necrosis Tumoral alfa/metabolismo , Mitofagia , Retroalimentación , Hepatocitos/metabolismo , Hígado/patología , Cirrosis Hepática/patología , Neoplasias Hepáticas/patología , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Proteínas Inhibidoras de STAT Activados/metabolismo , Proteínas Inhibidoras de STAT Activados/uso terapéutico
5.
Nano Lett ; 22(12): 4750-4757, 2022 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-35638865

RESUMEN

Single-atom materials are widely explored in catalysis, batteries, sensors, etc. However, limited by mass production and centimeter-scale assembly, they are rarely studied in thermoelectrics. Herein, we demonstrate a solvothermal synthesis assisted by a syringe-pump method to yield Bi2S3-supported Pt single-atom materials (Bi2S3-Pt1) at a 10 g scale. Different from Ptn clusters, Pt1 single atoms can increase carrier concentration at a high doping efficiency and provide a unique atomic environment to enhance carrier mobility, and an enlarged effective mass leads to an enhanced Seebeck coefficient. As a result, a high power factor (348 µW m-1 K-2) is achieved at 823 K. Benefiting from the scattering of phonons by Pt1 atomic sites, a minimum thermal conductivity of 0.37 W m-1 K-1 is achieved. Consequently, the Bi2S3-0.5 wt % Pt1 realizes a record-high zT of ∼0.75 at 823 K, being among the best in the state-of-the-art n-type environmentally friendly metal sulfides. The enhancement of the carrier mobility and suppression of the thermal conduction by the unique Pt1 single atoms will inspire various fields, as exemplified by electronic devices and thermal management.

6.
Angew Chem Int Ed Engl ; 61(45): e202212885, 2022 Nov 07.
Artículo en Inglés | MEDLINE | ID: mdl-36121390

RESUMEN

Phase-junction nanocomposites, made of nanograins with the same composition but different phases, offer a platform to optimize the physiochemical performance of materials. Herein, we demonstrate a straightforward strategy to synthesize Cu2-x S phase-junction nanocomposites by retaining surface 1-dodecanethiol (DDT) ligands, in contrast to the traditional method that strips the ligands. As a result, phase junctions between a conventional monoclinic (m) phase and an unconventional metastable tetragonal (t) phase are obtained. The significantly improved power factor is obtained due to the doping of the t-phase. The phase-junction interfaces reduce thermal conductivity. Finally, surface regulation of phase junctions pushes the peak zT to 2.1 at 932 K, being the highest reported for environment-friendly metal sulfides. This work provides a paradigm to optimize thermoelectric performance by controlling phase junctions through surface-ligand tuning.

7.
Cell Physiol Biochem ; 46(6): 2335-2346, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29742497

RESUMEN

BACKGROUND/AIMS: During the occurrence and progression of hepatocellular carcinoma (HCC), phosphotyrosine phosphatases (PTPs) are usually described as tumor suppressors or proto-oncogenes, and to some degree are correlated with the prognosis of HCC. METHODS: A total of 321 patients from the Cancer Genome Atlas (TCGA) database and 180 patients from our validated cohort with hepatocellular carcinoma were recruited in this study. Kaplan-Meier, univariate and multivariate Cox proportional hazards model were used to evaluate the risk factors for survival. Quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) were applied to detect the expression levels of PTP genes. RESULTS: After screening the data of TCGA, we identified five PTPs as HCC overall survival related PTP genes, among which only three (PTPN12, PTPRN, PTPN18) exhibited differential expression levels in our 180 paired HCC and adjacent tissues (P< 0.001). Further analysis revealed that expression of PTPN18 was positively, but PTPRN was negatively associated with prognosis of HCC both in TCGA cohort and our own cohort. As to PTPN12, results turned out to be opposite according to HBV status. In detail, higher expression of PTPN12 was associated with better outcome in HBV group but worse prognosis in Non-HBV group. CONCLUSION: Our results suggested that PTPN12, PTPRN and PTPN18 were independent prognostic factors in HCC.


Asunto(s)
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 12/genética , Proteínas Tirosina Fosfatasas no Receptoras/genética , Proteínas Tirosina Fosfatasas Clase 8 Similares a Receptores/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/diagnóstico , Estudios de Cohortes , Femenino , Regulación de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/diagnóstico , Masculino , Persona de Mediana Edad , Pronóstico , Proteína Tirosina Fosfatasa no Receptora Tipo 12/análisis , Proteínas Tirosina Fosfatasas no Receptoras/análisis , Proteínas Tirosina Fosfatasas Clase 8 Similares a Receptores/análisis
8.
Cell Physiol Biochem ; 41(6): 2289-2306, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28456796

RESUMEN

BACKGROUND & AIMS: To investigate the expression and prognostic value of α1-ACT (Alpha1-antichymotrypsin) in patients with HCC (hepatocellular carcinoma) and identify the mechanism by which α1-ACT inhibits proliferation and promotes apoptosis of HCC. METHODS: We first measured α1-ACT expression levels and determined their relationship with the clinicopathological characteristics and prognosis of patients with HCC.We then established stable HCC cell lines with both α1-ACT overexpression and knockdown and performed a functional analysis in vitro.We first examined the relationship between α1-ACT and the PTEN/PI3K/AKT/mTOR pathway using Western blotting. Then, we determined whether α1-ACT can directly bind to PTEN using co-immunoprecipitation. Finally, we measured α1-ACT expression to evaluate its correlation with the PI3K/AKT/mTOR pathway-related apoptosis proteins in a xenograft tumour mouse model using immunohistochemistry. RESULTS: The α1-ACT expression level was significantly lower in the HCC tissues than in the paratumour tissues and was negatively positively correlated with the level of Ki67, AFP, the AJCC stage, tumour size and tumour invasion. The overexpression of α1-ACT can inhibit cell proliferation and increase cell apoptosis by activating PI3K/AKT/mTOR-mediated apoptosis via binding to PTEN and activating it in vitro. Additionally, the overexpression of α1-ACT can also increase the proportion of cells in the G0/G1 stage by increasing cyclin p21 expression and inhibiting the migration and invasion abilities of HCC cells by regulating MMP2 and MMP9. The xenotransplantation studies with nude mice also showed that overexpression of α1-ACT inhibited tumourigenesis and knockdown of α1-ACT had the opposite effect. CONCLUSIONS: Our study demonstrates that α1-ACT suppresses liver cancer development and metastasis via targeting the PTEN/PI3K/AKT/mTOR signalling pathway, which may be a potential target for therapeutic intervention in HCC.


Asunto(s)
Carcinoma Hepatocelular/fisiopatología , Neoplasias Hepáticas/fisiopatología , Fosfohidrolasa PTEN/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serpinas/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Adulto , Animales , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Modelos Animales de Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Pronóstico , Interferencia de ARN , Serpinas/química , Serpinas/genética , Transducción de Señal/fisiología
9.
Cell Physiol Biochem ; 40(3-4): 707-715, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27898409

RESUMEN

BACKGROUND/AIMS: Long non-coding RNAs (lncRNAs) have been reported to play pivotal roles in multiple tumors and can act as tumor biomarkers. In this study, we explored the association of the expression of an lncRNA, DGCR5 with clinicopathological features and prognosis in HCC. METHODS: Expression levels of DGCR5 were detected by quantitative real-time PCR (qRT-PCR) and the clinical data was obtained, including basic information, data of clinicopathology and cancer specific survival rate. Receiver operating characteristic (ROC) curve, Kaplan-Meier methods and multivariable Cox regression models were used to analyze predictive efficiency, long-term survival outcomes and risk factors. RESULTS: DGCR5 was found down-regulated in HCC tissues (P<0.001) and serum (P = 0.0035) and low expression of DGCR5 was correlated with a poor cancer specific survival (CSS) (P = 0.0019), as the overall 5-year CSS rates were 10.3% (low expression group) and 36.6% (high expression group), respectively. A stratified analysis demonstrated that low DGCR5 expression was an independent negative prognostic factor for HCC. In addition, the area under the ROC curve was 0.782 with a sensitivity of 0.633 and a specificity of 0.833. CONCLUSIONS: Our results suggest that DGCR5 may be a participator in HCC and can serve as potential biomarker for the diagnosis and prognosis in HCC.


Asunto(s)
Carcinoma Hepatocelular/genética , Regulación hacia Abajo/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/genética , ARN Largo no Codificante/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patología , Femenino , Humanos , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Estabilidad del ARN/genética , ARN Largo no Codificante/metabolismo , Análisis de Supervivencia
10.
ACS Nano ; 18(21): 13924-13938, 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38743703

RESUMEN

The all-inorganic halide perovskite CsPbX3 (X = Cl, Br, or I) offers various advantages, such as tunable electronic structure and high carrier mobility. However, its potential application in thermoelectric materials remains underexplored. In this study, we propose a simple yet effective method to synthesize a CsPbX3/Bi0.4Sb1.6Te3 (BST) nanocomposite by sintering a uniformly mixed raw powder. The intrinsic excitation of the BST system is suppressed by exploiting the rich phase structure and tunable electrical transport properties of CsPbX3, and the thermoelectric properties were synergistically optimized. Notably, for CsPbI3, its phase-transition-induced dislocation arrays together with low group velocities drastically reduce thermal conductivity. As a result, the composite achieves an ultrahigh average figure-of-merit (ZT) of 1.4 from 298 to 523 K. The two-pair TE module demonstrates a superior conversion efficiency of 7.3%. This study expands the potential applications of inorganic halide perovskites, into thermoelectrics.

11.
Int J Surg ; 110(8): 4559-4570, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-38742845

RESUMEN

BACKGROUND: Early-onset colorectal cancer (EOCRC) is associated with a poorer prognosis relative to late-onset colorectal cancer (LOCRC), and its incidence has witnessed a gradual escalation in recent years. This necessitates a comprehensive examination of the underlying pathogenesis and the identification of therapeutic targets specific to EOCRC patients. The present study aimed to delineate the distinct molecular landscape of EOCRC by juxtaposing it with that of LOCRC. METHODS: A total of 11 344 colorectal cancer patients, diagnosed between 2003 and 2022, were enrolled in this study, comprising 578 EOCRC cases and 10 766 LOCRC cases. Next-generation sequencing technology was employed to assess the tumor-related mutation and tumor mutation burden (TMB) in these patients. PD-L1 expression was quantified using immunohistochemistry. Microsatellite instability (MSI) was determined via capillary electrophoresis (2B3D NCI Panel). RESULTS: Upon comparing LOCRC with EOCRC patients, the latter group demonstrated a tendency towards advanced TNM stage, lower tumor differentiation, and less favorable histological types. Among LOCRC patients, those with MSI-H status were found to have an earlier TNM stage compared to those with MSI-L/MSS status. Significantly, the incidence of MSI-H was notably higher in EOCRC (10.2%) compared to LOCRC (2.2%). Mutations in the 7-gene panel (ARID1A, FANCI, CASP8, DGFRA, DPYD, TSHR, and PRKCI) were more prevalent in LOCRC. Within the EOCRC cohort, patients with the MSI-H subtype displayed an earlier TNM stage but concurrently exhibited poorer tissue differentiation and a higher frequency of mucinous adenocarcinoma. Among EOCRC patients, FBXW7, FAT1, ATM, ARID1A, and KMT2B mutations were significantly enriched in the MSI-H subgroup. A comparative analysis of MSI-H patients revealed heightened mutation frequencies of FGFBR2, PBRM1, RNF43, LRP1B, FBXW7, ATM, and ARID1A in the EOCRC group. Furthermore, EOCRC patients demonstrated a higher overall TMB, particularly in the MSI-H subtype. PD-L1 expression was elevated in EOCRC and positively associated with MSI status. CONCLUSIONS: This study revealed a significantly higher MSI-H distribution rate in EOCRC, and EOCRC exhibits a distinct mutational signature coupled with higher PD-L1 expression. These findings hold promise in guiding personalized therapeutic strategies for improved disease management in EOCRC patients.


Asunto(s)
Edad de Inicio , Neoplasias Colorrectales , Inestabilidad de Microsatélites , Mutación , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Masculino , Femenino , Persona de Mediana Edad , Estudios de Casos y Controles , Adulto , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Estadificación de Neoplasias , Pronóstico , Secuenciación de Nucleótidos de Alto Rendimiento
12.
Adv Sci (Weinh) ; 10(12): e2205627, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36905238

RESUMEN

GPR176 belongs to the G protein-coupled receptor superfamily, which responds to external stimuli and regulates cancer progression, but its role in colorectal cancer (CRC) remains unclear. In the present study, expression analyses of GPR176 are performed in patients with colorectal cancer. Genetic mouse models of CRC coupled with Gpr176-deficiency are investigated, and in vivo and in vitro treatments are conducted. A positive correlation between GPR176 upregulation and the proliferation and poor overall survival of CRC is demonstrated. GPR176 is confirmed to activate the cAMP/PKA signaling pathway and modulate mitophagy, promoting CRC oncogenesis and development. Mechanistically, the G protein GNAS is recruited intracellularly to transduce and amplify extracellular signals from GPR176. A homolog model tool confirmed that GPR176 recruits GNAS intracellularly via its transmembrane helix 3-intracellular loop 2 domain. The GPR176/GNAS complex inhibits mitophagy via the cAMP/PKA/BNIP3L axis, thereby promoting the tumorigenesis and progression of CRC.


Asunto(s)
Neoplasias Colorrectales , Mitofagia , Animales , Ratones , Transducción de Señal/genética , Transformación Celular Neoplásica/genética , Proteínas de Unión al GTP/metabolismo , Carcinogénesis/genética , Neoplasias Colorrectales/metabolismo , Receptores Acoplados a Proteínas G/genética
13.
J Cancer ; 13(3): 752-763, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35154444

RESUMEN

Colorectal cancer (CRC) is a burdensome health concern worldwide. Long non-coding RNA (lncRNA) have emerged as vital roles in multiple cancers, including CRC. Increasing evidence has demonstrated that lncRNA CCDC144NL-AS1 acts crucial roles in tumor developments. Nevertheless, its role in CRC remains largely unknown. The level of CCDC144NL-AS1 expression was detected in 100 CRC tissues and paired adjacent tissues. The gain- and loss-of-function experiments were conducted to investigate the biological functions of CCDC144NL-AS1 in vitro and in vivo. The potential mechanism of CCDC144NL-AS1 exerting as competing endogenous RNAs (ceRNAs) was demonstrated by bioinformatics, luciferase reporter assay and in vitro experiments. CCDC144NL-AS1 was up-regulated in CRC tissues and cells. High CCDC144NL-AS1 was connected with the adverse clinicopathological features and worse prognosis of CRC. Furthermore, knockdown of CCDC144NL-AS inhibited the cell proliferation and led to the cell cycle G0-1/S arrest, whereas upregulated CCDC144NL-AS1 obtained the inverse results. Further study found that CCDC144NL-AS1 functioned as ceRNAs in regulating CRC proliferation. MiR-363-3p was the target of CCDC144NL-AS1, which sponges GALNT7 in regulating cell growth of CRC. The study demonstrated that the CCDC144NL-AS1/miR-363-3p/GALNT7 axis exerts on key roles in cell proliferation and presents an emerging target for CRC therapy and prognostic biomarker.

14.
Front Surg ; 9: 812343, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35178428

RESUMEN

INTRODUCTION: Transanal endoscopic microsurgery (TEM) is an organ-preserving treatment alternative for patients with early rectal cancer. However, TEM alone is associated with greater risk of local recurrence and inferior survival in comparison with total meso-rectal excision (TME). As an important adjuvant therapy, radiotherapy can effectively reduce the local recurrence rate of rectal cancer. This study aimed to investigate whether TEM followed by radiotherapy can be a valid alternative to TME in T2N0M0 distal rectal cancer treatment. METHODS: We plan to recruit 168 participants meeting established inclusion criteria. Following informed consent, participants will randomly receive treatment protocols of TEM followed by radiotherapy (a total dose of 45-50.4 Gy given in 25-28 factions) or TME. Depending on post-operative pathology, the participants will receive either long-term follow-up or further treatment. The primary endpoint of this trial is 3-year local recurrence rate. The secondary end points include 3-year disease-free survival rate, 3-year overall survival rate, 3-year mortality rate, post-operative quality of life, post-operative safety index, intraoperative evaluation index and post-operative short-term evaluation index. DISCUSSION: This trial is the first prospective randomized trial to investigate the rectum preserving treatment by using transanal local excision followed by radiotherapy. CLINICAL TRIAL REGISTRATION: The trial was prospectively registered at ClinicalTrials.gov NCT04098471 on September 20, 2019.

15.
J Exp Clin Cancer Res ; 41(1): 345, 2022 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-36522719

RESUMEN

BACKGROUND: N4-acetylcytidine (ac4C) as a significant RNA modification has been reported to maintain the stability of mRNA and to regulate the translation process. However, the roles of both ac4C and its 'writer' protein N-acetyltransferase 10 (NAT10) played in the disease especially colorectal cancer (CRC) are unclear. At this point, we discover the underlying mechanism of NAT10 modulating the progression of CRC via mRNA ac4C modification. METHODS: The clinical significance of NAT10 was explored based on the TCGA and GEO data sets and the 80 CRC patients cohort of our hospital. qRT-PCR, dot blot, WB, and IHC were performed to detect the level of NAT10 and ac4C modification in CRC tissues and matched adjacent tissues. CCK-8, colony formation, transwell assay, mouse xenograft, and other in vivo and in vitro experiments were conducted to probe the biological functions of NAT10. The potential mechanisms of NAT10 in CRC were clarified by RNA-seq, RIP-seq, acRIP-seq, luciferase reporter assays, etc. RESULTS: The levels of NAT10 and ac4C modification were significantly upregulated. Also, the high expression of NAT10 had important clinical values like poor prognosis, lymph node metastasis, distant metastasis, etc. Furthermore, the in vitro experiments showed that NAT10 could inhibit apoptosis and enhance the proliferation, migration, and invasion of CRC cells and also arrest them in the G2/M phase. The in vivo experiments discovered that NAT10 could promote tumor growth and liver/lung metastasis. In terms of mechanism, NAT10 could mediate the stability of KIF23 mRNA by binding to its mRNA 3'UTR region and up-regulating its mRNA ac4c modification. And then the protein level of KIF23 was elevated to activate the Wnt/ß-catenin pathway and more ß-catenin was transported into the nucleus which led to the CRC progression. Besides, the inhibitor of NAT10, remodelin, was applied in vitro and vivo which showed an inhibitory effect on the CRC cells. CONCLUSIONS: NAT10 promotes the CRC progression through the NAT10/KIF23/GSK-3ß/ß-catenin axis and its expression is mediated by GSK-3ß which forms a feedback loop. Our findings provide a potential prognosis or therapeutic target for CRC and remodelin deserves more attention.


Asunto(s)
Neoplasias Colorrectales , Vía de Señalización Wnt , Humanos , Ratones , Animales , Vía de Señalización Wnt/genética , beta Catenina/genética , beta Catenina/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Acetilación , ARN Mensajero/genética , ARN Mensajero/metabolismo , Acetiltransferasas/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias Colorrectales/patología , Línea Celular Tumoral , Proliferación Celular/genética , Movimiento Celular/genética , Proteínas Asociadas a Microtúbulos/genética
17.
Bioengineered ; 12(1): 5859-5869, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34477047

RESUMEN

Oxaliplatin (OXA) resistance is a great challenge for colon adenocarcinoma (COAD) chemotherapy. The promoting role of RecQ-Like Helicase 4 (RECQL4) in chemoresistance to platinum-based drugs has been identified, whereas the effect and specific mechanism of RECQL4 in regulating OXA resistance within COAD have not been explicated yet. In this work, RECQL4 mRNA expression was detected by RT-qPCR. RECQL4, phosphorylated PI3K (p-PI3K), PI3K, phosphorylated AKT (p-AKT), and AKT protein expression were measured by western blotting. CCK-8, flow cytometry, wound healing, and transwell assays were utilized to analyze OXA resistance, cell proliferation, apoptosis, cell cycle, migration and invasion. Herein, we found RECQL4 was upregulated in COAD, especially in OXA-resistant COAD tissues and cells. RECQL4 overexpression facilitated proliferation and metastasis of OXA-resistant COAD cells; on the contrary, RECQL4 knockdown attenuated proliferative and metastatic capabilities in OXA-resistant COAD cells. Moreover, RECQL4 promoted OXA resistance in OXA-resistant COAD cells via activating the P13 K/AKT signaling. To sum up, the results suggest that RECQL4 depletion may be a crucial mechanism to reverse OXA resistance in COAD via inhibition of the P13 K/AKT pathway in vitro, thereby providing a novel target for overcoming OXA resistance in COAD.


Asunto(s)
Adenocarcinoma , Neoplasias del Colon , Resistencia a Antineoplásicos/genética , Oxaliplatino/farmacología , RecQ Helicasas/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Antineoplásicos/farmacología , Línea Celular Tumoral , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , RecQ Helicasas/metabolismo , Transducción de Señal/genética
18.
Int J Biol Sci ; 17(15): 4165-4175, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34803490

RESUMEN

Background: Inflammation and apoptosis play a crucial role in the progression of nonalcoholic steatohepatitis (NASH). Suppressor of cytokine signaling 2 (SOCS2) is one of classic negative regulators of cytokine signaling, which has recently been described as anti-inflammatory mediators. However, the role of SOCS2 in macrophages during NASH progression and the relationship among SOCS2, inflammation, apoptosis and NASH is largely unknown. Herein, we aimed to study the function of SOCS2 in NASH progression. Methods: We detected SOCS2 expression in macrophages in human subjects without steatosis, with simple steatosis and with NASH to confirm the relationship between SOCS2 and NASH. Free fatty acids was used to establish stress environment in RAW 264.7 cell lines stably overexpressing or knockdown SOCS2. In vitro and vivo assays also performed to study the molecular function of SOCS2 in NASH progression. Findings: Our human samples illustrated that SOCS2 was decreased in macrophages during NASH progression and was negatively correlated to NASH level. Meanwhile, In vitro assays showed SOCS2 overexpression in macrophages suppressed inflammation and apoptosis via inhibiting NF-κB signaling pathway, while SOCS2 knock-down in macrophages caused an increased activation of NF-κB, which could be blocked by ammonium 1-pyrrolidinedithiocarbamate (PDTC). In addition, SOCS2 in macrophages also suppressed inflammation via limiting the activation of inflammasomes. Consistent with these, our BMT model also confirmed the SOCS2 function in macrophages during NASH. Interpretation: Our data strongly indicate that SOCS2 plays a role in inhibiting inflammation and apoptosis via NF-κB and inflammasome signaling pathway in macrophages during NASH. Further studies are required to explore the potential preventive and therapeutic strategies of SOCS2 for this common liver disease.


Asunto(s)
Apoptosis/fisiología , Inflamación/metabolismo , Macrófagos/metabolismo , FN-kappa B/metabolismo , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Animales , Trasplante de Médula Ósea , Dieta Alta en Grasa/efectos adversos , Ácidos Grasos no Esterificados/toxicidad , Regulación de la Expresión Génica/fisiología , Técnicas de Silenciamiento del Gen , Humanos , Inflamación/genética , Macrófagos/efectos de los fármacos , Ratones , FN-kappa B/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Células RAW 264.7 , Transducción de Señal , Estrés Fisiológico , Proteínas Supresoras de la Señalización de Citocinas/genética
19.
Cell Death Dis ; 12(2): 224, 2021 02 26.
Artículo en Inglés | MEDLINE | ID: mdl-33637680

RESUMEN

Colorectal cancer (CRC) is one of the most common cancers around the world and endangers human health seriously. Liver metastasis is an important factor affecting the long-term prognosis of CRC and the specific mechanism of CRLM (colorectal cancer with liver metastasis) is not fully understood. LZTS1 has been found dysregulated in many cancers, especially in CRC. Theories suggested that hypermethylation of the promoter regions of LZTS1 was responsible for LZTS1 abnormal expression in multiple malignant tumors. Although the role of LZTS1 in CRC cell proliferation has been reported, its role in CRLM remains unclear. Numerous studies reported Long non-coding RNA (lncRNA) could regulate the gene expression level by regulating gene methylation status in many tumors. However, whether there were lncRNAs could change the methylation status of LZTS1 or not in CRLM was unknown. In this study, we aimed to investigate whether there are lncRNAs can regulate the expression of LZTS1 through affecting DNA methylation in CRLM. We found that upregulated Lnc-LALC in CRC was negatively correlated with LZTS1 expression, and Lnc-LALC could regulate LZTS1 expression in both mRNA and protein level in our study. Functionally, Lnc-LALC enhanced the CRC cells metastasis ability in vitro and vivo through inhibiting the expression of LZTS1. Furthermore, the precise mechanisms exploration showed that lnc-LALC could recruit DNA methyltransferases (DNMTs) to the LZTS1 promoter by combining with Enhancer of zeste homolog 2(EZH2) and then altered the expression of LZTS1 via DNMTs-mediated DNA methylation. Collectively, our data demonstrated the important role of Lnc-LALC/ LZTS1 axis in CRLM development.


Asunto(s)
Adenocarcinoma/genética , Neoplasias Colorrectales/genética , Metilación de ADN , Proteínas de Unión al ADN/genética , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Neoplasias Hepáticas/genética , Regiones Promotoras Genéticas , ARN Largo no Codificante/genética , Proteínas Supresoras de Tumor/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/secundario , Anciano , Animales , Células CACO-2 , Movimiento Celular , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Transición Epitelial-Mesenquimal , Femenino , Células HCT116 , Células HT29 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundario , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Invasividad Neoplásica , ARN Largo no Codificante/metabolismo , Proteínas Supresoras de Tumor/metabolismo
20.
Clin Transl Med ; 11(11): e565, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34841662

RESUMEN

BACKGROUND: Though circular RNAs, new non-coding RNA classes have demonstrated that they have an essential role in the initiation as well as development of CRC (colorectal cancer), whereas in CRC the function and mechanism of hsa_circ_0001666 are less known. METHODS: Hsa_circ_0001666 was identified by bioinformatics analysis of a circRNA microarray from the GEO database, and its expression in both CRC cell lines and tissues was analysed. A series of in vitro along with in vivo experiments were carried out for exploring the hsa_circ_0001666 functions, including transwell, wound healing, flow cytometry, colony formation, Edu, CCK-8, soft agar colony formation, tumor xenografts and lung/liver metastasis in mice. RNA pull-down, RIP (RNA immunoprecipitation), luciferase reporter assay, FISH (fluorescence in situ hybridization) and rescue experiments were used for determining the correlation among hsa_circ_0001666, miR-576-5p and PCDH10. RESULTS: Hsa_circ_0001666 was downregulated in both CRC cell lines along with tumour tissues. A higher expression level of hsa_circ_0001666 indicated a better clinical prognosis in patients with CRC. Hsa_circ_0001666 knockdown significantly supported CRC cell proliferation along with invasion and inhibited cell apoptosis in vitro. Hsa_circ_0001666 knockdown accelerated the CRC growth and metastasis in vivo. Moreover, the mechanistic study showed that hsa_circ_0001666, acting as 'ceRNA' of miR-576-5p, prevented PCDH10 downregulation, as well as suppressed EMT and stemness of CRC cells, and the Wnt/ß-catenin signalling pathway. Inhibiting miR-576-5p or overexpressing PCDH10 could reverse phenotypic changes caused by knocking down of hsa_circ_0001666. CONCLUSIONS: Hsa_circ_0001666 suppresses CRC progression through the miR-576-5p/PCDH10 axis and may provide a new insight for the diagnosis and treatment of CRC.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , MicroARNs/efectos de los fármacos , Protocadherinas/efectos de los fármacos , ARN Circular/farmacología , Anciano , Proliferación Celular/genética , China , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , ARN Circular/uso terapéutico
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