RESUMO
Synthetic lethality through combinatorial targeting DNA damage response (DDR) pathways provides exciting anticancer therapeutic benefit. Currently, the long noncoding RNAs (lncRNAs) have been implicated in tumor drug resistance; however, their potential significance in DDR is still largely unknown. Here, we report that a human lncRNA, CTD-2256P15.2, encodes a micropeptide, named PAR-amplifying and CtIP-maintaining micropeptide (PACMP), with a dual function to maintain CtIP abundance and promote poly(ADP-ribosyl)ation. PACMP not only prevents CtIP from ubiquitination through inhibiting the CtIP-KLHL15 association but also directly binds DNA damage-induced poly(ADP-ribose) chains to enhance PARP1-dependent poly(ADP-ribosyl)ation. Targeting PACMP alone inhibits tumor growth by causing a synthetic lethal interaction between CtIP and PARP inhibitions and confers sensitivity to PARP/ATR/CDK4/6 inhibitors, ionizing radiation, epirubicin, and camptothecin. Our findings reveal that a lncRNA-derived micropeptide regulates cancer progression and drug resistance by modulating DDR, whose inhibition could be employed to augment the existing anticancer therapeutic strategies.
Assuntos
Endodesoxirribonucleases , Neoplasias , Peptídeos , Poli ADP Ribosilação , RNA Longo não Codificante , Reparo do DNA , Endodesoxirribonucleases/metabolismo , Humanos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Peptídeos/farmacologia , Poli Adenosina Difosfato Ribose/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
The maternal-to-zygotic transition (MZT) is a conserved and fundamental process during which the maternal environment is converted to an environment of embryonic-driven development through dramatic reprogramming. However, how maternally supplied transcripts are dynamically regulated during MZT remains largely unknown. Herein, through genome-wide profiling of RNA 5-methylcytosine (m5C) modification in zebrafish early embryos, we found that m5C-modified maternal mRNAs display higher stability than non-m5C-modified mRNAs during MZT. We discovered that Y-box binding protein 1 (Ybx1) preferentially recognizes m5C-modified mRNAs through π-π interactions with a key residue, Trp45, in Ybx1's cold shock domain (CSD), which plays essential roles in maternal mRNA stability and early embryogenesis of zebrafish. Together with the mRNA stabilizer Pabpc1a, Ybx1 promotes the stability of its target mRNAs in an m5C-dependent manner. Our study demonstrates an unexpected mechanism of RNA m5C-regulated maternal mRNA stabilization during zebrafish MZT, highlighting the critical role of m5C mRNA modification in early development.
Assuntos
5-Metilcitosina/metabolismo , Embrião não Mamífero/embriologia , Desenvolvimento Embrionário/fisiologia , Estabilidade de RNA/fisiologia , RNA Mensageiro Estocado/metabolismo , Peixe-Zebra/embriologia , Animais , Células HeLa , Humanos , Camundongos , RNA Mensageiro Estocado/genética , Peixe-Zebra/genéticaRESUMO
RNA binding protein RBM10 participates in various RNA metabolism, and its decreased expression or loss of function by mutation has been identified in many human cancers. However, how its dysregulation contributes to human cancer pathogenesis remains to be determined. Here, we found that RBM10 expression was decreased in breast tumors, and breast cancer patients with low RBM10 expression presented poorer survival rates. RBM10 depletion in breast cancer cells significantly promotes the cellular proliferation and migration. We further demonstrated that RBM10 forms a triple complex with YBX1 and phosphatase 1B (PPM1B), in which PPM1B serves as the phosphatase of YBX1. RBM10 knock-down markedly attenuated association between YBX1 and PPM1B, leading to elevated levels of YBX1 phosphorylation and its nuclear translocation. Furthermore, cancer cells with RBM10 depletion had a significantly accelerated tumor growth in nude mice. Importantly, these enhanced tumorigenic phenotypes can be reversed by overexpression of PPM1B. Our findings provide the mechanistic bases for functional loss of RBM10 in promoting tumorigenicity, and are potentially useful in the development of combined therapeutic strategies for cancer patients with defective RBM10.
Assuntos
Neoplasias da Mama , Carcinogênese , Animais , Camundongos , Humanos , Feminino , Camundongos Nus , Carcinogênese/genética , Fosforilação , Proliferação de Células/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Monoéster Fosfórico Hidrolases/genética , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Proteína 1 de Ligação a Y-Box/genética , Proteína 1 de Ligação a Y-Box/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteína Fosfatase 2C/genética , Proteína Fosfatase 2C/metabolismoRESUMO
BACKGROUND: The aim of this multicentre cohort study was to compare the long-term oncological outcomes of robotic gastrectomy (RG) and laparoscopic gastrectomy (LG) for patients with gastric cancer. METHODS: Patients with gastric cancer who underwent radical gastrectomy by robotic or laparoscopic approaches from 1 March 2010 to 31 December 2018 at 10 high-volume centres in China were selected from institutional databases. Patients receiving RG were matched 1 : 1 by propensity score with patients undergoing LG. The primary outcome was 3-year disease-free survival. Secondary outcomes were overall survival and disease recurrence. RESULTS: Some 2055 patients who underwent RG and 4309 patients who had LG were included. The propensity score-matched cohort comprised 2026 RGs and 2026 LGs. Median follow-up was 41 (i.q.r. 39-58) months for the RG group and 39 (38-56) months for the LG group. The 3-year disease-free survival rates were 80.8% in the RG group and 79.5% in the LG group (log rank P = 0.240; HR 0.92, 95% c.i. 0.80 to 1.06; P = 0.242). Three-year OS rates were 83.9 and 81.8% respectively (log rank P = 0.068; HR 0.87, 0.75 to 1.01; P = 0.068) and the cumulative incidence of recurrence over 3 years was 19.3% versus 20.8% (HR 0.95, 0.88 to 1.03; P = 0.219), with no difference between groups. CONCLUSION: RG and LG in patients with gastric cancer are associated with comparable disease-free and overall survival.
Assuntos
Laparoscopia , Levamisol/análogos & derivados , Procedimentos Cirúrgicos Robóticos , Neoplasias Gástricas , Humanos , Resultado do Tratamento , Estudos de Coortes , Neoplasias Gástricas/cirurgia , Gastrectomia , Pontuação de Propensão , Estudos Retrospectivos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgiaRESUMO
BACKGROUND: With the improvements in laparoscopic or robotic surgical techniques and instruments, a growing number of surgeons have attempted to complete all digestive tract reconstruction intracorporeally; these procedures include totally robotic gastrectomy (TRG) and totally laparoscopic gastrectomy (TLG). This study aimed to evaluate the safety and feasibility of the TRG and compare the short-term outcomes of the TRG and TLG in patients with gastric cancer. METHODS: Between January 2018 and June 2023, 346 consecutive patients who underwent TRG or TLG at a high-volume academic gastric cancer specialty center were included. 1:1 propensity score matching (PSM) was performed to reduce confounding bias. The surgical outcomes, postoperative morbidity, and surgical burden were compared in PSM cohort. RESULTS: After PSM, a well-balanced cohort of 194 patients (97 in each group) was included in the analysis. The total operation time of the TRG group was significantly longer than that of the TLG group (244.9 vs. 213.0 min, P < 0.001). There was no significant difference in the effective operation time between the 2 groups (217.8 vs. 207.2 min, P = 0.059). The digestive tract reconstruction time of the TRG group was significantly shorter than that of the TLG group (39.4 vs. 46.7 min, P < 0.001). The mean blood loss in the TRG group was less than that in the TLG group (101.1 vs. 126.8 mL, P = 0.014). The TRG group had more retrieved lymph nodes in the suprapancreatic area than that in the TLG group (16.6 vs 14.2, P = 0.002). The TRG group had a lower surgery task load index (38.9 vs. 43.1, P < 0.001) than the TLG group. No significant difference was found in terms of postoperative morbidity between the 2 groups (14.4% vs. 16.5%, P = 0.691). CONCLUSION: This study demonstrated that TRG is a safe and feasible procedure, and is preferable to TLG in terms of invasion and ergonomics. The TRG may maximize the superiority of robotic surgical systems and embodies the theory of minimally invasive surgery.
Assuntos
Gastrectomia , Laparoscopia , Duração da Cirurgia , Pontuação de Propensão , Procedimentos Cirúrgicos Robóticos , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/cirurgia , Gastrectomia/métodos , Procedimentos Cirúrgicos Robóticos/métodos , Laparoscopia/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Estudos de Viabilidade , Resultado do Tratamento , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologiaRESUMO
The regulatory role of N(6)-methyladenosine (m(6)A) and its nuclear binding protein YTHDC1 in pre-mRNA splicing remains an enigma. Here we show that YTHDC1 promotes exon inclusion in targeted mRNAs through recruiting pre-mRNA splicing factor SRSF3 (SRp20) while blocking SRSF10 (SRp38) mRNA binding. Transcriptome assay with PAR-CLIP-seq analysis revealed that YTHDC1-regulated exon-inclusion patterns were similar to those of SRSF3 but opposite of SRSF10. In vitro pull-down assay illustrated a competitive binding of SRSF3 and SRSF10 to YTHDC1. Moreover, YTHDC1 facilitates SRSF3 but represses SRSF10 in their nuclear speckle localization, RNA-binding affinity, and associated splicing events, dysregulation of which, as the result of YTHDC1 depletion, can be restored by reconstitution with wild-type, but not m(6)A-binding-defective, YTHDC1. Our findings provide the direct evidence that m(6)A reader YTHDC1 regulates mRNA splicing through recruiting and modulating pre-mRNA splicing factors for their access to the binding regions of targeted mRNAs.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Splicing de RNA , Proteínas de Ligação a RNA/metabolismo , Proteínas Repressoras/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Sítios de Ligação , Éxons , Células HeLa , Humanos , Fatores de Processamento de RNA , RNA Mensageiro/metabolismo , Fatores de Processamento de Serina-ArgininaRESUMO
BACKGROUND: Branching is a plastic character that affects plant architecture and spatial structure. The trait is controlled by a variety of plant hormones through coordination with environmental signals. Plant AT-rich sequence and zinc-binding protein (PLATZ) is a transcription factor that plays an important role in plant growth and development. However, systematic research on the role of the PLATZ family in apple branching has not been conducted previously. RESULTS: In this study, a total of 17 PLATZ genes were identified and characterized from the apple genome. The 83 PLATZ proteins from apple, tomato, Arabidopsis, rice, and maize were classified into three groups based on the topological structure of the phylogenetic tree. The phylogenetic relationships, conserved motifs, gene structure, regulatory cis-acting elements, and microRNAs of the MdPLATZ family members were predicted. Expression analysis revealed that MdPLATZ genes exhibited distinct expression patterns in different tissues. The expression patterns of the MdPLATZ genes were systematically investigated in response to treatments that impact apple branching [thidazuron (TDZ) and decapitation]. The expression of MdPLATZ1, 6, 7, 8, 9, 15, and 16 was regulated during axillary bud outgrowth based on RNA-sequencing data obtained from apple axillary buds treated by decapitation or exogenous TDZ application. Quantitative real-time PCR analysis showed that MdPLATZ6 was strongly downregulated in response to the TDZ and decapitation treatments, however, MdPLATZ15 was significantly upregulated in response to TDZ, but exhibited little response to decapitation. Furthermore, the co-expression network showed that PLATZ might be involved in shoot branching by regulating branching-related genes or mediating cytokinin or auxin pathway. CONCLUSION: The results provide valuable information for further functional investigation of MdPLATZ genes in the control of axillary bud outgrowth in apple.
Assuntos
Decapitação , Malus , Malus/metabolismo , Filogenia , Decapitação/metabolismo , Genes de Plantas , Brotos de Planta/genética , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMO
OBJECTIVE: A large-scale multicenter retrospective cohort study was conducted to compare the short- and long-term outcomes of robotic gastrectomy (RG) and laparoscopic gastrectomy (LG) for gastric cancer. SUMMARY OF BACKGROUND DATA: RG is being increasingly used worldwide, but data from large-scale multicenter studies on the short- and long-term oncologic outcomes of RG versus LG are limited. The potential benefits of RG compared with LG for gastric cancer remain controversial. METHODS: Data from eligible patients who underwent RG or LG for gastric cancer of 11 experienced surgeons from 7 centers in China between March 2010 and October 2019 were collected. The RG group was matched 1:1 with the LG group by using propensity score matching. The primary outcome was postoperative complications. RESULTS: After propensity score matching, a well-balanced cohort of 3552 patients was included for further analysis. The occurrence of overall complications (12.6% vs 15.2%, P = 0.023) was lower in the RG group than in the LG group. RG was associated with less blood loss (126.8 vs 142.5 mL, P < 0.001) and more retrieved lymph nodes in total (32.5 vs 30.7, P < 0.001) and in suprapancreatic areas (13.3 vs 11.6, P < 0.001).The long-term oncological outcomes were comparable between the two groups. CONCLUSIONS: The results of this multicenter study demonstrate that RG is a safe and effective treatment for gastric cancer when performed by experienced surgeons, although longer operation time and higher costs are still concerns about RG. This study provides evidence suggesting that RG may represent an alternative surgical treatment to LG.
Assuntos
Laparoscopia , Procedimentos Cirúrgicos Robóticos , Neoplasias Gástricas , Humanos , Procedimentos Cirúrgicos Robóticos/métodos , Estudos Retrospectivos , Neoplasias Gástricas/cirurgia , Resultado do Tratamento , Gastrectomia/métodos , Complicações Pós-Operatórias/cirurgia , ChinaRESUMO
Water-in-water (w/w) emulsions have been recognized for their broad applications in foods, cosmetics, and biomedical engineering. In this work, silica Janus nanosheets (JNs) with polyacrylic acid (PAA) chains grafted on one surface via crushing functional silica foams, and used silica JNs as Pickering stabilizer to produce stable water-in-water (w/w) emulsions from the aqueous two-phase system (ATPS) containing methacrylic acid (MAA) and NaCl are prepared. The interfacial area of w/w emulsions increases linearly with the concentration of silica JNs, and the interfacial coverage of nanosheets is calculated to be about 98%. After polymerizing w/w emulsions prepared from MAA/NaCl ATPS, it is found that silica JNs are entrapped at the interface of w/w emulsions with the smooth PAA-grafted surface located toward MAA-rich phase due to their specific interaction. These results show that functional silica JNs can be used as a promising amphiphilic Pickering stabilizer to produce well-defined w/w emulsions for numerous application fields.
RESUMO
RNA methylations, as the prevalent post-transcriptional modifications, are critical in regulating various biological processes, such as RNA transcription, splicing, structure, stability, and translation. Its dysregulation is closely related to the occurrence of human malignancies. The advance of high-throughput sequencing technology facilitates the investigations about how methylation of coding and non-coding RNAs regulates cancer progression through reshaping the transcriptomics. Here, we review the current progress about the regulatory role of several representative RNA modifications in cancers, including N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A) and 2'-O-methylation (Nm). Meanwhile, we also discuss the potential clinical value of RNA methylation in diagnostic and therapeutic implications of human cancers.
Assuntos
Biomarcadores Tumorais/metabolismo , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Neoplasias/patologia , Animais , Biomarcadores Tumorais/genética , Humanos , Metilação , Neoplasias/genética , Neoplasias/metabolismoRESUMO
CD8+CD103+ tissue-resident memory T cells (TRMs) are involved in tumor immune response and linked to favorable clinical outcome in human cancer. However, the distribution, phenotype, functional properties and clinical relevance of these cells in gastric cancer (GC) remain elusive. Here, our data show that, in comparison to non-tumor tissues, the percentages of CD8+CD103+ TRMs in tumors are significantly decreased. Most tumor-infiltrating CD8+CD103+ TRMs are CD45RA-CCR7- effector-memory cells with higher PD-1 and 4-1BB expression than those from non-tumor tissues. Further, tumor-infiltrating CD8+CD103+ TRMs show impaired cytolytic capacity due to decreased granzyme B and perforin expression. Moreover, ex vivo PD-1 blockade could restore the cytolytic capacity of tumor-infiltrating CD8+CD103+ TRMs, and such anti-PD-1-mediated reinvigoration of CD8+CD103+ TRMs could be further enhanced by 4-1BB co-stimulation. Finally, lower levels of Tumor-infiltrating CD8+CD103+ TRMs are positively correlated with GC progression and poor patients' survival. Our data suggest that restoring CD8+CD103+ TRM function by combining PD-1 blockade and 4-1BB co-stimulation may be a promising strategy for treating GC.
Assuntos
Neoplasias Gástricas , Linfócitos T CD8-Positivos , Humanos , Memória Imunológica , Cadeias alfa de Integrinas/metabolismo , Linfócitos do Interstício Tumoral , Células T de Memória , Fenótipo , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Gástricas/metabolismoRESUMO
BACKGROUND: The potential advantage of laparoscopic gastrectomy (LG) compared with open gastrectomy (OG) for serosa-invasive (pT4a) Siewert type II and III adenocarcinoma of the esophagogastric junction (AEG) remains uncertain. Thus, the purpose of this study was to investigate the short- and long-term outcomes of LG compared to OG for pT4a Siewert type II/III AEG cancers. METHODS: We retrospectively evaluated 283 patients with pathological confirmed T4a Siewert type II and type III AEG who underwent LG or OG in our center between January 2004 and September 2015. The short- and long-term outcomes were compared between the groups using a 1:1 matched propensity score matching method (PSM). RESULTS: The LG group had a longer operation time, less estimated blood loss, less time to first flatus, less time to start liquid diet, less time to first ambulation, and shorter length of incision than the OG group. The conversion rates were 5.4% in the LG groups. There was no significant difference in the overall complication rate between the LG and OG groups. The 5-year overall survival (OS) and the 5-year disease-free survival (DFS) were comparable between the LG and OG groups (35.4% vs 32.1%, p = 0.541; 34.1% vs 31.0%, p = 0.523, respectively). There was no significant difference in the recurrence rate and pattern between the LG and OG groups. CONCLUSIONS: Laparoscopic gastrectomy is associated with better short-term outcomes and similar long-term outcomes for pT4a Siewert type II/III AEG. This study reveals that LG could be a safe and feasible option for pT4a Siewert type II/III AEG compared to OG.
Assuntos
Adenocarcinoma , Laparoscopia , Neoplasias Gástricas , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Junção Esofagogástrica/patologia , Junção Esofagogástrica/cirurgia , Gastrectomia/métodos , Humanos , Laparoscopia/métodos , Pontuação de Propensão , Estudos Retrospectivos , Membrana Serosa , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: This study was designed to compare the postoperative complications after Robotic total gastrectomy (RTG) and robotic distal gastrectomy (RDG) and to systematically evaluate the safety and feasibility of RTG for the treatment of gastric cancer (GC). METHODS: Patients with GC who underwent RTG or RDG for curative intent between March 2010 and August 2019 were analyzed. We used propensity score matching (PSM) to reduce selection bias. The morbidity and mortality within 30 days after surgery between the RTG and the RDG groups were compared. RESULTS: According to Clavien-Dindo (C-D) classification, the morbidity and mortality of the RTG group were comparable to those of the RDG group. Subgroup analyses showed no significant difference between the RTG and RDG groups in all stratified parameters (all P > .05). Multivariate analysis revealed that age ≥70 years (P = .002) and surgeons' experience ≤25 cases (P = .013) were independent risk factors for overall complication. Surgeons' experience ≤25 cases (P = .010) was identified as an independent risk factor for severe complication. CONCLUSION: RTG is a safe and feasible surgical procedure for the treatment of GC with acceptable morbidity and mortality. More complications were observed for RTG, indicating that RTG is more invasive than RDG.
Assuntos
Laparoscopia , Procedimentos Cirúrgicos Robóticos , Neoplasias Gástricas , Humanos , Idoso , Neoplasias Gástricas/cirurgia , Pontuação de Propensão , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Procedimentos Cirúrgicos Robóticos/métodos , Estudos Retrospectivos , Laparoscopia/métodos , Gastrectomia/efeitos adversos , Gastrectomia/métodos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Resultado do TratamentoRESUMO
Neutrophils are conspicuous components of gastric cancer (GC) tumors, increasing with tumor progression and poor patient survival. However, the phenotype, regulation and clinical relevance of neutrophils in human GC are presently unknown. Most intratumoral neutrophils showed an activated CD54+ phenotype and expressed high level B7-H3. Tumor tissue culture supernatants from GC patients induced the expression of CD54 and B7-H3 on neutrophils in time-dependent and dose-dependent manners. Locally enriched CD54+ neutrophils and B7-H3+ neutrophils positively correlated with increased granulocyte-macrophage colony stimulating factor (GM-CSF) detection ex vivo; and in vitro GM-CSF induced the expression of CD54 and B7-H3 on neutrophils in both time-dependent and dose-dependent manners. Furthermore, GC tumor-derived GM-CSF activated neutrophils and induced neutrophil B7-H3 expression via JAK-STAT3 signaling pathway activation. Finally, intratumoral B7-H3+ neutrophils increased with tumor progression and independently predicted reduced overall survival. Collectively, these results suggest B7-H3+ neutrophils to be potential biomarkers in GC.
Assuntos
Antígenos B7/metabolismo , Carcinoma/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Ativação de Neutrófilo , Neutrófilos/metabolismo , Neoplasias Gástricas/metabolismo , Adulto , Idoso , Carcinoma/patologia , Progressão da Doença , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Técnicas In Vitro , Molécula 1 de Adesão Intercelular/metabolismo , Janus Quinases/efeitos dos fármacos , Janus Quinases/metabolismo , Masculino , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Prognóstico , Fator de Transcrição STAT3/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Adulto JovemRESUMO
OBJECTIVE: Regulated in development and DNA damage responses-1 (REDD1) is a conserved and ubiquitous protein, which is induced in response to multiple stimuli. However, the regulation, function and clinical relevance of REDD1 in Helicobacter pylori-associated gastritis are presently unknown. APPROACH: Immunohistochemistry, real-time PCR and Western blot analyses were performed to examine the levels of REDD1 in gastric samples from H. pylori-infected patients and mice. Gastric tissues from Redd1-/- and wildtype (WT, control) mice were examined for inflammation. Gastric epithelial cells (GECs), monocytes and T cells were isolated, stimulated and/or cultured for REDD1 regulation and functional assays. RESULTS: REDD1 was increased in gastric mucosa of H. pylori-infected patients and mice. H. pylori induced GECs to express REDD1 via the phosphorylated cytotoxin associated gene A (cagA) that activated MAPKp38 pathway to mediate NF-κB directly binding to REDD1 promoter. Human gastric REDD1 increased with the severity of gastritis, and mouse REDD1 from non-marrow chimera-derived cells promoted gastric inflammation that was characterized by the influx of MHCII+ monocytes. Importantly, gastric inflammation, MHCII+ monocyte infiltration, IL-23 and IL-17A were attenuated in Redd1-/- mice. Mechanistically, REDD1 in GECs regulated CXCL1 production, which attracted MHCII+ monocytes migration by CXCL1-CXCR2 axis. Then H. pylori induced MHCII+ monocytes to secrete IL-23, which favored IL-17A-producing CD4+ cell (Th17 cell) polarization, thereby contributing to the development of H. pylori-associated gastritis. CONCLUSIONS: The present study identifies a novel regulatory network involving REDD1, which collectively exert a pro-inflammatory effect within gastric microenvironment. Efforts to inhibit this REDD1-dependent pathway may prove valuable strategies in treating of H. pylori-associated gastritis.
Assuntos
Citocinas/metabolismo , Mucosa Gástrica/microbiologia , Gastrite/microbiologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/patogenicidade , Células Th17/microbiologia , Fatores de Transcrição/metabolismo , Animais , Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Mucosa Gástrica/imunologia , Mucosa Gástrica/metabolismo , Gastrite/imunologia , Gastrite/metabolismo , Infecções por Helicobacter/complicações , Helicobacter pylori/imunologia , Helicobacter pylori/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Fenótipo , Fosforilação , Células Th17/imunologia , Células Th17/metabolismo , Fatores de Transcrição/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
BHLHE40, a member of the basic helix-loop-helix transcription factor family, has been reported to play an important role in inflammatory diseases. However, the regulation and function of BHLHE40 in Helicobacter pylori (H pylori)-associated gastritis is unknown. We observed that gastric BHLHE40 was significantly elevated in patients and mice with H pylori infection. Then, we demonstrate that H pylori-infected GECs express BHLHE40 via cagA-ERK pathway. BHLHE40 translocates to cell nucleus, and then binds to cagA protein-activated p-STAT3 (Tyr705). The complex increases chemotactic factor CXCL12 expression (production). Release of CXCL12 from GECs fosters CD4+ T cell infiltration in the gastric mucosa. Our results identify the cagA-BHLHE40-CXCL12 axis that contributes to inflammatory response in gastric mucosa during H pylori infection.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Quimiocina CXCL12/metabolismo , Células Epiteliais/metabolismo , Gastrite/microbiologia , Infecções por Helicobacter/metabolismo , Proteínas de Homeodomínio/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Linfócitos T CD4-Positivos/citologia , Núcleo Celular/metabolismo , Feminino , Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiologia , Gastrite/metabolismo , Regulação da Expressão Gênica , Helicobacter pylori , Humanos , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , Estômago/microbiologia , Regulação para CimaRESUMO
BACKGROUND AND AIM: Tubulointerstitial nephritis antigen-like 1 (TINAGL1), as a novel matricellular protein, has been demonstrated to participate in cancer progression, whereas the potential function of TINAGL1 in gastric cancer (GC) remains unknown. METHODS: The expression pattern of TINAGL1 in GC was examined by immunohistochemistry, ELISA, real-time polymerase chain reaction, and Western blot. Correlation between TINAGL1 and matrix metalloproteinases (MMPs) was analyzed by the GEPIA website and Kaplan-Meier plots database. The lentivirus-based TINAGL1 knockdown, CCK-8, and transwell assays were used to test the function of TINAGL1 in vitro. The role of TINAGL1 was confirmed by subcutaneous xenograft, abdominal dissemination, and lung metastasis model. Microarray experiments, ELISA, real-time polymerase chain reaction, and Western blot were used to identify molecular mechanism. RESULTS: TINAGL1 was increased in GC tumor tissues and associated with poor patient survival. Moreover, TINAGL1 significantly promoted GC cell proliferation and migration in vitro as well as facilitated GC tumor growth and metastasis in vivo. TINAGL1 expression in GC cells was accompanied with increasing MMPs including MMP2, MMP9, MMP11, MMP14, and MMP16. GEPIA database revealed that these MMPs were correlated with TINAGL1 in GC tumors and that the most highly expressed MMP was MMP2. Mechanically, TINAGL1 regulated MMP2 through the JNK signaling pathway activation. CONCLUSIONS: Our data highlight that TINAGL1 promotes GC growth and metastasis and regulates MMP2 expression, indicating that TINAGL1 may serve as a therapeutic target for GC.
Assuntos
Proliferação de Células/genética , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Expressão Gênica/genética , Lipocalinas/genética , Lipocalinas/metabolismo , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Metástase Neoplásica/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Regulação para Cima/genética , Regulação para Cima/fisiologia , Animais , Linhagem Celular , Movimento Celular/genética , Modelos Animais de Doenças , Progressão da Doença , Proteínas da Matriz Extracelular/fisiologia , Feminino , Humanos , Lipocalinas/fisiologia , Camundongos Nus , Terapia de Alvo Molecular , Neoplasias Gástricas/terapiaRESUMO
BACKGROUND: The robotic surgical system has several technical advantages over laparoscopic instruments. The technical feasibility and safety of robotic gastrectomy (RG) for gastric cancer have been reported by increasing number of studies. However, the long-term survival and recurrence outcomes after RG for locally advanced gastric cancer (AGC) have seldom been reported. This study aimed to compare long-term oncologic outcomes for patients with locally AGC after RG or laparoscopic gastrectomy (LG). METHODS: This study comprised 1170 patients underwent RG or LG, respectively, for locally AGC between March 2010 and February 2017. The primary outcome was the 3-year disease-free survival (DFS). The secondary endpoint included 3-year overall survival (OS) and recurrence patterns. One-to-one propensity score matching (PSM) was performed to reduce confounding bias. The outcomes were compared in PSM cohort. RESULTS: After PSM, a well-balanced cohort of 816 patients (408 in each group) were included in the analysis. The 3-year DFS rate was 76.2% in the robotic group and 70.1% in the laparoscopic group (P = 0.076). The 3-year OS rates was 76.7% in the robotic group and 73.3% in the laparoscopic group (P = 0.246). In the subgroup analyses for potential confounding variables, neither 3-year DFS nor 3-year OS survival were significantly different between the two groups (all P > 0.05). The two groups showed similar recurrence patterns within 3 years after surgery (P > 0.05). CONCLUSION: For patients with locally AGC, RG can result in comparable long-term survival outcomes without an increase in recurrence rate.
Assuntos
Laparoscopia , Procedimentos Cirúrgicos Robóticos , Neoplasias Gástricas , Gastrectomia , Humanos , Pontuação de Propensão , Estudos Retrospectivos , Neoplasias Gástricas/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: In this study, we investigated the incidence and risk factors for postoperative complications after robotic gastrectomy (RG) in patients with gastric cancer. METHODS: A total of 817 patients who underwent RG for gastric cancer between March 2010 and August 2019 were analyzed retrospectively. Postoperative complications were categorized according to the Clavien-Dindo classification, and possible risk factors were evaluated. RESULTS: Among 817 patients who underwent RG, overall, severe, local and systemic complication rates were 13.8, 4.2, 7.0 and 6.9%, respectively. Multivariable analysis revealed that an age of 70 years or older (P < 0.001) and multiorgan resection (P = 0.031) were independent risk factors for the occurrence of overall complications. Multivariable analysis showed that an age of 70 years or older (P = 0.005) and surgeons' experience ≤ 25 cases (P = 0.004) were independent risk factors for severe complications. Regarding local complications, an age of 70 years or older (P < 0.001), multiorgan resection (P = 0.010) and surgeons' experience ≤ 25 cases (P = 0.005) were identified as independent risk factors. An age of 70 years or older (P < 0.001), a BMI of 25 or higher (P = 0.045) and the presence of comorbidity (P = 0.029) were identified as independent risk factors for systemic complications. CONCLUSIONS: The present study demonstrated that RG is a safe and feasible procedure for the treatment of gastric cancer, and it has an acceptable postoperative morbidity. Elderly patients and insufficient surgeon experience were two major risk factors for the occurrence of complications following RG. We suggest that surgeons choose patients in good condition during their RG learning phase to reduce learning-associated morbidity.
Assuntos
Laparoscopia , Procedimentos Cirúrgicos Robóticos , Neoplasias Gástricas , Idoso , Gastrectomia/efeitos adversos , Humanos , Incidência , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de Risco , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Neoplasias Gástricas/cirurgiaRESUMO
BACKGROUND: Few studies have been designed to evaluate the short-term outcomes between robotic-assisted total gastrectomy (RATG) and laparoscopy-assisted total gastrectomy (LATG) for advanced gastric cancer (AGC). The purpose of this study was to assess the short-term outcomes of RATG compared with LATG for AGC. METHODS: We retrospectively evaluated 126 and 257 patients who underwent RATG or LATG, respectively. In addition, we performed propensity score matching (PSM) analysis between RATG and LATG for clinicopathological characteristics to reduce bias and compared short-term surgical outcomes. RESULTS: After PSM, the RATG group had a longer mean operation time (291.14 ± 59.18 vs. 270.34 ± 52.22 min, p = 0.003), less intraoperative bleeding (154.37 ± 89.68 vs. 183.77 ± 95.39 ml, p = 0.004) and more N2 tier RLNs (9.07 ± 5.34 vs. 7.56 ± 4.50, p = 0.016) than the LATG group. Additionally, the total RLNs of the RATG group were almost significantly different compared to that of the LATG group (34.90 ± 13.05 vs. 31.91 ± 12.46, p = 0.065). Moreover, no significant differences were found between the two groups in terms of the length of incision, proximal resection margin, distal resection margin, residual disease and postoperative hospital stay. There was no significant difference in the overall complication rate between the RATG and LATG groups after PSM (23.8% vs. 28.6%, p = 0.390). Grade II complications accounted for most of the complications in the two cohorts after PSM. The conversion rates were 4.55 and 8.54% in the RATG and LATG groups, respectively, with no significant difference (p = 0.145), and the ratio of splenectomy were 1.59 and 0.39% (p = 0.253). The mortality rates were 0.8 and 0.4% for the RATG and LATG groups, respectively (p = 1.000). CONCLUSION: This study demonstrates that RATG is comparable to LATG in terms of short-term surgical outcomes.