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Autophagy is a cellular catabolic process characterized by the formation of double-membrane autophagosomes. Transmission electron microscopy is the most rigorous method to clearly visualize autophagic engulfment and degradation. A large number of studies have shown that autophagy is closely related to the digestion, secretion, and regeneration of gastrointestinal (GI) cells. However, the role of autophagy in GI diseases remains controversial. This article focuses on the morphological and biochemical characteristics of autophagy in GI diseases, in order to provide new ideas for their diagnosis and treatment.
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Enfermedades Gastrointestinales , Humanos , Autofagia , Microscopía Electrónica de TransmisiónRESUMEN
PURPOSE: This research aimed to explore prognostic factors for early-onset colorectal cancer (EO-CRC) patients with liver metastasis (LM) and develop nomogram for predicting cancer-specific survival (CSS) probability quantitatively. METHODS: Our study included 4368 EO-CRC patients with LM registered in the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2017. Potential prognostic factors for EO-CRC patients with LM were identified by multivariable Cox regression analysis. Prognostic nomogram was subsequently constructed based on these prognostic factors. The discriminative ability, calibration, and clinical usefulness of the nomogram were assessed by the area under the receiver operating characteristic (ROC) curves (AUC), calibration curves, and decision curve analysis (DCA). RESULTS: In the training cohort, marital status, primary tumor location, histopathological grade, T stage, number of metastatic organs, carcinoembryonic antigen (CEA), perineural invasion (PI), surgery of primary site, chemotherapy, radiation therapy, and metastatic lymph nodes ratio (LNR) were prognostic factors for cancer-specific mortality of EO-CRC patients with LM. The 1-, 2-, and 3-year AUC values of the prognostic nomogram were 0.777, 0.781, and 0.788, respectively. Calibration curves indicated acceptable agreement between nomogram-predicted survival and actual observed survival at 1, 2, and 3 years. DCA curves exhibited good positive net benefits in the prognostic model in most threshold probabilities at different time points. All of these results were reproducible in the validation cohort. CONCLUSIONS: This study identified prognostic factors for EO-CRC patients with LM and developed a prognostic nomogram with good performance and clinical usability, which may help clinicians make better treatment decisions.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Neoplasias Colorrectales/patología , Humanos , Nomogramas , Pronóstico , Programa de VERFRESUMEN
In this study, it was ascertained that SNHG16 was up-regulated in gastrointestinal stromal tumor (GIST) tissues and cells, and was responsible for the aggravated malignant behaviors of GIST cells. CTCF served as a transcription activator responsible for the overexpression of SNHG16 in GIST cells. MiR-128-3p was negatively regulated by SNHG16 and exerted anti-tumor effects. Moreover, CASC3 was the direct target mRNA of miR-128-3p, through which miR-128-3p exerted function influence on GIST cell malignant behaviors. SNHG16 competitively bound with miR-128-3p against CASC3, thus positively regulating CASC3 expression. Finally, functional assays carried out in vitro proved SNHG16 could modulate GIST cell proliferation, migration, invasion and apoptosis via miR-128-3p/CASC3 axis. Animal experiments were also designed and implemented in a rescue way and evidenced that up-regulation of CASC3 countervailed the inhibitory impacts of SNHG16 silence on the progression of GIST. In summary, SNHG16 up-regulated by CTCF facilitated the progression of GIST through miR-128-3p/CASC3.
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Tumores del Estroma Gastrointestinal , MicroARNs , ARN Largo no Codificante , Animales , Apoptosis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Tumores del Estroma Gastrointestinal/genética , MicroARNs/genética , MicroARNs/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
In this study, we investigated the in vitro effect of tomentosin on cell proliferation by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, reactive oxygen species by 2',7'-dichlorofluorescein diacetate staining assay, apoptosis (AO/EtBr, propidium iodide, and 4',6-diamidino-2-phenylindole staining, mitochondrial membrane potential), cell adherent, cell migration, inflammation, apoptosis, and oxidative stress from gastric cancer cells (GCCs) AGS. Upon their relative cell proliferative, inflammatory, and apoptotic molecular markers were analyzed by using the enzyme-linked immunosorbent assay and Western blot analysis method. Treatment with tomentosin (IC50 = 20 µM) significantly inhibited cell proliferation and oxidative stress-induced anti-cell proliferative (proliferating cell nuclear antigen and cyclin-D1) also regulated expression, drastically diminished tumor necrosis factor-α, nuclear factor-κB, interleukin-6, and interleukin-1ß expression levels, significantly upregulated Bcl-2 and Bax expression. Thus, this tomentosin can significantly reduce GCC proliferation via cytotoxicity which is stimulated apoptosis markers via morphology staining changes and inhibitory inflammatory markers. The tomentosin-induced oxidative stress may be involved to stimulate apoptotic mechanisms via mitochondria-mediated signaling by the inhibition of inflammation. Taken together, our findings suggest a possible future use of chemotherapeutic agents for pharmacological benefits and as an anti-cancer treatment option.
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Apoptosis/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Lactonas/farmacología , Proteínas de Neoplasias/biosíntesis , Sesquiterpenos/farmacología , Neoplasias Gástricas/metabolismo , Línea Celular Tumoral , Humanos , Neoplasias Gástricas/patologíaRESUMEN
BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are considered to reflect the systemic inflammatory response and clinical prognosis. However, the independent prognostic values of the NLR and PLR for patients with gastrointestinal stromal tumor (GIST) remain debatable. This study aims to evaluate the prognostic value of preoperative NLR and PLR in GIST patients. METHODS: We retrospectively reviewed all GIST patients diagnosed and surgically treated at Union Hospital between 2005 and 2018. The preoperative NLR and PLR were calculated to evaluate recurrence-free survival (RFS) and overall survival (OS) by Kaplan-Meier analysis. Univariate and multivariate Cox regression analyses were performed to estimate the independent prognostic values. RESULTS: The median follow-up time was 49 months (interquartile range, 22-74 months). The preoperative PLR was significantly increased in the GIST patients with intermediate and high tumor risks. Increases in the NLR (≥2.34) and PLR (≥185.04) were associated with shorter RFS and OS (P < 0.01). Moreover, the multivariate analysis revealed that elevated PLR was an independent factor for shorter RFS (hazard ratio [HR]: 3.041; 95% confidence interval [CI]: 2.001-4.622; P < 0.001) and OS (HR: 1.899; 95% CI: 1.136-3.173; P = 0.014). CONCLUSIONS: The preoperative PLR is a potential biomarker of GIST and is related to the clinical outcome. An elevated preoperative PLR predicts poor prognosis of patients with primary GIST after complete surgical resection.
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Neoplasias Gastrointestinales/sangre , Tumores del Estroma Gastrointestinal/sangre , Inflamación/sangre , Recuento de Leucocitos , Recuento de Plaquetas , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Femenino , Estudios de Seguimiento , Neoplasias Gastrointestinales/inmunología , Neoplasias Gastrointestinales/mortalidad , Neoplasias Gastrointestinales/cirugía , Tumores del Estroma Gastrointestinal/inmunología , Tumores del Estroma Gastrointestinal/mortalidad , Tumores del Estroma Gastrointestinal/cirugía , Humanos , Inflamación/inmunología , Inflamación/mortalidad , Estimación de Kaplan-Meier , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Neutrófilos , Pronóstico , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Long non-coding RNAs (lncRNAs) are increasingly investigated in numerous carcinomas containing gastric cancer (GC). The aim of our research is to inquire about the expression profile and role of LBX2-AS1 in GC. METHODS: The expressions of LBX2-AS1, miR-219a-2-3p, FUS and LBX2 were measured by qRT-PCR. Western blot evaluated FUS and LBX2 protein levels. Cell proliferation and apoptosis were, respectively, evaluated by CCK-8, colony formation, EdU, flow cytometry and TUNEL assays. FISH and subcellular fractionation assays examined the position of LBX2-AS1. The binding between genes were certified by RIP, RNA pull-down, ChIP and luciferase reporter assays. Pearson correlation analysis analyzed the association of genes. Kaplan-Meier method detected the relationship of LBX2-AS1 expression with overall survival. RESULTS: The up-regulation of LBX2-AS1 in GC tissues and cells was verified. Function assays proved that LBX2-AS1 down-regulation restricted the proliferation ability. Then, we unveiled the LBX2-AS1/miR-219a-2-3p/FUS axis. Additionally, LBX2-AS1 positively regulated LBX2 mRNA stability via FUS. LBX2 transcriptionally modulated LBX2-AS1. In the end, rescue and in vivo experiments validated the whole regulatory mechanism. CONCLUSION: LBX2-AS1/miR-219a-2-3p/FUS/LBX2 positive feedback loop mainly affected the proliferation and apoptosis abilities of GC cells, offering novel therapeutic targets for the treatment of patients with GC.
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Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/metabolismo , MicroARNs/genética , ARN Largo no Codificante/genética , Proteína FUS de Unión a ARN/metabolismo , Neoplasias Gástricas/patología , Animales , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Retroalimentación Fisiológica , Proteínas de Homeodominio/genética , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Pronóstico , ARN sin Sentido/genética , Proteína FUS de Unión a ARN/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Long non-coding RNAs (lncRNAs) highly upregulated in liver cancer (HULC) has been identified as an oncogene involved in many human cancers. Herein, we aimed to further explore the role and molecular mechanism of HULC in gastric cancer (GC) progression. The levels of HULC, miR-9-5p and myosin heavy chain 9 (MYH9) mRNA were detected by qRT-PCR. The targeted interaction between HULC and miR-9-5p was verified by dual-luciferase reporter and RNA pull-down assays. Cell proliferation assay, cell colony formation, flow cytometry and transwell assay were used to determine cell proliferation, colony formation, apoptosis and migration and invasion, respectively. Xenograft assay was used to observe the effect of HULC on GC growth in vivo. Our results revealed that HULC was upregulated and miR-9-5p was downregulated in GC, and both were associated with clinicopathologic features of GC patients. A positive correlation was found between HULC expression and epithelial-to-mesenchymal transition (EMT) of GC tissues. Moreover, HULC repressed miR-9-5p expression by binding to miR-9-5p. The regulatory effects of HULC knockdown on GC cell proliferation, migration, invasion, EMT and apoptosis were reversed by introduction of anti-miR-9-5p. HULC regulated MYH9 expression by acting as a molecular sponge of miR-9-5p in GC cells. HULC knockdown inhibited tumor growth in vivo. In conclusion, our data demonstrated that HULC knockdown repressed GC progression at least partly by regulating miR-9-5p/MYH9 axis.
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MicroARNs/fisiología , Cadenas Pesadas de Miosina/fisiología , ARN Largo no Codificante/fisiología , Neoplasias Gástricas/patología , Adulto , Anciano , Animales , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Invasividad Neoplásica , Neoplasias Gástricas/etiologíaRESUMEN
BACKGROUND: B7 homolog 1 (B7-H1) overexpression on tumor cells is an important mechanism of immune evasion in gastric cancer (GC). Elucidation of the regulation of B7-H1 expression is urgently required to guide B7-H1-targeted cancer therapy. Interferon gamma (IFN-γ) is thought to be the main driving force behind B7-H1 expression, and epigenetic factors including histone acetylation are recently linked to the process. Here, we investigated the potential role of histone deacetylase (HDAC) in IFN-γ-induced B7-H1 expression in GC. The effect of Vorinostat (SAHA), a small molecular inhibitor of HDAC, on tumor growth and B7-H1 expression in a mouse GC model was also evaluated. RESULTS: RNA-seq data from The Cancer Genome Atlas revealed that expression of B7-H1, HDAC1-3, 6-8, and 10 and SIRT1, 3, 5, and 6 was higher, and expression of HDAC5 and SIRT4 was lower in GC compared to that in normal gastric tissues; that HDAC3 and HDAC1 expression level significantly correlated with B7-H1 in GC with a respective r value of 0.42 (p < 0.001) and 0.21 (p < 0.001). HDAC inhibitor (Trichostatin A, SAHA, and sodium butyrate) pretreatment suppressed IFN-γ-induced B7-H1 expression on HGC-27 cells. HDAC1 and HDAC3 gene knockdown had the same effect. SAHA pretreatment or HDAC knockdown resulted in impaired IFN-γ signaling, demonstrated by the reduction of JAK2, p-JAK1, p-JAK2, and p-STAT1 expression and inefficient STAT1 nuclear translocation. Furthermore, SAHA pretreatment compromised IFN-γ-induced upregulation of histone H3 lysine 9 acetylation level in B7-H1 gene promoter. In the grafted mouse GC model, SAHA treatment suppressed tumor growth, inhibited B7-H1 expression, and elevated the percentage of tumor-infiltrating CD8+ T cells. CONCLUSION: HDAC is indispensable for IFN-γ-induced B7-H1 in GC. The study suggests the possibility of targeting B7-H1 using small molecular HDAC inhibitors for cancer treatment.
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Antígeno B7-H1/genética , Perfilación de la Expresión Génica/métodos , Inhibidores de Histona Desacetilasas/administración & dosificación , Histona Desacetilasas/genética , Interferón gamma/farmacología , Neoplasias Gástricas/tratamiento farmacológico , Acetilación/efectos de los fármacos , Animales , Linfocitos T CD8-positivos/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Histonas/metabolismo , Humanos , Ratones , Proteínas Mitocondriales/genética , Análisis de Secuencia de ARN/métodos , Sirtuinas/genética , Neoplasias Gástricas/genética , Vorinostat/administración & dosificación , Vorinostat/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Wee1 is an oncogenic nuclear kinase, which can regulate the cell cycle as a crucial G2M checkpoint. Overexpression of Wee1 can be observed in various cancer types, which may lead to a poor prognosis, but the potential therapeutic value of Wee1 in colorectal cancer has not been fully studied. In the present study, the role of Wee1 in colonic cancer was investigated. Wee1 inhibition by small interfering RNA was demonstrated to significantly restrain cancer cell proliferation and sensitize the p53 mutant colonic cancer cell lines HT29 and SW480 to the effect of treatment with ionizing radiation. The anticancer effect of the Wee1 inhibitor MK1775 was investigated in these two colonic cancer cell lines. MK1775 was demonstrated to induce significant DNA damage, suppress cell viability and induce apoptosis. In addition, MK1775 sensitized HT29 and SW480 cells to the effect of irinotecan. Annexin V/propidium iodide staining demonstrated that combination therapy can induce increased apoptosis compared with MK1775 or irinotecan monotherapy. The results of western blot analysis also indicated increased expression of the DNA damage marker histone H2AX, and apoptosisassociated protein cleaved caspase 3, in HT29 and SW480 cells. In conclusion, the present study indicated that Wee1 may be a valuable target for treatment of p53 mutant colonic cancer.
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Antineoplásicos Fitogénicos/farmacología , Camptotecina/análogos & derivados , Proteínas de Ciclo Celular/antagonistas & inhibidores , Neoplasias del Colon/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirazoles/farmacología , Pirimidinas/farmacología , Proteína p53 Supresora de Tumor/genética , Apoptosis/efectos de los fármacos , Camptotecina/farmacología , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Daño del ADN/efectos de los fármacos , Humanos , Irinotecán , Mutación , Proteínas Nucleares/metabolismo , Proteínas Tirosina Quinasas/metabolismo , PirimidinonasRESUMEN
Globally, gastric cancer is the second leading cause of cancer deaths because of the lack of effective treatments for patients with advanced tumors when curative surgery is not possible. Thus, there is an urgent need to identify molecular targets in gastric cancer that can be used for developing novel therapies and prolonging patient survival. Checkpoint kinase 1 (Chk1) is a crucial regulator of cell cycle transition in DNA damage response (DDR). In our study, we report that Chk1 plays an important role in promoting gastric cancer cell survival and growth, which serves as an effective therapeutic target in gastric cancer. First, Chk1 ablation by small interfering RNA could significantly inhibit cell proliferation and sensitize the effects of ionizing radiation (IR) treatment in both p53 wild type gastric cancer cell line AGS, and p53 mutant cell line MKN1. Secondly, we tested the anticancer effects of Chk1 chemical inhibitor LY2606368, which is a novel Chk1/2 targeted drug undergoing clinical trials in many malignant diseases. We found that LY2606368 can induce DNA damage, and remarkably suppress cancer proliferation and induce apoptosis in AGS and MKN1 cells. Moreover, we identified that LY2606368 can significantly inhibit homologous recombination (HR) mediated DNA repair and thus showed marked synergistic anticancer effect in combination with poly (ADP-ribose) polymerase 1 (PARP1) inhibitor BMN673 in both in vitro studies and in vivo experiments using a gastric cancer PDx model. The synergy between LY2606368 and PARP1 was likely caused by impaired the G2M checkpoint due to LY2606368 treatment, which forced mitotic entry and cell death in the presence of BMN673. In conclusion, we propose that Chk1 is a valued target for gastric cancer treatment, especially Chk1 inhibitor combined with PARP inhibitor may be a more effective therapeutic strategy in gastric cancer.
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Alcohol abuse is an important cause of gastric mucosal epithelial cell injury and gastric ulcers. A number of studies have demonstrated that autophagy, an evolutionarily conserved cellular mechanism, has a protective effect on cell survival. However, it is not known whether autophagy can protect gastric mucosal epithelial cells against the toxic effects of ethanol. In the present study, gastric mucosal epithelial cells (GES-1 cells) and Wistar rats were treated with ethanol to detect the adaptive response of autophagy. Our results demonstrated that ethanol exposure induced gastric mucosal epithelial cell damage, which was accompanied by the downregulation of mTOR signaling pathway and activation of autophagy. Suppression of autophagy with pharmacological agents resulted in a significant increase of GES-1 cell apoptosis and gastric mucosa injury, suggesting that autophagy could protect cells from ethanol toxicity. Furthermore, we evaluated the cellular oxidative stress response following ethanol treatment and found that autophagy induced by ethanol inhibited generation of reactive oxygen species and degradation of antioxidant and lipid peroxidation. In conclusion, these findings provide evidence that ethanol can activate autophagy via downregulation of the mTOR signaling pathway, serving as an adaptive mechanism to ameliorate oxidative damage induced by ethanol in gastric mucosal epithelial cells. Therefore, modifying autophagy may provide a therapeutic strategy against alcoholic gastric mucosa injury. Impact statement The effect and mechanism of autophagy on ethanol-induced cell damage remain controversial. In this manuscript, we report the results of our study demonstrating that autophagy can protect gastric mucosal epithelial cells against ethanol toxicity in vitro and in vivo. We have shown that ethanol can activate autophagy via downregulation of the mTOR signaling pathway, serving as an adaptive mechanism to ameliorate ethanol-induced oxidative damage in gastric mucosal epithelial cells. This study brings new and important insights into the mechanism of alcoholic gastric mucosal injury and may provide an avenue for future therapeutic strategies.
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Autofagia , Células Epiteliales/efectos de los fármacos , Etanol/toxicidad , Mucosa Gástrica/efectos de los fármacos , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Animales , Ratas WistarRESUMEN
Estrogen plays a role in the processes of tumorigenesis, metastasis, and drug resistance in estrogen receptor (ER)-positive breast cancer (BC). Whether estrogen contributes to ER-negative BC is unclear. Here, we aimed to investigate whether estrogen could stimulate the secretion of stromal-derived factor-1 (SDF-1α) by cancer-associated fibroblasts (CAFs) to promote the progression of ER-negative BC. We transplanted ER-negative BC cells into ovariectomized mice, which was followed by continuous injection of estrogen, and found that estrogen promoted the tumorigenesis of BC. Furthermore, High levels of SDF-1α and tumor-infiltrating myeloid-derived suppressor cells (MDSCs) were detected in the estrogen treatment group. Estrogen stimulates secretion of SDF-1α by CAFs extracted from BC patients. Recombinant SDF-1α could recruit MDSCs isolated from bone marrow cells of mice. In addition, the co-culture of CAFs and MDSCs demonstrated that the recruitment of MDSCs was increased when CAFs were exposed to estrogen. Using AMD3100 to block the SDF-1α/CXCR4 axis or gemcitabine to delete MDSCs, we observed that both of these agents could neutralize the effect of estrogen on tumorigenesis. Together, these results suggest that estrogen may promote the progression of ER-negative BC by stimulating CAFs to secrete SDF-1α, which can recruit MDSCs to the tumor microenvironment to exert tumor-promoting effects.
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Neoplasias de la Mama/metabolismo , Quimiocina CXCL12/metabolismo , Receptor alfa de Estrógeno/metabolismo , Estrógenos/farmacología , Células Supresoras de Origen Mieloide/citología , Microambiente Tumoral , Animales , Movimiento Celular , Quimiotaxis , Técnicas de Cocultivo , Progresión de la Enfermedad , Femenino , Fibroblastos/metabolismo , Humanos , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Proteínas Recombinantes/metabolismo , Transducción de SeñalRESUMEN
OBJECTIVES: To investigate gastrointestinal stromal tumor (GIST) clinicopathologic characteristics in young adults. METHODS: Clinicopathologic data from GIST patients under 35 years diagnosed at our hospital from January 2005 to December 2014 were retrospectively collected. RESULTS: Thirty-one (5.3%, 31/585) patients were included; 17 (54.8%) were female. The most common presentation and primary tumor site were gastrointestinal bleeding (n = 18, 58.1%) and the small intestine (n = 13, 41.9%), respectively. Fifteen (48.4%) GISTs were classified as having a high relapse risk; two (6.4%), intermediate; nine (29.0%), low; and five (16.1%), very low. All patients underwent tumor resection. With a median follow-up of 51 months for 20 (64.5%) patients, 12 (60%) were given imatinib methylate as adjuvant therapy. One (5%) patient died of peritoneal GIST dissemination, four (20%) developed abdominal recurrences, two (10%) had hepatic metastasis, and thirteen (65%) were disease free. The 5-year disease-free survival rate was 51.2%. CONCLUSIONS: GISTs rarely occur in young adults. The most common location is the small intestine. A slight female predominance was observed in the current study. Adjuvant therapy longer than the recommended duration may be beneficial for GISTs with a high relapse risk. Combined targeted therapy and surgery is appropriate for recurrent and metastatic GISTs in select patients. J. Surg. Oncol. 2016;114:977-981. © 2016 Wiley Periodicals, Inc.
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Neoplasias Gastrointestinales/diagnóstico , Tumores del Estroma Gastrointestinal/diagnóstico , Adolescente , Adulto , Antineoplásicos/uso terapéutico , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/patología , Neoplasias Gastrointestinales/cirugía , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/patología , Tumores del Estroma Gastrointestinal/cirugía , Humanos , Mesilato de Imatinib/uso terapéutico , Intestino Delgado/patología , Intestino Delgado/cirugía , Masculino , Pronóstico , Estudios Retrospectivos , Adulto JovenRESUMEN
The phosphoinositide 3-kinase/Akt pathway activation commonly occurs in various types of human cancer and has an important role in chemoresistance. Combination of traditional chemotherapy drugs and molecular-targeted agents is a promising strategy for cancer therapy, which has shown enhanced cytotoxicity and lower drug resistance. The present study found that the Akt inhibitor, MK-2206, can increase the effect of cisplatin in the gastric cancer cell line AGS, which has higher Akt phosphorylation, but exhibited a poor combination effect in MKN-45 and MGC-803 cells, which have limited Akt activation. The MTT assay demonstrated that sequential treatment of cisplatin, followed by the Akt inhibitor, MK-2206, caused a synergistic effect of proliferation inhibition, and the apoptosis assay by propidium iodide/fluorescein isothiocyanate staining also showed that combination treatment induced more apoptosis compared to the monotherapy groups. Using western blot analysis, MK-2206 was shown to significantly suppress the phosphorylation of Akt (Ser473), however, the expression of total Akt remained the same, and the combination treatment also increased the expression of cleaved poly adenosine diphosphate ribose polymerase, which contributed to apoptosis.
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PURPOSE: MicroRNAs (miRs) have been frequently reported dysregulating in tumors and playing a crucial role in tumor development and progression. However, the expression of miR-155 and its role in gastric cancer (GC) are still obscure. METHODS: qRT-PCR was applied to detect miR-155 expression in 60 matched GC samples and four GC cell lines, and the relationship between miR-155 levels and clinicopathological features of GC was analyzed. Next, the effects of miR-155 on GC cell growth were evaluated by gain- and loss-of-function analysis. Finally, the target gene(s) of miR-155 in GC cells were explored. RESULTS: Our results revealed that miR-155 levels were significantly lower in both GC tissues and GC cell lines than in their normal controls, and its expression inversely correlated with tumor size and the pathologic stage. Moreover, our study showed that enforced expression of miR-155 impaired GC cell proliferation, promoted G1 phase arrest and induced apoptosis in vitro. In addition, we identified cyclin D1 as the direct target of miR-155, and knockdown of cyclin D1 partially phenocopied the role of miR-155 in GC cells. CONCLUSIONS: Our findings suggest that miR-155 may act as a potential diagnostic marker for early-stage GC and may represent a novel therapeutic target for GC treatment.
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Proliferación Celular/genética , Ciclina D1/genética , MicroARNs/genética , Neoplasias Gástricas/patología , Apoptosis , Ciclo Celular/genética , Línea Celular Tumoral , Regulación hacia Abajo , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismoRESUMEN
AIM: To compare the efficacy of using covered self-expandable metal stents (CSEMSs) and uncovered self-expandable metal stents (UCSEMSs) to treat objective jaundice caused by an unresectable malignant tumor. METHODS: We performed a comprehensive electronic search from 1980 to May 2015. All randomized controlled trials comparing the use of CSEMSs and UCSEMSs to treat malignant distal biliary obstruction were included. RESULTS: The analysis included 1417 patients enrolled in 14 trials. We did not detect significant differences between the UCSEMS group and the CSEMS group in terms of cumulative stent patency (hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.19-4.53; p = 0.93, I2 = 0%), patient survival (HR 0.77, 95% CI 0.05-10.87; p = 0.85, I2 = 0%), overall stent dysfunction (relative ratio (RR) 0.85, M-H, random, 95% CI 0.57-1.25; p = 0.83, I2 = 63%), the overall complication rate (RR 1.26, M-H, fixed, 95% CI 0.94-1.68; p = 0.12, I2 = 0%) or the change in serum bilirubin (weighted mean difference (WMD) -0.13, IV fixed, 95% CI 0.56-0.3; p = 0.55, I2 = 0%). However, we did detect a significant difference in the main causes of stent dysfunction between the two groups. In particular, the CSEMS group exhibited a lower rate of tumor ingrowth (RR 0.25, M-H, random, 95% CI 0.12-0.52; p = 0.002, I2 = 40%) but a higher rate of tumor overgrowth (RR 1.76, M-H, fixed, 95% CI 1.03-3.02; p = 0.04, I2 = 0%). Patients with CSEMSs also exhibited a higher migration rate (RR 9.33, M-H, fixed, 95% CI 2.54-34.24; p = 0.008, I2 = 0%) and a higher rate of sludge formation (RR 2.47, M-H, fixed, 95% CI 1.36-4.50; p = 0.003, I2 = 0%). CONCLUSIONS: Our meta-analysis indicates that there is no significant difference in primary stent patency and stent dysfunction between CSEMSs and UCSEMSs during the period from primary stent insertion to primary stent dysfunction or patient death. However, when taking further management for occluded stents into consideration, CSEMSs is a better choice for patients with malignant biliary obstruction due to their removability.
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Colestasis/cirugía , Stents Metálicos Autoexpandibles , Neoplasias del Sistema Biliar/complicaciones , Neoplasias del Sistema Biliar/mortalidad , Neoplasias del Sistema Biliar/cirugía , Colestasis/etiología , Colestasis/mortalidad , Humanos , Stents Metálicos Autoexpandibles/efectos adversos , StentsRESUMEN
Monoacylglycerol lipase (MAGL) is involved in the degradation of triacylglycerol. Previous studies have demonstrated that MAGL regulates tumor growth and metastasis via fatty acid networks, and is associated with colorectal cancer. JZL184 is a MAGL inhibitor, which in the present study was administered to colorectal cancer cell lines, resulting in decreased tumor proliferation, increased apoptosis and increased tumor cell sensitivity to 5-fluorouracil. Bcell lymphoma 2 (Bcl2) and Bcl2associated X protein (Bax) are key proteins in apoptosis. The expression levels of Bcl2/Bax were determined in colorectal cancer cell lines following JZL184 administration, and it was observed that the mRNA and protein expression levels of Bcl2 were decreased, whereas the expression levels of Bax were increased. These results indicated that JZL184 may induce tumor cell apoptosis by regulating the expression of Bcl2 and Bax. Epithelial-mesenchymal transition (EMT) is closely associated with metastasis. Administration of JZL184 in various malignant colorectal cancer cell lines suppressed migration and altered the expression of EMT markers; Ecadherin was increased, whereas the expression levels of vimentin and zinc finger protein SNAI1 were decreased. These results suggested that JZL184 was able to regulate the EMT process, in order to control the migration of colorectal cancer cells, particularly in tumors with a stronger metastatic capability. Therefore, in colorectal cancer, MAGL may be considered a potential therapeutic target and JZL184 may be a possible therapeutic agent.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Benzodioxoles/farmacología , Movimiento Celular/efectos de los fármacos , Piperidinas/farmacología , Proliferación Celular , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Humanos , Monoacilglicerol Lipasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
BACKGROUND: Nowadays, laparoscopic abdominoperineal resection (LAPR) not only has the same oncologic safety of open surgery and but also has the common advantages of laparoscopic surgery. However, given the difficulty in operation and long operative time, laparoscopic extraperitoneal colostomy construction is rarely practiced and reported. In this study, we describe technique of extraperitoneal colostomy using circular stapler following LAPR and demonstrate its efficacy and safety. METHODS: This is a retrospective analysis of prospectively maintained data of 42 patients who underwent LAPR with circular stapler-assisted extraperitoneal colostomy in our department between July 2011 and June 2014. RESULTS: The mean time for extraperitoneal colostomy construction was 25 min (18-33 min). The mean operative time, estimated blood loss, postoperative gastrointestinal function recovery time, and duration of postoperative hospital stay were 160 min (115-225 min), 45 ml (10-250 ml), 33 h (26-45 h), and 8.6 days (6-13 days), respectively; 4.8 % of the patients had postoperative short-term complications. There were no stenosis, prolapse, and parastomal hernia observed in follow-up period. At 6 months after operation, 26 patients (62 %) claimed to be satisfied with their postoperative stool habits, 29 patients (69 %) had sensation to defecate per stoma, and 11 (26.2 %) patients had the ability to defer defecation for solid or liquid stool per stoma. CONCLUSION: Circular stapler-assisted extraperitoneal colostomy is an easy, effective, and safe technique following LAPR and appears to minimize the occurrence of stomal complications and improve the quality of life for patients.
Asunto(s)
Colostomía , Neoplasias Gastrointestinales/cirugía , Laparoscopía , Grapado Quirúrgico , Adulto , Anciano , Femenino , Neoplasias Gastrointestinales/patología , Humanos , Masculino , Persona de Mediana Edad , Tempo Operativo , Calidad de Vida , Estudios Retrospectivos , Estomas QuirúrgicosRESUMEN
The sonic hedgehog (Shh) pathway is known to be vital in embryonic development and cancer propagation due to its irreplaceable role in cell proliferation and differentiation. GDC0449, a basal cell skin cancer target drug approved by the Food and Drugs Administration, is a smoothened (Smo)-specific antagonist. Although it has been clinically verified as a valid drug for the treatment of skin and pancreatic cancer, the application of GDC0449 in gastric cancer requires further investigation. In the present study, high-glucose Dulbecco's modified Eagle's medium with 10% fetal bovine serum was used for routine SGC7901 cell line culture. A Cell Counting Kit8 assay was employed for determination of the reproductive rate of the cells. Flow cytometry was performed to determine the apoptosis status of the SGC7901 cell line through Q4 analysis. Reverse transcription-quantitative polymerase chain reaction and Western blot analyses were used as target molecule detection vehicles. As expected, GDC0449 reduced the expression levels of Shhassociated molecules, including Smo and gli1, compared with the blank group. The rate of cell proliferation was markedly limited and was accompanied by an increase in the apoptotic rate following GDC0449 exposure. In addition, further investigations confirmed B cell lymphoma2 (Bcl2) as the downstream molecular mechanism of GDC0449 efficacy. Of note, representatives of the cancer stem cell (CSC) surface marker, CD44 and CD133, demonstrated a similar trend to the Smo restriction observed. By repressing the expression of Bcl2, GDC0449 inhibited the normal proliferation of SGC7901 cells, and accelerated the apoptotic rate of the cells. It may also alter CSC properties due to the reduction in the expression of surface markers.