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1.
Mol Cell ; 81(16): 3339-3355.e8, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34352206

RESUMO

Cancer cells selectively promote translation of specific oncogenic transcripts to facilitate cancer survival and progression, but the underlying mechanisms are poorly understood. Here, we find that N7-methylguanosine (m7G) tRNA modification and its methyltransferase complex components, METTL1 and WDR4, are significantly upregulated in intrahepatic cholangiocarcinoma (ICC) and associated with poor prognosis. We further reveal the critical role of METTL1/WDR4 in promoting ICC cell survival and progression using loss- and gain-of-function assays in vitro and in vivo. Mechanistically, m7G tRNA modification selectively regulates the translation of oncogenic transcripts, including cell-cycle and epidermal growth factor receptor (EGFR) pathway genes, in m7G-tRNA-decoded codon-frequency-dependent mechanisms. Moreover, using overexpression and knockout mouse models, we demonstrate the crucial oncogenic function of Mettl1-mediated m7G tRNA modification in promoting ICC tumorigenesis and progression in vivo. Our study uncovers the important physiological function and mechanism of METTL1-mediated m7G tRNA modification in the regulation of oncogenic mRNA translation and cancer progression.


Assuntos
Colangiocarcinoma/genética , Proteínas de Ligação ao GTP/genética , Metiltransferases/genética , Biossíntese de Proteínas , Animais , Carcinogênese/genética , Colangiocarcinoma/patologia , Progressão da Doença , Receptores ErbB/genética , Guanosina/análogos & derivados , Guanosina/genética , Humanos , Camundongos , Processamento Pós-Transcricional do RNA/genética , RNA Mensageiro/genética , RNA de Transferência/genética
2.
Eur Radiol ; 31(11): 8615-8627, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33877387

RESUMO

OBJECTIVES: Pretreatment evaluation of tumor biology and microenvironment is important to predict prognosis and plan treatment. We aimed to develop nomograms based on gadoxetic acid-enhanced MRI to predict microvascular invasion (MVI), tumor differentiation, and immunoscore. METHODS: This retrospective study included 273 patients with HCC who underwent preoperative gadoxetic acid-enhanced MRI. Patients were assigned to two groups: training (N = 191) and validation (N = 82). Univariable and multivariable logistic regression analyses were performed to investigate clinical variables and MRI features' associations with MVI, tumor differentiation, and immunoscore. Nomograms were developed based on features associated with these three histopathological features in the training cohort, then validated, and evaluated. RESULTS: Predictors of MVI included tumor size, rim enhancement, capsule, percent decrease in T1 images (T1D%), standard deviation of apparent diffusion coefficient, and alanine aminotransferase levels, while capsule, peritumoral enhancement, mean relaxation time on the hepatobiliary phase (T1E), and alpha-fetoprotein levels predicted tumor differentiation. Predictors of immunoscore included the radiologic score constructed by tumor number, intratumoral vessel, margin, capsule, rim enhancement, T1D%, relaxation time on plain scan (T1P), and alpha-fetoprotein and alanine aminotransferase levels. Three nomograms achieved good concordance indexes in predicting MVI (0.754, 0.746), tumor differentiation (0.758, 0.699), and immunoscore (0.737, 0.726) in the training and validation cohorts, respectively. CONCLUSION: MRI-based nomograms effectively predict tumor behaviors in HCC and may assist clinicians in prognosis prediction and pretreatment decisions. KEY POINTS: • This study developed and validated three nomograms based on gadoxetic acid-enhanced MRI to predict MVI, tumor differentiation, and immunoscore in patients with HCC. • The pretreatment prediction of tumor microenvironment may be useful to guide accurate prognosis and planning of surgical and immunological therapies for individual patients with HCC.

3.
Hepatology ; 74(3): 1339-1356, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33638162

RESUMO

BACKGROUND AND AIMS: The dynamic N6-methyladenosine (m6 A) mRNA modification is essential for acute stress response and cancer progression. Sublethal heat stress from insufficient radiofrequency ablation (IRFA) has been confirmed to promote HCC progression; however, whether m6 A machinery is involved in IRFA-induced HCC recurrence remains open for study. APPROACH AND RESULTS: Using an IRFA HCC orthotopic mouse model, we detected a higher level of m6 A reader YTH N6-methyladenosine RNA binding protein 1-3 (YTHDF1) in the sublethal-heat-exposed transitional zone close to the ablation center than that in the farther area. In addition, we validated the increased m6 A modification and elevated YTHDF1 protein level in sublethal-heat-treated HCC cell lines, HCC patient-derived xenograft (PDX) mouse model, and patients' HCC tissues. Functionally, gain-of-function/loss-of-function assays showed that YTHDF1 promotes HCC cell viability and metastasis. Knockdown of YTHDF1 drastically restrains the tumor metastasis evoked by sublethal heat treatment in tail vein injection lung metastasis and orthotopic HCC mouse models. Mechanistically, we found that sublethal heat treatment increases epidermal factor growth receptor (EGFR) m6 A modification in the vicinity of the 5' untranslated region and promotes its binding with YTHDF1, which enhances the translation of EGFR mRNA. The sublethal-heat-induced up-regulation of EGFR level was further confirmed in the IRFA HCC PDX mouse model and patients' tissues. Combination of YTHDF1 silencing and EGFR inhibition suppressed the malignancies of HCC cells synergically. CONCLUSIONS: The m6 A-YTHDF1-EGFR axis promotes HCC progression after IRFA, supporting the rationale for targeting m6 A machinery combined with EGFR inhibitors to suppress HCC metastasis after RFA.

4.
Cancer Lett ; 503: 1-10, 2021 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-33444692

RESUMO

Ablative treatment evokes antitumor immunity, but knowledge on the emerging irreversible electroporation (IRE)-induced immunity in hepatocellular carcinoma (HCC) is limited. To investigate the immune effects induced by IRE and its role in preventing post-ablation HCC progression, a C57BL/6J mouse model bearing subcutaneous H22 hepatoma was employed. IRE treatment significantly suppresses HCC growth, and treated mice are tumor-free after secondary tumor injection and show increased splenic interferon-gamma (IFN-γ)+CD8+ T cells. Additionally, more CD8+ T and dendritic cells, but not CD4+ T, B or NK cells, infiltrate into peri-ablation zones after IRE at day 7. Depletion of CD8+ T cells induces local tumor regrowth and distant metastasis after IRE. Vaccination using IRE-processed H22 lysates prevents tumorigenesis in mice, suggesting a protective immune response. IRE also alleviates immunosuppression by reducing local and splenic Treg and PD-1+ T cells. Regarding mechanism, IRE induces cell necrosis and significant release of danger-associated molecular patterns including ATP, high mobility group box 1 and calreticulin that are pivotal to CD8+ T cell immunity. Together, IRE is a promising approach to evoke CD8+ T cell immunity, which help prevent post-ablation HCC progression.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma Hepatocelular/terapia , Interferon gama/metabolismo , Neoplasias Hepáticas/terapia , Ablação por Radiofrequência/métodos , Animais , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Progressão da Doença , Eletroporação , Células Hep G2 , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Baço/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
ACS Omega ; 5(14): 8272-8282, 2020 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-32309738

RESUMO

Binder, as one of the key components, plays a crucial role in improving the capacity and cycling performance of lithium-sulfur (Li-S) batteries. In this work, commercially available, low-cost, water-soluble polyvinyl alcohol (PVA) has been systematically investigated as a functional polymer binder for high-sulfur-loading cathodes, with the aim of enhancing sulfur utilization, reducing capacity decay, and extending cycling life of the cathodes. In comparison with polyvinylidene fluoride as a conventional binder, PVA shows a valuable polysulfide entrapping ability and a much stronger binding strength. Its superior polysulfide entrapping ability has been verified through theoretical density functional theory calculations and an experimental ex situ adsorption study. In electrochemical Li-S battery performance evaluation, at a sulfur loading density of 3.5 mg cm-2, the sulfur cathode assembled with the PVA binder displays at 0.5 C a very slow capacity decay of only 0.010% per cycle over 250 cycles. Additionally, the strong binding strength of PVA allows the fabrication of thick sulfur cathodes with a high sulfur loading density of 10.5 mg cm-2, which shows a high areal capacity of 4.0 mA h cm-2 and a high cycling stability (capacity decay of 0.1% per cycle). In consideration of the superior capacity retention and cycling performance of its enabled cathodes, the cost-effective PVA is a promising candidate for high-sulfur-loading cathodes in practical applications.

6.
J Exp Clin Cancer Res ; 38(1): 454, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31694662

RESUMO

BACKGROUND: Limited effective intervention for advanced hepatocellular carcinoma (HCC) is available. This study aimed to investigate the potential clinical utility of apatinib, a highly selective inhibitor of the vascular endothelial growth factor receptor-2 (VEGFR2) tyrosine kinase, as a radiosensitizer in the treatment of HCC. METHODS: Four human HCC cell lines SMMC-7721, MHCC-97H, HCCLM3 and Hep-3B were treated with apatinib, irradiation or combination treatment. Colony formation assay, flow cytometry and nuclear γ-H2AX foci immunofluorescence staining were performed to evaluate the efficacy of combination treatment. RNA sequencing was conducted to explore the potential mechanism. The impact of combination treatment on tumor growth was assessed by xenograft mice models. RESULTS: Colony formation assay revealed that apatinib enhanced the radiosensitivity of HCC cell lines. Apatinib suppressed repair of radiation-induced DNA double-strand breaks. Flow cytometry analysis showed that apatinib increased radiation-induced apoptosis. Apatinib radiosensitized HCC via suppression of radiation-induced PI3K/AKT pathway. Moreover, an in vivo study indicated apatinib combined with irradiation significantly decreased xenograft tumor growth. CONCLUSIONS: Our results indicate that apatinib has therapeutic potential as a radiosensitizer in HCC, and PI3K/AKT signaling pathway plays a critical role in mediating radiosensitization of apatinib.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas/farmacologia , Radiossensibilizantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Camundongos , Tolerância a Radiação/efeitos dos fármacos , Radioterapia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Cancer Lett ; 460: 29-40, 2019 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-31173855

RESUMO

Incomplete radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC) could initiate malignant transition. Patient-derived xenograft (PDX) mice model was established to investigate the effect of VEGF pathway in incomplete RFA of HCC with high fidelity. Cancer stem cell markers and metastatic markers were increased after incomplete RFA, with increased VEGFR1 and decreased VEGFR2 expression. In vitro experiments revealed sublethal heat treatment promoted migration ability of HepG2, HCCLM3, and SMMC7721 cells, which coincided with enhanced ability of sphere formation and up-regulation of VEGFR1, CD133, CD44, and EpCAM. Moreover, HCC cells secreted more VEGF after heat-treatment. VEGF promoted migration and enhanced stemness of HCC cells, which could not be suppressed by VEGFR2 inhibitor. PIGF, the ligand of VEGFR1, significantly increased migration and stemness of HCC cells. Blocking VEGFR1 reduced heat-induced enhancement of migration and stemness, whereas inhibition of VEGFR2 could not. In conclusion, VEGFR1 plays a critical role in sublethal heat treatment-induced enhancement of migration and stemness in HCC, suggesting that VEGFR1 may serve as a potential and promising therapeutic target for preventing recurrence after RFA.


Assuntos
Carcinoma Hepatocelular/cirurgia , Movimento Celular , Neoplasias Hepáticas/cirurgia , Células-Tronco Neoplásicas/metabolismo , Ablação por Radiofrequência/efeitos adversos , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/secundário , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos BALB C , Invasividade Neoplásica , Células-Tronco Neoplásicas/patologia , Fenótipo , Transdução de Sinais , Falha de Tratamento , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
ACS Appl Mater Interfaces ; 11(19): 17730-17741, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31013045

RESUMO

Surface modification has been proven to be an effective approach for ion exchange membranes to achieve separation of counterions with different valences by altering interfacial construction of membranes to improve ion transfer performance. In this work, we have fabricated a series of novel cation exchange membranes (CEMs) by modifying sulfonated polysulfone (SPSF) membranes via codeposition of mussel-inspired dopamine (DA) and 4'-aminobenzo-15-crown-5 (ACE), followed by glutaraldehyde cross-linking, aiming at achieving selective separation of specific cations. The as-prepared membranes before and after modification were systematically characterized in terms of their structural, physicochemical, electrochemical, and electrodialytic properties. In the electrodialysis process, the modified membranes exhibit distinct perm selectivity to K+ ions in binary (K+/Li+, K+/Na+, K+/Mg2+) and ternary (K+/Li+/Mg2+) systems. In particular, at a constant current density of 5.0 mA·cm-2, modified membrane M-co-0.50 shows significantly prominent perm selectivity [Formula: see text] in the K+/Mg2+ system and M-co-0.75 exhibits remarkable performance in the K+/Li+ system [Formula: see text], superior to commercial monovalent-selective CEM (CIMS, [Formula: see text], [Formula: see text]). Besides, in the K+/Li+/Mg2+ ternary system, K+ flux reaches 30.8 nmol·cm-2·s-1 for M-co-0.50, while it reaches 25.8 nmol·cm-2·s-1 for CIMS. It possibly arises from the effects of pore-size sieving and the synergistic action of electric field driving and host-guest molecular recognition of ACE and K+ ions. This study can provide new insights into the separation of specific alkali metal ions, especially on reducing influence of coexisting cations K+ and Na+ on Li+ ion recovery from salt lake and seawater.


Assuntos
Cátions/química , Dopamina/química , Água do Mar/química , Sódio/isolamento & purificação , Compostos de Anilina/química , Reagentes para Ligações Cruzadas/química , Coronantes/química , Glutaral/química , Troca Iônica , Membranas Artificiais , Polímeros/química , Potássio/química , Potássio/isolamento & purificação , Sódio/química , Sulfonas/química
9.
Membranes (Basel) ; 9(3)2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30845765

RESUMO

A facile membrane surface modification process for improving permselectivity and antimicrobial property was proposed. A polydopamine (PDA) coating was firstly fabricated on pristine anion exchange membrane (AEM), followed by in situ reduction of Ag without adding any extra reductant. Finally, 2,5-diaminobenzene sulfonic acid (DSA) was grafted onto PDA layer via Michael addition reaction. The as-prepared AEM exhibited improved permselectivity (from 0.60 to 1.43) and effective inhibition of bacterial growth. In addition, the result of the long-term (90-h continuous electrodialysis) test expressed the excellent durability of the modified layer on membrane surface, because the concentration of Cl- and SO4²- in diluted chamber fluctuated ~0.024 and 0.030 mol·L-1 with no distinct decline. The method described in this work makes the full use of multifunctional PDA layer (polymer-like coating, in situ reduction and post-organic reaction), and a rational design of functional AEM was established for better practical application.

10.
Oncogene ; 37(26): 3514-3527, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29559743

RESUMO

Recent studies indicated that insufficient radiofrequency ablation (RFA) could endow hepatocellular carcinoma (HCC) with higher aggressive potential. Stress-induced phosphoprotein 1 (STIP1), which was found highly expressed in HCC, is a chaperone molecule mediating cell homeostasis under thermal stress. We aimed to explore the role of STIP1 on the metastasis of residual HCC after RFA. Mice model with orthotopic HCC implants or caudal vein injection were employed to assess potential of lung metastasis and/or intrahepatic metastasis (IHM) of HCC cells. Cell culture model was used to determine cell invasion, mesenchymal marker genes expression, and underlying molecular mechanisms. Clinical specimens were collected to analyze the relationship between STIP1 and clinical outcome. We found that insufficient RFA elicited more IHM of HCCLM3 tumors, which could be reduced by silencing STIP1. Knockdown of STIP1 also significantly decreased lung metastatic potential of HCCLM3 cells. In vitro, HCCLM3 and HepG2 displayed a spindle-shaped morphology with upregulation of STIP1 and mesenchymal markers after sublethal heat exposure. Mechanistically, heat exposure induced the formation of STIP1-heat shock protein 90 (HSP90) complex, which could shuttle epithelial transcription repressor Snail1 into nucleus and regulate mesenchymal gene transcription. Blocking the HSP90-STIP1 complex reduced the invasive potential of HCC cells after heat exposure. Using clinical specimen, we found that STIP1 was expressed significantly higher in metastatic tumor tissues and in sera from metastatic HCC patients (p < 0.05). The high expression of STIP1 was significantly linked to shorter recurrence-free survival (p < 0.05). To sum up, our study found that STIP1 is positively associated with the sublethal heat-induced cancer cell metastasis through mediating the mesenchymal gene transcription. Blocking STIP1 activity may suppress HCC cell metastatic potential after RFA.


Assuntos
Carcinoma Hepatocelular/patologia , Ablação por Cateter/métodos , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas de Choque Térmico/metabolismo , Neoplasias Hepáticas/patologia , Ablação por Radiofrequência/métodos , Fatores de Transcrição da Família Snail/metabolismo , Animais , Carcinoma Hepatocelular/mortalidade , Linhagem Celular Tumoral , Movimento Celular/genética , Modelos Animais de Doenças , Proteínas de Choque Térmico/genética , Células Hep G2 , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Pulmonares/secundário , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Interferência de RNA , RNA Interferente Pequeno/genética
11.
J Exp Clin Cancer Res ; 37(1): 6, 2018 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-29335007

RESUMO

BACKGROUND: Stress-Inducible Protein-1 (STIP1) is a co-chaperone that associates directly with heat shock proteins, and regulates motility of various types of cancer. In the present study, we investigated the role of STIP1 on metastasis of gastric cancer (GC). METHODS: In vivo metastatic experimental model was employed to investigate the effect of STIP1 on metastasis of GC cells. Loss-of-function and gain-of-function experiments were performed to examine the role of STIP1 on metastasis of GC cells. Western blot, immunofluorescence staining, migration and invasion assays, microarray and KEGG pathway analysis were applied to explore the underlying mechanism. RESULTS: In current study, we demonstrated that STIP1 promoted lung metastasis of GC cells in vivo. Furthermore, STIP1 significantly enhanced migration and invasion abilities of GC cells. In contrast, knock-down of STIP1 yielded the opposite effects on these phenotypes in vitro. STIP1 promoted tumor metastasis through inducing epithelial-to-mesenchymal transition in GC cells. Mechanistically, STIP1 promoted GC metastasis via up-regulation of targeted genes in Wnt/ß-catenin signaling pathway, including c-Myc and Cyclin D1, and accompanied with nuclear translocation of ß-catenin. CONCLUSIONS: Our findings indicate that elevated expression of STIP1 exhibited a metastasis-promoting effect in GC cells through activation of Wnt/ß-catenin signaling pathway. STIP1 may be served as a potential therapeutic target for preventing GC metastasis.


Assuntos
Proteínas de Choque Térmico/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Via de Sinalização Wnt , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Expressão Gênica , Proteínas de Choque Térmico/genética , Xenoenxertos , Humanos , Neoplasias Pulmonares/secundário , Metaloproteinases da Matriz/metabolismo , Camundongos , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias Gástricas/genética
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