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Adenocarcinoma , Neoplasias Esofágicas , Neoplasias Primárias Múltiplas , Neoplasias Gástricas , Humanos , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/cirurgia , Estudos Retrospectivos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Neoplasias Gástricas/cirurgia , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Adenocarcinoma/cirurgia , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/terapia , Neoplasias Primárias Múltiplas/cirurgia , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Carcinoma de Células Escamosas do Esôfago/terapia , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/cirurgia , Gastrectomia/métodos , Terapia CombinadaRESUMO
BACKGROUND: Da Vinci Robotics-assisted total mesorectal excision (TME) surgery for rectal cancer is becoming more widely used. There is no strong evidence that robotic-assisted surgery and laparoscopic surgery have similar outcomes in elderly patients with TME for rectal cancer. AIM: To determine the improved oncological outcomes and short-term efficacy of robot-assisted surgery in elderly patients undergoing TME surgery. METHODS: A retrospective study of the clinical pathology and follow-up of elderly patients who underwent TME surgery at the Department of Gastrointestinal Oncology at the Affiliated Hospital of Nanjing University of Chinese Medicine was conducted from March 2020 through September 2023. The patients were divided into a robot-assisted group (the R-TME group) and a laparoscopic group (the L-TME group), and the short-term efficacy of the two groups was compared. RESULTS: There were 45 elderly patients (≥ 60 years) in the R-TME group and 50 elderly patients (≥ 60 years) in the L-TME group. There were no differences in demographics, conversion rates, or postoperative complication rates. The L-TME group had a longer surgical time than the R-TME group [145 (125, 187.5) vs 180 (148.75, 206.25) min, P = 0.005), and the first postoperative meal time in the L-TME group was longer than that in the R-TME (4 vs 3 d, P = 0.048). Among the sex and body mass index (BMI) subgroups, the R-TME group had better outcomes than did the L-TME group in terms of operation time (P = 0.042) and intraoperative assessment of bleeding (P = 0.042). In the high BMI group, catheter removal occurred earlier in the R-TME group than in the L-TME group (3 vs 4 d, P = 0.001), and autonomous voiding function was restored. CONCLUSION: The curative effect and short-term efficacy of robot-assisted TME surgery for elderly patients with rectal cancer are similar to those of laparoscopic TME surgery; however, robotic-assisted surgery has better short-term outcomes for individuals with risk factors such as obesity and pelvic stenosis. Optimizing the learning curve can shorten the operation time, reduce the recovery time of gastrointestinal function, and improve the prognosis.
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BACKGROUND: Neoadjuvant chemotherapy (NAC) is a frequently intervention for patients with locally advanced gastric cancer (GC). Nevertheless, its impact on the tumor immune microenvironment remains unclear. METHODS: We used immunohistochemistry to identify T-cell subpopulations, tumor-associated neutrophils (TANs), and tumor-associated macrophages (TAMs) in the GC microenvironment (GCME) among paired samples (pre-chemotherapy and post-chemotherapy) from 48 NAC-treated patients. Multiplex immunofluorescence (mIF) was performed to assess immune biomarkers, including CK, CD4, CD8, FOXP3, PD1, PD-L1, CD163, CD86, myeloperoxidase and Arginase-1 in paired samples from 6 GC patients whose response to NAC were rigorously defined. RESULTS: NAC was intricately linked to enhanced CD8+:CD4+ ratio, reduced CD163+ M2-like macrophages, augmented CD86+ M1: CD163+ M2-like macrophage ratio, and diminished FOXP3+ regulatory T cells (T-regs) and TANs density. Based on mIF, PD1+CD8+T-cells, FOXP3+T-regs, PD-L1+ TANs, and CD163+ M2-like macrophages exhibited marked reduction and greater co-localization with tumor cells following NAC. The pre-NAC FOXP3+ T-regs and CD163+ M2-like macrophages content was substantially elevated in the response cohort, whereas, the post-NAC CD8+:CD4+ and CD86+ M1: CD163+ M2-like macrophage ratios were intricately linked to the tumor pathologic response. We observed greater CD163+ M2-like macrophages and tumor cells co-localization following NAC, which was correlated with tumor pathologic response. Lastly, multivariate analysis revealed that post-NAC CD8+:CD4+ and CD86+ M1: CD163+ M2-like macrophage ratios were stand-alone indicators of positive patient prognosis. CONCLUSIONS: NAC converts the GCME to an anti-tumorigenic state that is conducive to enhanced patient outcome. These finding can significantly benefit the future planning of highly efficacious and personalized GC immunotherapy.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Antígeno B7-H1 , Terapia Neoadjuvante , Biomarcadores , Prognóstico , Carcinogênese , Fatores de Transcrição Forkhead , Microambiente TumoralRESUMO
In gastric cancer, lymph node metastasis (LNM) is the major metastasis route, and lymphatic invasion is the precursor of LNM. Tumor-associated neutrophils (TANs) promote LNM. However, the molecular mechanisms underlying TANs-mediated lymphatic invasion and/or LNM remain unclear. Herein, we revealed that high level of TANs was the independent risk factor for lymphatic invasion and LNM respectively, and lymphatic tumor cell-neutrophil clusters were positively correlated with LNM. Crosstalk between neutrophils and tumor cells was required for enhanced tumor cell invasiveness, endowing neutrophils to boost epithelial-to-mesenchymal transition (EMT) of tumor cells and in turn promoting LNM. Mechanically, tumor cells educated neutrophils via TGFß1 to produce more FAM3C through Smad2/3 signaling activation, and FAM3C promoted tumor cell EMT through JNK-ZEB1/Snail signaling pathway. The crosstalk enhanced the affinity of neutrophils with tumor cells through interaction of integrins α6ß1 and α6ß4 with CD151. Furthermore, studies using tumor-bearing mice demonstrated that neutrophils were the important driver for gastric cancer tumorigenesis and invasiveness. The study clearly identifies the functional roles of TANs in promoting tumor invasion, and facilitates a better understanding of novel mechanisms responsible for LNM of gastric cancer, which provides potential targets for developing new strategies to prevent or treat LNM in gastric cancer.
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Transição Epitelial-Mesenquimal , Invasividade Neoplásica , Proteínas de Neoplasias , Neutrófilos , Neoplasias Gástricas , Neoplasias Gástricas/patologia , Humanos , Proteínas de Neoplasias/metabolismo , Citocinas/metabolismo , Transdução de Sinais , Linhagem Celular Tumoral , Animais , Camundongos , Camundongos Endogâmicos C57BL , Masculino , Feminino , Pessoa de Meia-Idade , IdosoRESUMO
BACKGROUND: Perioperative chemotherapy has been accepted as one of the most common approaches for locally advanced gastric cancer. However, the efficacy of chemotherapy varies among patients, and there is no effective method to predict the chemotherapy efficacy currently. We previously established the first larval zebrafish patient-derived xenografts (zPDXs) of gastric cancer as a platform for the translational research and personalized treatment. The objective of this study was to investigate the feasibility of screening individualized chemotherapeutics using the zPDXs. METHODS: We further optimized this zPDXs platform including administration route, drug dosing, and rhythm to develop a stable and reliable protocol for chemotherapeutics screening. Using the novel platform, we investigated the chemosensitivity of 5-fluorouracil, cisplatin, docetaxel, and doxorubicin for gastric cancer patients. RESULTS: We showed that the engrafted zebrafish retained the original prominent cell components of the corresponding human tumor tissues, and we successfully obtained the results of chemosensitivity of 5-fluorouracil, cisplatin, docetaxel, and doxorubicin for 28 patients with locally advanced gastric cancer. These patients underwent radical gastrectomy for curative intent and 27 cases received postoperative adjuvant chemotherapy. We revealed that the chemosensitivity obtained from zPDXs was consistent with the clinical responses in these patients (P = 0.029). More importantly, the responder drug(s) from zPDXs used or not was the only risk factor for early-stage recurrence in these 27 patients (P = 0.003). CONCLUSION: Our study with the largest sample size so far suggests that larval zPDXs help to predict the chemotherapeutics response and to achieve precise chemotherapy for gastric cancer.
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ADP-ribosylation factor 3 (ARF3) has confirmed participate in diverse biological processes in many cancers. However, the expression patterns and roles of ARF3 in gastric cancer (GC) remains largely unknown. In our study, by using qRT-PCR and western blot, we found that, in In GC tissues and cells, the expression of ARF3 was significantly down-regulated. Functional experiments demonstrated that ARF3 inhibited proliferation, induced cycle arrest and enhanced apoptosis of GC cells. Moreover, by performing western blot, we found that ARF3 could regulate the protein expression of key factors of AKT and ERK pathway. Using orthotopic xenograft mouse models, it is showed that ARF3 could inhibit GC tumorigenesis in vivo. To sum up, ARF3 may suppress proliferation, induced cycle arrest and promotes apoptosis of GC by modulating AKT and ERK pathway. It might act as a potential biomarker for GC prognosis.
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Fatores de Ribosilação do ADP/metabolismo , Apoptose , Proliferação de Células , Sistema de Sinalização das MAP Quinases , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/patologia , Animais , Biomarcadores Tumorais/metabolismo , Carcinogênese , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Regulação para Baixo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , RNA Mensageiro/metabolismo , Neoplasias Gástricas/metabolismoRESUMO
BACKGROUND: Pathogens capable of impacting gastrointestinal tract tumor development are located in the oral cavity, but whether these oral bacteria are able to colonize the gastric mucosa in gastric cancer (GC) patients and whether Helicobacter pylori infection can influence this process remains to be established. METHODS: Microbial 16S rDNA deep sequencing was conducted to characterize bacteria present in paired gastric mucosa and tongue coating samples in 27 patients with superficial gastritis (SG) and 11 GC patients. RESULTS: While the overall composition of the gastric mucosa and tongue coating microbiomes differed substantially, certain bacteria were present in both of these communities. The co-occurrence of bacteria between the tongue coating and gastric mucosa differed significantly between SG and GC patients. Of the 15 most abundant shared oral bacteria genera (the core shared oral bacteria), which were associated with differences in microbiota composition between these tongue coating and gastric mucosa, three were enriched in the gastric mucosa of GC patients relative to SG patients, whereas, 12 were depleted in GC patient samples. Furthermore, the prevalence and relative abundance of these core shared oral bacteria in the gastric mucosa were also linked to H. pylori infection status, and the core shared oral bacteria were also associated with the overall composition of the gastric mucosal microbiome. CONCLUSIONS: Helicobacter pylori infections are linked to the co-occurrence of bacteria in the oral microbiome and the gastric mucosal microbiome. Ectopic colonization of oral microbes may be a primary driver of H. pylori-induced gastric microbial dysbiosis in patients with GC.
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Infecções por Helicobacter , Helicobacter pylori , Mucosa Gástrica , Helicobacter pylori/genética , Humanos , Boca , RNA Ribossômico 16SRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Normalization of the tumor vasculature can enhance tumor perfusion and the microenvironment, leading to chemotherapy potentiation. Shenmai injection (SMI) is a widely used traditional Chinese herbal medicine for the combination treatment of cancer in China. AIM OF THIS STUDY: This study aimed to investigate whether SMI can regulate tumor vasculature to improve chemotherapy efficacy and identify the underlying mechanism. MATERIALS AND METHODS: The antitumor effect of SMI combined with 5-florouracil (5-FU) was investigated in xenograft tumor mice. Two-photon microscopy, laser speckle contrast imaging and immunofluorescence staining were used to investigate the effects of SMI on tumor vasculature in vivo. The mRNA and protein expression of pro- and anti-angiogenic factors were measured by Q-PCR and ELISA. Histone acetylation and transcriptional regulation were detected by Western blot and ChIP assay. RESULTS: SMI promoted normalization of tumor microvessels within a certain time window, which was accompanied by enhanced blood perfusion and 5-FU distribution in tumors. SMI significantly increased the expression of antiangiogenic factor angiostatin and decreased the pro-angiogenic factors VEGF, FGF and PAI-1 by day 10. SMI combined with neoadjuvant chemotherapy in colorectal cancer patients also showed a significant increase in angiostatin and decrease in VEGF and FGF in surgically resected tumors when compared to the neoadjuvant chemotherapy group. Further in vitro and in vivo studies revealed that SMI downregulated VEGF, FGF and PAI-1 mRNA expression by inhibiting histone H3 acetylation at the promoter regions. The enhanced production of angiostatin was attributed to the regulation of the plasminogen proteolysis system via SMI-induced PAI-1 inhibition. CONCLUSION: SMI can remodel the homeostasis of pro- and anti-angiogenic factors to promote tumor vessel normalization, and thus enhance drug delivery and anti-tumor effect. This study provides additional insights into the pharmacological mechanisms of SMI on tumors from the perspective of vascular regulation.
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Inibidores da Angiogênese/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Homeostase/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Angiostatinas/biossíntese , Animais , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Terapia Combinada , Combinação de Medicamentos , Medicamentos de Ervas Chinesas/farmacologia , Fluoruracila/administração & dosagem , Fluoruracila/farmacologia , Histonas/antagonistas & inibidores , Histonas/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Inibidor 1 de Ativador de Plasminogênio/genética , Receptores de Fatores de Crescimento de Fibroblastos/genética , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: How gastric cancer (GC) incidence is associated with changes in the gastric microbiome has not been firmly established. The present study therefore aims to investigate the microbial communities present within the gastric mucosa of patients with superficial gastritis (SG) or GC. METHODS: Paired tumor and paracancerous samples of the gastric mucosa were collected from 18 patients being surgically treated for GC and from 32 patients with SG being treated via gastroscopy. The gastric microbiome in these samples was then profiled via 16S rRNA sequencing, with a linear discriminant analysis effect size (LEfSe) approach used to identify and compare different bacteria, and with PICRUSt used for predictive functional analyses. RESULTS: GC patients exhibited a distinct gastric microbiota profile from that observed in SG patients. These changes were evident in both tumor and paracancerous tissues from GC patients. Specifically, we found that 6 bacterial genera were specifically enriched in GC tissue samples relative to SG samples, while 18 genera were depleted in these same samples. Based on the differential abundance of these bacteria, we were able to calculate microbial dysbiosis index (MDI) values, which were significantly higher in GC patients than in SG patients. In addition, MDI values were negatively correlated with gastric Shannon index and were positively correlated with relative Helicobacter spp. abundance. Importantly, these MDI values were readily able to discriminate between GC and SG patient samples. Functional analysis suggested that GC patients were more likely to harbor a nitrosating microbial community. CONCLUSIONS: GC patients exhibited a gastric microbiome profile distinct from that observed in SG patients, with these differences being evident in both tumor and paracancerous tissues. Differences in the relative abundance of Helicobacter spp. may be the primary driver of gastric dysbiosis in GC patients.
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Bactérias/isolamento & purificação , Mucosa Gástrica/microbiologia , Gastrite/microbiologia , Microbioma Gastrointestinal , Lesões Pré-Cancerosas/microbiologia , Neoplasias Gástricas/microbiologia , Idoso , Bactérias/genética , Biópsia , Disbiose , Feminino , Gastrectomia , Mucosa Gástrica/patologia , Mucosa Gástrica/cirurgia , Gastrite/patologia , Gastrite/cirurgia , Gastroscopia , Humanos , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/patologia , Lesões Pré-Cancerosas/cirurgia , Ribotipagem , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgiaRESUMO
Shenmai injection (SMI) is a well-defined herbal preparation that is widely and clinically used as an adjuvant therapy for cancer. Previously, we found that SMI synergistically enhanced the activity of chemotherapy on colorectal cancer by promoting the distribution of drugs in xenograft tumors. However, the underlying mechanisms and bioactive constituents remained unknown. In the present work, the regulatory effects of SMI on tumor vasculature were determined, and the potential anti-angiogenic components targeting tumor endothelial cells (TECs) were identified. Multidimensional pharmacokinetic profiles of ginsenosides in plasma, subcutaneous tumors, and TECs were investigated. The results showed that the concentrations of protopanaxadiol-type (PPD) ginsenosides (Rb1, Rb2/Rb3, Rc, and Rd) in both plasma and tumors, were higher than those of protopanaxatriol-type (Rg1 and Re) and oleanane-type (Ro) ginsenosides. Among PPD-type ginsenosides, Rd exhibited the greatest concentrations in tumors and TECs after repeated injection. In vivo bioactivity results showed that Rd suppressed neovascularization in tumors, normalized the structure of tumor vessels, and improved the anti-tumor effect of 5-fluorouracil (5FU) in xenograft mice. Furthermore, Rd inhibited the migration and tube formation capacity of endothelial cells in vitro. In conclusion, Rd may be an important active form to exert the anti-angiogenic effect on tumor after SMI treatment.
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The consensus of endoscopic therapy for early gastric cancer (EGC) mainly depends on its clinicopathological features. However, the roles of tumor-associated neutrophils (TANs) in EGC remain uncertain. Here, we explored its predictive role for lymph node metastasis (LNM) in EGC. Three hundred twenty-two patients who underwent radical gastrectomy for EGC were enrolled. Preoperative peripheral blood was used to analyze the neutrophil-to-lymphocyte ratio (NLR), and the different status of TANs was determined by hematoxylin-and-eosin staining (H&E) and immunohistochemistry (IHC). TANs, rather than NLR, were positively associated with tumor size, Lauren classification, lymphovascular invasion (LVI), and LNM. Univariate analysis revealed that TANs were associated with LNM as well as tumor size, depth of invasion, Lauren classification, histological classification, LVI, and perineural invasion. In addition to histological classification and LVI, TANs were found to be an independent risk factor for LNM in EGC (P = 0.013). Stratification analysis by depth of invasion showed LVI in SM1 tumor, and both LVI and TANs (P = 0.042) in SM2 tumor were independent risk factors for LNM. In conclusion, TANs in EGC can predict LNM, and TANs may help to estimate LNM precisely in addition to the current criteria.
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BACKGROUND: LncRNAs act as functional regulators in tumor progression through interacting with various signaling pathways in multiple types of cancer. However, the effect of LINC02418 on colorectal cancer (CRC) progression and the underling mechanisms remain unclear. METHODS: LncRNA expression profile in CRC tissues was investigated by the TCGA database. The expressional level of LINC02418 in CRC patients was determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Kaplan-Meier analyses was used to investigate the correlation between LINC02418 and overall survival (OS) of CRC patients. Cell proliferative, migratory and invasive abilities were detected by CCK-8 assays, colony formation assays and trans-well assays in HCT116 and LoVo cells which were stably transduced with sh-LINC02418 or sh-NC. The binding between LINC02418 and miR-34b-5p, and the interaction between miR-34b-5p and BCL2 were determined by dual-luciferase assays. Western blot experiments were conducted to further explore the effect of miR-34b-5p on BCL2 signaling pathway. Rescue experiments were performed to uncover the role of LINC02418/miR-34b-5p/BCL2 axis in CRC progression. RESULTS: LINC02418 was upregulated in human colon cancer samples when compared with adjacent tissue, and its high expressional level correlated with poor prognosis of CRC patients. LINC02418 promoted cancer progression by enhancing tumor growth, cell mobility and invasiveness of colon cancer cells. Additionally, LINC02418 could physically bind to miR-34b-5p and subsequently affect BCL2 signaling pathway. Down-regulation of LINC02418 reduced cell proliferation, while transfection of miR-34b-5p inhibitor or BCL2 into LINC02418-silenced CRC cells significantly promoted CRC cells growth. CONCLUSIONS: LINC02418 was upregulated in human CRC samples and could be used as the indicator for prediction of prognosis. LINC02418 acted as a tumor driver by negatively regulating cell apoptosis through LINC02418/miR-34b-5p/BCL2 axis in CRC.
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Cancer-associated fibroblasts (CAFs) play a major role in the progression of stomach cancer, but the related mechanisms are not fully understood. H. pylori infection is recognized as one of the strongest risk factors for gastric carcinoma, but its effects on CAFs remain unknown. We aimed to determine the causative relationship between H. pylori infection in fibroblasts and the promoted cancer pathogenesis and progression in gastric cancer. Primary CAFs and normal activated fibroblasts (NAFs) were generated from gastric cancer patients. Gene signature of H. pylori-infected human stomach fibroblasts was performed using the RNA-seq analysis. Spheroid cell invasion assay and zebrafish cell line-derived xenograft (zCDX) model were introduced to evaluate tumor invasion induced by CAFs. The molecule interactions were determined using the kinetic binding analysis with the Biolayer Interferometry (BLI). Clinical significance and relevance were also assessed using the database analyses. H. pylori infection activated stomach fibroblasts and caused multiple gene alterations, including vascular adhesion molecule 1 (VCAM1). H. pylori infection increased VCAM1 expression in CAFs in gastric carcinoma via activation of JAK/STAT1 signaling pathway, and VCAM1 levels were positively associated with tumor progression and dismal prognosis in stomach cancer patients. Furthermore, CAFs-derived VCAM1 molecularly interacted with integrin αvß1/5 in gastric cancer cells facilitated tumor invasion in vitro and in vivo. Our results identify a novel mechanism underlying CAFs to promote tumor invasion during H. pylori infection. These studies facilitate us for a better understanding of the molecular process of gastric carcinoma progression, and provide the potential strategies for gastric cancer therapy.
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Fibroblastos Associados a Câncer/metabolismo , Infecções por Helicobacter/metabolismo , Helicobacter pylori/patogenicidade , Invasividade Neoplásica/fisiopatologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/microbiologia , Molécula 1 de Adesão de Célula Vascular/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Transição Epitelial-Mesenquimal/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Infecções por Helicobacter/microbiologia , Humanos , Transdução de Sinais/fisiologia , Estômago/microbiologia , Estômago/patologia , Neoplasias Gástricas/patologiaRESUMO
Chemoresistance remains the major obstacle to achieve optimal prognosis in gastric cancer patients, and the underlying molecular mechanisms of cancer-associated fibroblasts (CAFs) in gastric cancer chemoresistance remain poorly understood. We identified the high pretherapeutical serum IL-8 level in gastric cancer patients was associated with poor response to platinum-based therapy, and it increased gradually during neoadjuvant chemotherapy and it decreased after radical surgery. Immunohistochemistry assays showed that IL-8 was highly expressed in gastric cancer tissues in chemoresistant patients, and located in CAFs. Primary CAFs produced more IL-8 than the corresponding normal fibroblasts, and human stomach fibroblast line Hs738 secreted more IL-8 after co-cultured with conditioned media from AGS or MGC-803â¯cells. IL-8 increased the IC50 of cisplatin (CDDP) in AGS or MGC-803 in vitro. Simultaneously, IL-8 treatment enhanced the expression of PI3K, phosphorylated-AKT (p-AKT), phosphorylated-IKb (p-IKb), phosphorylated-p65 (p-p65) and ABCB1, and ABCB1 and p-p65 were overexpressed in tumor tissues of chemoresistant patients. Collectively, CAFs derived IL-8 promotes chemoresistance in human gastric cancer via NF-κB activation and ABCB1 up-regulation. Our study provides a novel strategy to improve the chemotherapeutical efficacy and the prognosis of gastric cancer.
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Fibroblastos Associados a Câncer/metabolismo , Cisplatino/farmacologia , Interleucina-8/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacologia , Fibroblastos Associados a Câncer/patologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Interleucina-8/biossíntese , Interleucina-8/sangue , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Neoplasias Gástricas/sangue , Neoplasias Gástricas/patologia , Microambiente Tumoral , Regulação para CimaRESUMO
BACKGROUND: The patients with hepatocellular carcinoma (HCC) have poor prognosis due to being diagnosed at late stage or recurrence following surgery. It's critical to identify effective biomarkers that can improve overall diagnosis and treatment of HCC. METHODS: We performed a meta-analysis of all relative studies reporting the clinicopathological significance of CDH1 hypermethylation in HCC by using Review Manager 5.2. A comprehensive literature search was performed in EMBASE, PubMed, Web of Science and Google Scholar databases. Kaplan Meier Plotter online database was used for the determination of correlation between CDH1 mRNA expression and overall survival in patients with HCC. Odds Ratios (OR) with 95% corresponding confidence intervals (CIs) were calculated. A total of 12 relevant studies were included in the meta-analysis with 981 patients. RESULTS: The positive rate of CDH1 hypermethylation was significantly higher in HCC than in normal liver tissue; and the pooled OR was 4.34 with 95% CI 2.50-7.56, P<0.00001. CDH1 promoter in HCC was more frequently hypermethylated compared to the group of chronic liver disease (CLD); OR was 4.83 with 95% CI 2.67-8.72, P<0.00001. However, the rate of CDH1 promoter hypermethylation was not correlated with different grades as well as stages. High CDH1 mRNA expression was significantly correlated to better overall survival in all 231 HCC patients compared to 133 HCC patients with low level CDH1 mRNA expression; HR was 0.6 with 95% CI 0.42-0.85, P=0.0034. CONCLUSION: In summary, CDH1 promoter hypermethylation is a risk factor and promising biomarker for HCC carcinogenesis and diagnosis, as well as a predictor of poor prognosis.
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Bevacizumab (Bv) can be used synergistically with fluoropyrimidine-based chemotherapy to treat colorectal cancer. Whether and how it affects the delivery of fluoropyrimidine drugs is unknown. The present study aimed to explore the effect of Bv on the delivery of 5-fluorouracil (5-FU) to tumors and the underlying mechanism from metabolic perspective. Bv enhanced the anti-tumor effects of 5-FU in LoVo colon cancer xenograft mice and increased the 5-FU concentration in tumors without affecting hepatic 5-FU metabolism. Interestingly, Bv remarkably upregulated thymidine phosphorylase (TP) in tumors, which mediated the metabolic activation of 5-FU. Although TP is reported to promote angiogenesis and resistance, the combination of Bv and 5-FU resulted in anti-angiogenesis and vessel normalization in tumors, indicating that the elevated TP mainly contributed to the enhanced response to 5-FU. Bv also induced TP upregulation in LoVo cancer cells. Treatment with vascular endothelial growth factor receptor 2 (VEGFR2) antagonist apatinib and VEGFR2 silencing further confirmed TP upregulation. Bv and apatinib both enhanced the cytotoxicity of 5-FU in LoVo cells, but there was no synergism with adriamycin and paclitaxel. We further demonstrated that the effect of Bv was dependent on VEGFR2 blockade and specificity protein 1 activation via MDM2 inhibition. In summary, Bv enhanced the accumulation of 5-FU in tumors and the cytotoxicity of 5-FU via TP upregulation. We provide data to better understand how Bv synergizes with 5-FU from metabolic perspective, and it may give clues to the superiority of Bv in combination with fluoropyrimidine drugs compared to other chemotherapeutic drugs in colon cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Bevacizumab/farmacologia , Neoplasias do Colo/tratamento farmacológico , Fluoruracila/farmacologia , Transdução de Sinais/efeitos dos fármacos , Timidina Fosforilase/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Sinergismo Farmacológico , Fluoruracila/uso terapêutico , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Piridinas/farmacologia , Piridinas/uso terapêutico , Fator de Transcrição Sp1/metabolismo , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Colorectal cancer is currently the third most common cancer in males and the second in females worldwide. In spite of marked progress having been achieved in surgical resection, radiotherapy and chemotherapy, the prognosis for patients with colorectal cancer remains poor. Previous studies have demonstrated that the abnormal expression of microRNAs contributed to human cancer carcinogenesis and progression, suggesting miRNAs as novel therapeutic targets in colorectal cancer. The aim of the present study was to investigate the expression, functions and underlying molecular mechanisms of microRNA-184 (miR-184) in colorectal cancer. The results identified that miR-184 was significantly downregulated in colorectal cancer tissues and cell lines. In vitro functional studies demonstrated that miR-184 significantly inhibited colorectal cancer cell proliferation, migration and invasion. Notably, insulin-like growth factor 1 receptor (IGF-1R) was identified as a direct target of miR-184 in colorectal cancer. Furthermore, the functions of IGF-1R small interfering RNA were similar to those induced by miR-184 in colorectal cancer, suggesting IGF-1R as a functional target of miR-184 in colorectal cancer. The results of the present study indicated that miR-184 may be a novel therapeutic strategy regimen of targeted therapy for colorectal cancer.
RESUMO
Development of cancer metastasis is a key contributor to mortality in patients with colorectal cancer. High expression of RING-box 2 (RBX2) in cancer cells is known to play a key role in tumor progression. However, the role of RBX2 in colorectal cancer progression is not well elucidated. In this study, we silenced RBX2 via CRISPR/Cas9 in two colorectal cancer cell lines, HCT116 and SW480. RBX2 knockout attenuated proliferation, colony formation and enhanced sensitivity of colorectal cancer cells to paclitaxel treatment. Invasive property of HCT116 and SW480 cells was also attenuated by RBX2 silencing. We confirmed that increased RBX2 correlated with higher tumor cells growth and metastasis abilities by ectopic expression of RBX2 in HCT116 and SW480 cells. In vivo studies suggested that knockout of RBX2 inhibited xenografts growth and metastasis to lung tissue, whereas ectopic expression of RBX2 promoted these cellular functions. Mechanically, RBX2 induced gastric cancer cell growth and metastasis by activating mammalian target of rapamycin/S6 kinase 1 (mTOR/S6K1). Treatment of everolimus, the specific mTOR inhibitor, significantly attenuated RBX2-mediated cell proliferation and mobility in vitro. Taken together, these results revealed a novel role of RBX2 in colorectal cancer cell growth and metastasis via the mTOR pathway and suggested RBX2 may serve as a therapeutic target in colorectal cancer.
RESUMO
Colorectal cancer is one of the major health problems, with invade surrounding tissues, and migrate to distant organs being the most critical concern, thus identified metastasis associated hallmarks and more efficacious treatment are urgently needed. It found that forkhead box q1 (FOXQ1) is aberrant expression in variety of human cancers and FOXQ1 is involved in oncogenic pathways. However, the role of FOXQ1 has been unexplored in colorectal cancer metastasis to date. Here, expression of FOXQ1 was higher in colorectal cancer tissue samples and cancer cell lines than in normal colorectal tissue and cell lines. Further research suggested that FOXQ1 positively regulated cell proliferation in colorectal cancer and down-regulation of CDK6, extracellular regulated protein kinases 1/2 (ERK1/2) and mammalian target of rapamycin (mTOR). In corresponding to this result, over-expression of FOXQ1 significantly promoted colorectal cancer growth in vivo. Moreover, down regulation of FOXQ1 expression in colorectal carcinoma cell HCT116 and LOVO strikingly inhibits tumor growth in vivo. Finally, FOXQ1-dependent inhibition of colorectal cancer cell migration and invasion and down-regulation of focal adhesion kinase (FAK), phosphatidyl inositol 3-kinase (PI3K) phosphorylation, AKT (v-akt murine thymoma viral oncogene) phosphorylation and matrix metalloproteinase-2/9 (MMP-2/9) expression. These integrated efforts have identified FOXQ1 as a tumor promoter and might provide promising approaches for colorectal cancer metastasis treatment.