RESUMEN
The long non-coding RNA p21 (lncRNA-p21) was a tumor suppressor gene in most cancer types including gastric cancer (GC). We aimed to identify a specific lncRNA-p21-involved pathway in regulating the proliferation and apoptosis of GC cells. A lower lncRNA-p21 expression in tumors was associated with advanced disease stage and predicted worse survival of GC patients. LncRNA-p21 overexpression in GC cell line somatic gastric cancer (SGC)-7901 and human gastric cancer (HGC)-27 suppressed cell proliferation and enhanced apoptosis, while lncRNA-p21 knockdown caused the opposite effects. Through bioinformatics analysis and luciferase-based reporter assays, we identified miR-514b-3p as a sponge target of lncRNA-p21. Cdc42 guanine nucleotide exchange factor 9 (ARHGEF9), functioned as a tumor suppress factor in GC, was found as the downstream target of miR-514-3p, and their expressions were negatively correlated in GC tumor tissues. In addition, like lncRNA-p21 overexpression alone, miR-514-3p inactivation alone also led to decreased proliferation and increased apoptosis in SGC-7901 and HGC-27 cells, which were markedly attenuated by additional ARHGEF9 knockdown. Xenograft SGC-7901 cells with more lncRNA-p21 or ARHGEF9 expressions or with less miR-514-3p expression exhibited obviously slower in vivo growth than the control SGC-7901 cells in nude mice. Our study reveals a novel lncRNA-p21/miR-514b-3p/ARHGEF9 pathway that can be targeted for GC therapy.
Asunto(s)
MicroARNs , ARN Largo no Codificante , Factores de Intercambio de Guanina Nucleótido Rho , Neoplasias Gástricas , Animales , Apoptosis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Ratones Desnudos , MicroARNs/genética , MicroARNs/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Factores de Intercambio de Guanina Nucleótido Rho/genética , Factores de Intercambio de Guanina Nucleótido Rho/metabolismo , Neoplasias Gástricas/metabolismoRESUMEN
PURPOSE: Targeting DNA repair mechanisms to induce apoptosis may be a promising strategy for breast cancer treatment. Olaparib is proved to have anticancer effect by inhibiting DNA repairing protein poly (ADP-ribose) polymerase (PARP). However, the cytotoxicity of olaparib is very limited to homologous recombination-proficient cells. This study aims to examine the effect and mechanism of olaparib treatment in breast cancer cell lines. METHODS: We investigated the cytotoxic effect of various doses of olaparib treatment to MCF-7 and ZR-75-1 cells in vitro. mRNA and protein levels of PARP and APE1 were examined by real-time PCR and western blot, respectively. APE1-deficient cell lines were created by RNA interference and used for in vitro cytotoxicity study as well as in vivo study. RESULTS: 2 µM or higher concentrations of olaparib lead to significant cell death and ROS production. Moreover, olaparib treatment not only inhibits PARP1, but also reduces the expression of APE1 in both mRNA and protein levels. Deficiency of APE1 resulted in increased sensitivity of MCF-7 and ZR-75-1 cells to olaparib treatment. In vivo study showed that reduction of APE1 significantly reduced the volume and weight of MCF-7 xenografted tumors when treated with olaparib, which suggests the synergistic function of inhibition of APE1 in promoting antitumor effects of olaparib treatment. CONCLUSION: To acquire better benefits for HR-proficient breast cancer patients, developing chemotherapeutic drugs antagonize APE1 would be an effective strategy to improve the clinical outcome of PARP inhibitors.
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Neoplasias de la Mama/genética , ADN-(Sitio Apurínico o Apirimidínico) Liasa/genética , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ftalazinas/farmacología , Piperazinas/farmacología , Poli(ADP-Ribosa) Polimerasa-1/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Especies Reactivas de Oxígeno/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: To assess the efficacy of neoadjuvant endocrine therapy in female HR-positive/HER2-negative breast cancer patients. DATA AND METHODS: We identified female patients aged ≥18 years with cT1-4N0-XM0, HR(+), and HER2(-) breast cancer from the National Cancer Database. The patients who underwent surgery first were categorized as "surgery-first," while those who received NET before surgery were classified as "NET." Propensity score-matching, Cox proportional-hazard model, variance inflation factors, and interaction analysis were employed to estimate the correlation between NET and survival outcomes. RESULTS: Among 432,387 cases, 2914 NET patients and 2914 surgery-first patients were matched. Compared with the surgery-first group, the NET group received less adjuvant chemotherapy (p < 0.001). Furthermore, the NET group exhibited higher survival probabilities compared with the surgery-first group (3 years: 91.4% vs. 82.1%; 5 years: 82.1% vs. 66.8%). Multivariate Cox analysis indicated that NET was associated with improved OS (surgery-first vs. NET: HR 2.17, 95% CI: 1.93-2.44). Age over 55 years old, having public insurance, higher CDCC score, higher NSBR grade, ER(+)PR(-), and advanced clinical stage were related to worse OS (all p < 0.05). There was an interaction between age, race, income, and home and treatment regimen (all p < 0.05). CONCLUSION: NET may be a more effective treatment procedure than surgery-first in female HR-positive/HER2-negative, non-metastatic breast cancer patients. Future clinical studies with more detailed data will provide higher-level evidence-based data.
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Neoplasias de la Mama , Terapia Neoadyuvante , Receptor ErbB-2 , Humanos , Femenino , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/cirugía , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/terapia , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Receptor ErbB-2/metabolismo , Anciano , Adulto , Resultado del Tratamiento , Antineoplásicos Hormonales/uso terapéutico , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Mastectomía , Quimioterapia Adyuvante/métodosRESUMEN
Glioblastoma multiforme (GBM) is highly invasive, with a high recurrence rate and limited treatment options, and is the deadliest glioma. Exosomes (Exos) have attracted much attention in the diagnosis and treatment of GBM and are expected to address the severe limitations of biopsy conditions. Exos in the cerebrospinal fluid (CSF) have great potential in GBM dynamic monitoring and intervention strategies. Here, we evaluated the difference in the proteome information of Exos from the CSF (CSF-Exos) between GBM patients and low-grade glioma patients, and the correlations between GBM-CSF-Exos and immunosuppressive properties. Our results indicates that GBM-CSF-Exos contained a unique protein, LGALS9 ligand, which bound to the TIM3 receptor of dendritic cells (DCs) in the CSF to inhibit antigen recognition, processing and presentation by DCs, leading to failure of the cytotoxic T-cell-mediated antitumor immune response. Blocking the secretion of exosomal LGALS9 from GBM tumors could cause mice to exhibit sustained DC tumor antigen-presenting activity and long-lasting antitumor immunity. We concluded that GBM cell-derived exosomal LGALS9 acts as a major regulator of tumor progression by inhibiting DC antigen presentation and cytotoxic T-cell activation in the CSF and that loss of this inhibitory effect can lead to durable systemic antitumor immunity.
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Presentación de Antígeno , Neoplasias Encefálicas/inmunología , Células Dendríticas/inmunología , Exosomas/inmunología , Galectinas/líquido cefalorraquídeo , Glioblastoma/inmunología , Animales , Antígenos de Neoplasias/inmunología , Neoplasias Encefálicas/líquido cefalorraquídeo , Carcinogénesis/inmunología , Línea Celular Tumoral , Técnicas de Inactivación de Genes , Glioblastoma/líquido cefalorraquídeo , Receptor 2 Celular del Virus de la Hepatitis A/inmunología , Humanos , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Proteómica , Linfocitos T Citotóxicos/inmunologíaRESUMEN
Gastric cancer ranks as the third most lethal cancer worldwide. Although many efforts have been made to identify novel markers for early diagnosis and effective drugs for the treatment of gastric cancer, the outcome is still poor due to delayed diagnosis and lack of therapeutic options. MicroRNAs (miRNAs) play crucial roles during tumorigenesis, and several miRNAs were found to be critical for gastric cancer development, offering promise as therapeutic targets. The results of this study indicate that a novel miRNA, miR-1292-5p, is downregulated both in gastric carcinoma in vivo and in gastric cancer cell lines in vitro. In addition, we showed that attenuation of miR-1292-5p inhibited the growth, migration and invasion of the AGS and SGC-7901 gastric cancer cell lines. Importantly, our results demonstrate that the proto-oncogenic protein DEK is a direct target of miR-1292-5p in gastric carcinoma. Our results therefore demonstrate a tumor suppressor role of miR-1292-5p in gastric carcinoma and hint at the diagnostic and therapeutic potential of the miR-1292-5p/DEK pathway in gastric cancer.
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BACKGROUND: MiR-34a dysregulation has been implicated in tumorigenesis and progression of gastric cancer, but its role in prognosis of patients with gastric cancer remains unknown. The aim of this study was to investigate the expression and prognostic significance of miR-34a in gastric cancer patients after radical gastrectomy. METHODS: Quantitative real-time polymerase chain reaction was performed to detect the expression of miR-34a in human gastric cancer cell lines and tissues in 76 patients with gastric adenocarcinoma from China. Results are assessed for association with clinical features and overall survival (OS) using Kaplan-Meier analysis. Prognostic values of miR-34a expression and clinical outcomes were evaluated by Cox regression analysis. A molecular prognostic stratification scheme incorporating miR-34a expression was determined using receiver operating characteristic analysis. RESULTS: The results show that the expression level of miR-34a was decreased in human gastric cancer cell lines and tissues, and down-regulated expression of miR-34a was associated with Lauren classification (P = 0.034). Decreased miR-34a expression in gastric cancer tissues was positively correlated with poor OS of gastric cancer patients (P = 0.013). Further multivariate Cox regression analysis suggested that miR-34a expression was an independent prognostic indicator for gastric cancer (P = 0.027). Applying the prognostic value of miR-34a expression to tumor node metastasis (TNM) stage system showed a better prognostic value in patients with gastric cancer than miR-34a expression (P = 0.0435) or TNM stage (P = 0.0249) alone. CONCLUSION: The results reinforce the critical role for the down-regulated miR-34a expression in gastric cancer and suggest that miR-34a could be a prognostic indicator for this disease.
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Gastrectomía , MicroARNs/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/cirugía , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Técnicas In Vitro , Estimación de Kaplan-Meier , Análisis Multivariante , Pronóstico , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
The nephrotoxicity induced by cisplatin (DDP) severely limits the clinical efficacy of this widely used anticancer agent. The observed nephrotoxicity may be the result of DDP-induced inflammation and apoptosis. Saikosaponin-D (SSD), a triterpenoid saponin, has numerous pharmacological properties. The goal of the present study was to investigate whether and how SSD protected against DDP-induced nephrotoxicity. Non-cytotoxic levels of SSD significantly increased the viability rate, improved the nuclear morphology, and attenuated the caspase-3 activation and programmed apoptosis of DDP-treated HK-2 cells. In addition, SSD treatment markedly inhibited the release of tumour necrosis factor (TNF)-α, interleukin-1ß (IL-1ß), and interleukin-6 (IL-6), as well as the production of nitric oxide and the expression of inducible nitric oxide synthase (iNOS) by these cells. More importantly, SSD effectively blocked the DDP-induced activation of NF-κB, P38, JNK, and MAPKs. Furthermore, we found that U0126 (a specific inhibitor of MAPKs) strongly inhibited the IKK/IκB/NF-κB-dependent release of pro-inflammatory cytokines and iNOS gene expression. Finally, we demonstrated that SSD decreased the level of reactive oxygen species (ROS) accumulation and that the specific ROS scavenger N-acetylcysteine (NAC) markedly inhibited the DDP-induced activation of MAPK and phosphorylation of the downstream signal NF-κB, which in turn reduced the levels of pro-inflammatory cytokine release and iNOS gene expression. Our results suggest that the SSD-mediated alleviation of DDP-induced nephrotoxicity was due to uncoupling of the ROS, P38, and JNK/NF-κB signalling pathways.
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Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Cisplatino , Enfermedades Renales/tratamiento farmacológico , Ácido Oleanólico/análogos & derivados , Saponinas/uso terapéutico , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Humanos , Enfermedades Renales/inducido químicamente , Enfermedades Renales/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ácido Oleanólico/farmacología , Ácido Oleanólico/uso terapéutico , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Saponinas/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
AIM: To investigate the unbalance of proliferation and apoptosis and the functions of cell-cycle proteins and apoptotic factor in metastasis of hepatocellular carcinoma (HCC) and their effect in prognosis. METHODS: Proliferation index and apoptosis index, as well as seven relatively molecular markers, namely p15, p34, p53, p57, p73, survivin and nm23, were evaluated by immunohistochemistry and TUNEL in HCC tissues and compared to adjacent non-cancerous tissues and normal liver tissues. Furthermore, the prognostic significance by follow-up and mutual relationships for each clinicopathologic factor and molecular marker were analysed. RESULTS: The dysregulation between proliferation and apoptosis and the abnormal expression of seven molecular markers were observed in HCC tissues. The unbalance of proliferation and apoptosis and abnormal expressions of p15, p34, p57 and nm23 were correlated with TNM stage and extrahepatic metastasis. In particular, the abnormal co-expression of nm23/p57 correlated with advanced TNM stage and bigger tumor size and was an independent prognostic factor of HCC. CONCLUSION: The unbalance of proliferation and apoptosis and abnormal expression of cell-cycle proteins promote metastasis of HCC. Moreover, the abnormal co-expression of nm23/p57 may be a useful molecular marker for metastasis and unfavourable prognosis for HCC.