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In the course of antitumor therapy, the complex tumor microenvironment and drug-mediated changes in cell signaling and biological processes lead to drug resistance. The effect of sorafenib is greatly limited by the specific tumor microenvironment induced by antiangiogenic therapy and ferroptosis resistance induced by the upregulation of nuclear factor erythroid-2 related factor 2 (NRF2). In this study, a pH responsive and amphiphilic hyperbranched polyglycerol, HDP, is synthesized based on a co-graft click chemistry pathway. This nano-scale carrier provides excellent drug-loading capacity, storing stability and pH responsibility, and effectively co-delivery of sorafenib and siRNA. Sorafenib and siNRF2 plays a greatly synergistic effect in inducing reactive oxygen species (ROS), iron overloading, depleting glutathione (GSH), and promoting lipid peroxidation. Importantly, verified in two different animal experiments, HDP-ss (HDP loaded with both siNRF2 and sorafenib) presents a superior anti-tumor effect, by achieving a tumor inhibition rate of ≈94%. Thus, HDP can serve as an excellent targeted delivery nanocarrier with good biocompatibility in antitumor therapy, and combined application of siNRF2 effectively improves the antitumor effect of sorafenib by overcoming NRF2-mediated ferroptosis resistance. Taken together, this study provides a novel therapeutic strategy to combat the drug resistance in antiangiogenic therapy and ferroptosis.
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Carcinoma Hepatocelular , Ferroptosis , Neoplasias Hepáticas , Factor 2 Relacionado con NF-E2 , Sorafenib , Sorafenib/farmacología , Sorafenib/química , Ferroptosis/efectos de los fármacos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Humanos , Animales , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Portadores de Fármacos/química , Especies Reactivas de Oxígeno/metabolismo , Nanopartículas/química , Línea Celular Tumoral , Ratones , Glutatión/metabolismoRESUMEN
BACKGROUND AND AIMS: Methylation landscape is important for maintaining the silence of cannabinoid receptor-interacting protein 1 (CNRIP1) in some tumors. However, the role of CNRIP1 in intrahepatic cholangiocarcinoma (ICC) remains poorly defined. APPROACH AND RESULTS: In our study, we showed that CNRIP1 was down-regulated in ICC tissues, and low expression of CNRIP1 was significantly associated with poor prognosis of patients with ICC in 3-year overall survival and tumor-free survival. Investigating the genomic DNA methylation profile, we disclosed a CpG island site named CNRIP1 MS-2 (CNRIP1 methylation site-2) that contributes to the down-regulation of CNRIP1. In addition, the methylation level of CNRIP1 MS-2 was correlated to the pathological grade, metastasis, and tumor-node-metastasis classification in ICC. Notably, we observed that CNRIP1 suppressed tumor cell migration, invasion, and proliferation by inhibiting the activity of pyruvate kinase M2 (PKM2). Sustained overexpression of CNRIP1 suppressed the in vivo tumor growth in a mouse xenograft model. It was also found that CNRIP1 overexpression activated Parkin (an E3 ubiquitin ligase), which resulted in the protein degradation of PKM2 in ICC cells. CONCLUSIONS: We identified that CNRIP1 acted as a putative tumor suppressor in ICC, which suggested that CNRIP1 could be a candidate biomarker for predicting tumor recurrence in patients with ICC. Furthermore, these findings highlight a potential therapeutic approach in targeting the CNRIP1/Parkin/PKM2 pathway for the treatment of ICC.
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Neoplasias de los Conductos Biliares/etiología , Proteínas Portadoras/metabolismo , Colangiocarcinoma/etiología , Proteínas de la Membrana/metabolismo , Hormonas Tiroideas/metabolismo , Animales , Apoptosis , Neoplasias de los Conductos Biliares/metabolismo , Western Blotting , Proliferación Celular , Células Cultivadas , Colangiocarcinoma/metabolismo , Metilación de ADN , Regulación hacia Abajo , Humanos , Ratones , Trasplante de Neoplasias , Reacción en Cadena en Tiempo Real de la Polimerasa , Ubiquitinación , Proteínas de Unión a Hormona TiroideRESUMEN
GOALS: We aim to draw a conclusion which type of hepatectomy could be the priority for hilar cholangiocarcinoma patients. BACKGROUND: Surgery is established as only potentially curative treatment for hilar cholangiocarcinoma. However, whether hepatectomy should be preferred to the left-side hepatectomy, which includes left hemihepatectomy, extended left hemihepatectomy, and left trisectionectomy, or right-side hepatectomy, which represents right hemihepatectomy, extended right hemihepatectomy, and right trisectionectomy, is debated. In this meta-analysis, we evaluated and compared the efficacy and safety of left-side hepatectomy and right-side hepatectomy in patients with hilar cholangiocarcinoma. STUDY: We systematically retrieved the MEDLINE, PubMed, and Cochrane library and related bibliography up to February 2020. The primary outcome is overall survival, and the secondary outcome includes 1-, 3-, and 5-year survival rates, morbidity, mortality, R0 resection rate, and operation time. Based on heterogeneity, fixed-effects model or random-effects models were established through meta-analysis. RESULTS: Eleven studies (11 cohort studies, totally 1031 patients) were involved in this study. The overall survival of patients who underwent left-side hepatectomy was comparable to that of patients who underwent right-side hepatectomy (hazard ratio, 1.27 [95% confidence interval, 0.98-1.63]). And there was no significant difference observed in 1-year (relative risk, 1.01 [95% CI, 0.89-1.15]), 3-year (relative risk, 0.94 [95% confidence interval, 0.80-1.11]), and 5-year survival (relative risk, 0.82 [95% confidence interval, 0.67-1.01]) rates between the left-side hepatectomy group and the right-side hepatectomy group. Comparing with the right-side hepatectomy cluster, the hilar cholangiocarcinoma patients in the left-side hepatectomy cluster presented better overall postoperative morbidity (relative risk, 0.82 [95% confidence interval, 0.71-0.96]) and major postoperative morbidity (relative risk, 0.73 [95% confidence interval, 0.56-0.95]). The post-hepatectomy liver failure rate (relative risk, 0.22 [95% confidence interval, 0.09-0.56]) and procedure-related mortality (relative risk, 0.41 [95% confidence interval, 0.23-0.70]) in the left-side hepatectomy group were better than those of the right-side hepatectomy group. Besides, the R0 resection rate was similar between the left-side hepatectomy group and the right-side hepatectomy group (relative risk, 0.95 [95% confidence interval, 0.87-1.03]). And the operation time for the left-side hepatectomy was significantly longer than that for the right-side hepatectomy (mean difference, 38.68 [95% confidence interval, 7.41-69.95]). CONCLUSION: Through meta-analysis, we explored the comparable long-term outcomes and better short-term outcomes in the left-side hepatectomy group as is compared to the right-side hepatectomy group of hilar cholangiocarcinoma patients. In this study, the evidence obtained might indicate that the choice of left-side hepatectomy or right-side hepatectomy depends on the site of hilar cholangiocarcinoma in every patient.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Tumor de Klatskin , Neoplasias de los Conductos Biliares/cirugía , Conductos Biliares Intrahepáticos/cirugía , Colangiocarcinoma/cirugía , Hepatectomía/efectos adversos , Humanos , Tumor de Klatskin/cirugía , Pronóstico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: N6-methyladenosine (m6A) modification is an emerging layer of epigenetic regulation which is widely implicated in the tumorigenicity of hepatocellular carcinoma (HCC), offering a novel perspective for investigating molecular pathogenesis of this disease. The role of AlkB homolog 5 (ALKBH5), one of the m6A demethylases, has not been fully explored in HCC. Here we clarify the biological profile and potential mechanisms of ALKBH5 in HCC. METHODS: Expression of ALKBH5 and its correlation with clinicopathological characteristics of HCC were evaluated using tissue microarrays and online datasets. And biological effects of ALKBH5 in HCC were determined in vitro and in vivo. Subsequently, methylated RNA immunoprecipitation sequencing (MeRIP-seq) combined with RNA sequencing (RNA-seq), and following m6A dot blot, MeRIP-qPCR, RIP-qPCR or dual luciferase reporter assays were employed to screen and validate the candidate targets of ALKBH5. RESULTS: We demonstrated that ALKBH5 was down-regulated in HCC, and decreased ALKBH5 expression was an independent prognostic factor of worse survival in HCC patients. Functionally, ALKBH5 suppressed the proliferation and invasion capabilities of HCC cells in vitro and in vivo. Mechanistically, ALKBH5-mediated m6A demethylation led to a post-transcriptional inhibition of LY6/PLAUR Domain Containing 1 (LYPD1), which could be recognized and stabilized by the m6A effector IGF2BP1. In addition, we identified that LYPD1 induced oncogenic behaviors of tumors in contrast to ALKBH5. Dysregulation of ALKBH5/LYPD1 axis impelled the progression of HCC. CONCLUSION: Our study reveals that ALKBH5, characterized as a tumor suppressor, attenuates the expression of LYPD1 via an m6A-dependent manner in HCC cells. Our findings enrich the landscape of m6A-modulated tumor malignancy, and provide new insights into potential biomarkers and therapeutic targets of HCC treatment.
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Adenosina/análogos & derivados , Desmetilasa de ARN, Homólogo 5 de AlkB/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Epigénesis Genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Proteínas Supresoras de Tumor/genética , Adenosina/metabolismo , Animales , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Proteínas Portadoras , Línea Celular Tumoral , Proliferación Celular , Modelos Animales de Enfermedad , Proteínas Ligadas a GPI/genética , Regulación Neoplásica de la Expresión Génica , Xenoinjertos , Humanos , Neoplasias Hepáticas/patología , Ratones , Modelos Biológicos , Pronóstico , Unión Proteica , Transducción de SeñalRESUMEN
BACKGROUND: Cholangiocarcinoma (CCA) is a kind of devastating malignancy, which is correlated with the extremely high mortality. Due to the occult pathogenesis of CCA, most patients are diagnosed in the advanced stage. However, the efficacy of chemotherapy and immunotherapy is limited for these patients. The cause for this phenomenon is unclear, the recent researches indicate that it could be related to predisposing genetic factors and tumor microenvironment (TME) changes. The TME is created by the tumor and dominated by tumor-induced interactions. And the tumor prognosis could be influenced by the extent of infiltrating immune cells and stromal cells in TME. MATERIALS AND METHODS: The abundance ratio of immune cells for each sample was obtained via the CIBERSORT algorithm, and we used ESTIMATE score system to calculate the immune and stromal scores in CCA. The CCA cases in TCGA database were categorized into high and low score groups according to their immune/stromal scores. And then, we identified the differential expressed genes (DEGs) in two groups. Functional enrichment analysis and protein-protein interaction networks were carried out for DEGs. Interestingly, we found out that apolipoprotein B (APOB) is the most down-regulated among these genes. Then we performed the immunohistochemistry staining of APOB in a CCA tumor microarray which contained 100 CCA cases, APOB was down-regulated in CCA samples. Thus, we evaluated the APOB function in the TME of CCA through TIMER. RESULTS AND CONCLUSION: The results demonstrate that the infiltration degree of immune cells in CCA could be influenced by the expression of APOB, and the APOB expression could be mediated by DNA methylation. Our study not only indicates APOB is a potential target for CCA immunotherapy but also provides new ideas for researchers to explore the immunotherapy of various tumors.
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The function of the N6-methyladenosine (m6A) methyltransferase RNA-binding motif protein 15 (RBM15) in hepatocellular carcinoma (HCC) has not been thoroughly investigated. Here we determined the clinical value, biological functions, and potential mechanisms of RBM15 in HCC. Expression of RBM15 was identified using tissue microarrays and online databases. A risk-prediction model based on RBM15 was developed and validated. We determined the biological role of RBM15 on HCC cells in vitro and in vivo. RNA sequencing was used to screen candidate targets of RBM15. Subsequently, the m6A dot blot assay, methylated RNA immunoprecipitation qPCR, dual-luciferase reporter assays, RNA decay assay, and RNA immunoprecipitation qPCR were employed to explore the mechanisms of RBM15. Our study showed that RBM15 was highly expressed in HCC, and overexpression of RBM15 indicated a worse outcome. A new nomogram combining RBM15 with age and TNM stage was developed and validated to predict the outcome of HCC patients; our nomogram increased the prediction accuracy of the TNM system. Functionally, RBM15 facilitates the proliferation and invasiveness of HCC. RBM15-mediated m6A modification contributed to a post-transcriptional activation of YES proto-oncogene 1 (YES1) in an insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1)-dependent manner. In addition, YES1 was confirmed as an oncogene in HCC cells by activating the mitogen-activated protein kinase (MAPK) pathway. In conclusion, RBM15-mediated m6A modification might facilitate the progression of HCC via the IGF2BP1-YES1-MAPK axis. RBM15 may be a promising biomarker in the outcome prediction of HCC.
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Lipid metabolic reprogramming plays a pivotal role in hepatocellular carcinoma (HCC) development, but the underlying mechanisms are incompletely characterized. Long chain acyl CoA synthetase 4 (ACSL4), a member of acyl-CoA synthetases (ACS) family, has been identified as a novel marker of alpha-fetoprotein-high subtype HCC and as an oncogene. Here, we identified a new function of ACSL4 in HCC lipid metabolism. ACSL4 can modulate de novo lipogenesis by accumulating intracellular triglycerides, cholesterols, and lipid droplets in HCC. Mechanistically, ACSL4 upregulates the master lipogenesis regulator sterol regulatory element binding protein 1 (SREBP1) and its downstream lipogenic enzymes in HCC cells via c-Myc. Moreover, SREBP1 is crucial for ACSL4-mediated regulation of lipogenesis as well as HCC cell proliferation and metastasis, as SREBP1 overexpression rescues lipogenic deficiency and decreased oncogenic capabilities associated with ACSL4 suppression in vitro and in vivo. Clinically, our data showed that the expression of ACSL4 was positively correlated with that of SREBP1 in HCC patients, and the combinational biomarkers showed strong predictive value for HCC. Together, our findings uncover a new mechanism by which ACSL4 modulates aberrant lipid metabolism and promotes the progression of HCC.
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Carcinoma Hepatocelular/patología , Coenzima A Ligasas/metabolismo , Ácidos Grasos/metabolismo , Neoplasias Hepáticas/patología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Animales , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Metabolismo de los Lípidos , Neoplasias Hepáticas/metabolismo , Ratones , Trasplante de Neoplasias , Transducción de Señal , Regulación hacia ArribaRESUMEN
To achieve highly systemic therapeutic efficacy, chemotherapy is combined with photothermal therapy for chemo-photothermal synergistic therapy; however, this strategy suffers from high toxicity and unsatisfactory sensitivity for cancer cells. Herein, we developed a pH- and photothermal-responsive zeolitic imidazolate framework (ZIF-8) compound for loading a dual-drug in the tumor site and improving their curative effects. Since autophagy always accompanies tumor progression and metastasis, there is an unmet need for an anticancer treatment related to the regulation of autophagy. Green tea polyphenols, namely, (-)-epigallocatechin-3-gallate (EGCG) and doxorubicin (DOX), both of which exhibit anticancer activity, were dual-loaded via polydopamine (PDA) coating ZIF-8 (EGCG@ZIF-PDA-PEG-DOX, EZPPD for short) through hierarchical self-assembly. PDA could transfer photothermal energy to increase the temperature under near-infrared (NIR) laser irradiation. Due to its pH-response, EZPPD released EGCG and DOX in the tumor microenvironment, wherein the temperature increased with the help of PDA and NIR laser irradiation. The duo of DOX and EGCG induced autophagic flux and accelerated the formation of autophagosomes. In a mouse HeLa tumor model, photothermal-chemotherapy could ablate the tumor with a significant synergistic effect and potentiate the anticancer efficacy. Thus, the results indicate that EZPPD renders the key traits of a clinically promising candidate to address the challenges associated with synergistic chemotherapy and photothermal utilization in antitumor therapy.
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Antibióticos Antineoplásicos/farmacología , Antioxidantes/farmacología , Catequina/análogos & derivados , Doxorrubicina/farmacología , Indoles/química , Polímeros/química , Neoplasias del Cuello Uterino/terapia , Zeolitas/química , Animales , Antibióticos Antineoplásicos/síntesis química , Antibióticos Antineoplásicos/química , Antioxidantes/síntesis química , Antioxidantes/química , Catequina/síntesis química , Catequina/química , Catequina/farmacología , Doxorrubicina/síntesis química , Doxorrubicina/química , Femenino , Células HeLa , Humanos , Ratones , Ratones Desnudos , Fototerapia , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Células Tumorales Cultivadas , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patologíaRESUMEN
BACKGROUND: Mammalian Ste20-like kinase 4 (MST4), also known as serine/threonine kinase 26 (STK26), promotes development of several cancers and is found to be highly expressed in the placenta. However, in choriocarcinoma that originated from the placenta, the expression of MST4 was undetermined and its mechanism was unknown. In this study, the expression of MST4 in choriocarcinoma as well as the underlying mechanism was explored. PURPOSE: To detect the expression of MST4 in patient samples and mechanism of mediating EMT by MST4 in choriocarcinoma. PATIENTS AND METHODS: The metastatic lesions of choriocarcinoma (n=17) and volunteer villus (n=17) were collected to determine MST4 expression using immunohistochemistry and H&E staining. We use siRNA and lentiviral vector to knockdown MST4 and use plasmid to overexpress MST4 in choriocarcinoma. Then, we apply real-time polymerase chain reaction (RT-PCR), Western blot assay and immunofluorescence assay to detect target protein expressions. Cell invasion and migration and cell proliferation were detected by transwell assay and wound healing assay and CCK-8 and cell colony formation. RESULTS: MST4 is lowly expressed in the metastatic lesions of choriocarcinoma patients when compared with normal villus. Knockdown of MST4 activated epithelial-mesenchymal transition (EMT) process, significantly increasing the ability of invasion and migration in choriocarcinoma cell lines (JAR and JEG-3). In contrast, the EMT process was restrained in choriocarcinoma cell lines with overexpressed MST4. Meanwhile, genome-wide gene expression array, Western blot and ELISA revealed that tumor growth factor-beta 1 (TGF-ß1) has significantly increased. The EMT process and metastatic prompting biofunction were reversed after using TGF-ß1 inhibitor (LY364947) in the choriocarcinoma cell lines with MST4 knockdown. CONCLUSION: Our studies demonstrated that MST4 was lowly expressed in patient samples. Additionally, JAR and JEG-3 increase cell invasion and migration ability while there is no influence on cell proliferation with MST4 knockdown. Conversely, the metastatic ability of JAR and JEG-3 was decreased with overexpressed MST4. Moreover, TGF-ß1 was a key factor after MST4 knockdown. In conclusion, MST4 affects choriocarcinoma EMT by mediating TGF-ß1 expression.
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Exosomes play an important role in intercellular communication and metastatic progression of hepatocellular carcinoma (HCC). However, cellular communication between heterogeneous HCC cells with different metastatic potentials and the resultant cancer progression are not fully understood in HCC. Here, HCC cells with high-metastatic capacity (97hm and Huhm) were constructed by continually exerting selective pressure on primary HCC cells (MHCC-97H and Huh7). Through performing exosomal miRNA sequencing in HCC cells with different metastatic potentials (MHCC-97H and 97hm), many significantly different miRNA candidates were found. Among these miRNAs, miR-92a-3p was the most abundant miRNA in the exosomes of highly metastatic HCC cells. Exosomal miR92a-3p was also found enriched in the plasma of HCC patient-derived xenograft mice (PDX) model with high-metastatic potential. Exosomal miR-92a-3p promotes epithelial-mesenchymal transition (EMT) in recipient cancer cells via targeting PTEN and regulating its downstream Akt/Snail signaling. Furthermore, through mRNA sequencing in HCC cells with different metastatic potentials and predicting potential transcription factors of miR92a-3p, upregulated transcript factors E2F1 and c-Myc were found in high-metastatic HCC cells promote the expression of cellular and exosomal miR-92a-3p in HCC by directly binding the promoter of its host gene, miR17HG. Clinical data showed that a high plasma exosomal miR92a-3p level was correlated with shortened overall survival and disease-free survival, indicating poor prognosis in HCC patients. In conclusion, hepatoma-derived exosomal miR92a-3p plays a critical role in the EMT progression and promoting metastasis by inhibiting PTEN and activating Akt/Snail signaling. Exosomal miR92a-3p is a potential predictive biomarker for HCC metastasis, and this may provoke the development of novel therapeutic and preventing strategies against metastasis of HCC.
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Carcinoma Hepatocelular/genética , Exosomas/metabolismo , Neoplasias Hepáticas/genética , MicroARNs/metabolismo , Fosfohidrolasa PTEN/genética , Animales , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/secundario , Línea Celular Tumoral , Movimiento Celular/genética , Supervivencia sin Enfermedad , Factor de Transcripción E2F1/metabolismo , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Ratones , MicroARNs/genética , Persona de Mediana Edad , Metástasis de la Neoplasia/genética , Fosfohidrolasa PTEN/metabolismo , Pronóstico , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Transducción de Señal/genética , Regulación hacia Arriba , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
INTRODUCTION: Solid pseudopapillary tumors (SPT) account for 1% to 3% of all pancreatic tumors. They have low malignant potential with a favorable prognosis, and predominantly occur in young women. The pathogenesis and clinical behavior of SPT are still uncertain. In addition, most ruptures of SPT were associated with blunt abdominal trauma, while spontaneous ruptures seemed to be quite rare. Up to now, there have been only 3 spontaneous ruptured SPT cases reported worldwide. PATIENT CONCERNS: Here, we reported a 22-year-old female patient with left lower abdominal pain. Computed tomography (CT) showed that a hemorrhagic complex solid cystic mass located in the lesser omentum sac. DIAGNOSIS: According to pathological findings of tumor specimen, the diagnosis of solid pseudopapillary tumor (SPT) of the pancreas was made. INTERVENTIONS: Distal pancreatectomy and splenectomy was carried out. OUTCOMES: The patient recovered to normal status within 10 days after surgery. CONCLUSION: Besides, we reviewed about 50 cases in literatures to find out the clinical characteristics and differential diagnostic strategies of SPT.
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Neoplasias Pancreáticas/patología , Femenino , Humanos , Pancreatectomía , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/cirugía , Rotura Espontánea , Esplenectomía , Adulto JovenRESUMEN
MicroRNAs (miRNAs) have been validated to play prominent roles in the occurrence and development of many kinds of malignant cancer. MiR-424-5p has been reported to participate in various tumors proliferation and metastasis as a suppressor. On the contrary, miR-424-5p would promote cell proliferation in some tumors. However, the expression of miR-424-5p in intrahepatic cholangiocarcinoma (ICC) is rarely reported and its mechanism remains unclear. Here, we discover that miR-424-5p is frequently downregulated in ICC tissues compared with adjacent normal tissues and in ICC cells. Over-expression of miR-424-5p significantly inhibits the invasion and migration of ICC cells in vitro. Importantly, miR-424-5p is found to be a suppressor of ARK5, by binding to 3'-UTR of ARK5 mRNA and then inhibiting mTOR phosphorylated, thus deregulating epithelial-mesenchymal transition (EMT) of ICC. Furthermore, ARK5 is found to play a role in ICC metastasis and regulating EMT. Knockdown of ARK5 inhibits invasion and migration of ICC, while the over-expression gives an opposite effect. Besides, high-expression of ARK5 is also associated with poor prognosis. In conclusion, our study reveals that miR-424-5p is critical to the invasion, migration and EMT progression in ICC cells. Targeting the pathway described here may be a novel approach to inhibit metastasis of ICC and the restoration of miR-424-5p expression may be a promising strategy for ICC therapy.
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Movimiento Celular/fisiología , Proliferación Celular/fisiología , Supervivencia Celular/fisiología , Colangiocarcinoma/metabolismo , Neoplasias Hepáticas/metabolismo , MicroARNs/metabolismo , Proteínas Quinasas/metabolismo , Proteínas Represoras/metabolismo , Western Blotting , Línea Celular , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Supervivencia Celular/genética , Colangiocarcinoma/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Neoplasias Hepáticas/genética , MicroARNs/genética , Proteínas Quinasas/genética , Proteínas Represoras/genéticaRESUMEN
BACKGROUND: Cholangiocarcinoma (CCA) is a subtype of highly malignant hepatic tumor, which has low 5-year survival rate and poor clinical outcome. Only a few patients can be detected early and accepted with the surgery. Most of CCA patients are diagnosed in advanced stage, and the treatments are limited. As for the inoperable, advanced CCA patients, chemotherapy is the main treatment, due to lacking molecular targets, therapeutic effect is limited. MATERIALS AND METHODS: To explore potential therapeutic targets for CCA, we analyzed three microarray datasets derived from the Gene Expression Omnibus (GEO) database. Then, we used GEO2R tools of NCBI to discover the differentially expressed genes (DEGs) from the CCA and normal liver tumor microarrays (TMA). Subsequently, we used the Database for Annotation, Visualization and Integrated Discovery (DAVID GO) to perform the Gene Ontology function (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Then, we carried out the Cytoscape software to search for the hub genes downregulated in CCA and identify the protein-protein interaction (PPI) of these genes. Besides, we used the GEPIA tool to evaluate the differential expressions of hub genes in CCA patients. Then, we also used MEXPRESS database to detect the promoter methylation levels of hub genes in CCA and normal tissue samples. In addition, we evaluated the expression of these genes in CCA lines and normal bile tract cells after 5-AZA (DNA methyltransferase inhibitor) treatment. RESULTS: A total of 115 downregulated DEGs were identified. Among them, 10 hub genes with a high degree of connectivity were picked out. Among these 10 hub genes, F2, AHSG, ALDH8A1, SERPIND1 and AGXT showed higher DNA methylation levels of promoter in CCA compared with normal liver tissues. Therefore, these 5 genes may be the potential DNA methylation biomarkers and therapeutic targets in CCA.
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Dimethyl fumarate (DMF) is generally used to treat psoriasis and multiple sclerosis. In the present study, we aimed to investigate the effects of DMF on hepatocellular carcinoma progression and its mechanism of action. In vitro, cell viability was examined using CCK-8 assay; cell cycle was analyzed by flow cytometry; angiogenesis was detected using tube formation assay; and autophagic flux assay results were examined using fluorescence microscopy. We also used western blotting to explore the potential mechanisms. In vivo, tumor xenograft experiment was performed with nude mice, and liver function, renal function, and routine blood counts were assessed using biochemical tests. Dimethyl fumarate inhibited tumor growth and angiogenesis in hepatocellular carcinoma, both in vitro and in vivo. Dimethyl fumarate decreased autophagy in hepatocellular carcinoma cells. Treatment with DMF activated SOCS3, which led to repression of JAK1 and STAT3 phosphorylation. DMF inhibited cell proliferation, angiogenesis, and autophagy via activation of the SOCS3/JAK1/STAT3 signaling pathway. This finding may provide a novel approach for the treatment of hepatocellular carcinoma.
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BACKGROUND: Hepatocellular carcinomas (HCC) constantly rank among the malignancies with the highest death tolls on the global scale. Moreover, HCC are associated with a limited set of therapeutic options. This is particularly true in the case of advanced stage cancers, where long-term survival is uncommon. For the inoperable, advanced HCC patients, chemotherapy is the main modality of treatment. Due to the lack of known molecular targets, the efficacy of the chemotherapy is limited. CONCLUSION: These findings clearly indicate that DNA methylation plays a key role in regulating ACADS expression and that it can be a potential therapeutic target for treating HCC. MATERIALS AND METHODS: A thorough comparative analysis of 282 cancer samples with 47 normal samples from GEO datasets resulted in the observation that that the level of ACADS was significantly downregulated in HCC. Loss-of-function analyses were then conducted to understand the biological function of ACADS in HCC. It was noted that ACADS was involved in the proliferation and metastasis of HCC. Experiments involving the knockdown of DMNT expression led to the discovery that the expression of ACADS in the HCC cells was significantly increased. The TCGA database was then employed to identify tumor tissue samples which showed higher methylation levels at cg01535453, cg08618068, and cg10174836 (which are the target sites of the ACADS CpG islands) as compared with normal liver tissue samples. All these findings indicated that ACADS might be a novel methylation biomarker associated with HCC.
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Acil-CoA Deshidrogenasa/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Acil-CoA Deshidrogenasa/genética , Animales , Apoptosis , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Islas de CpG , Regulación hacia Abajo , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/genética , Ratones , Ratones Desnudos , Neoplasias ExperimentalesRESUMEN
Liver cancer is a kind of lethal and aggressive malignant neoplasm with a high rate of relapse and metastasis after therapy. An important cause for the relapse and metastasis is the existence of liver cancer stem cells (CSCs), which have high resistance to chemotherapy and high tumorigenic potential. Therefore, it is crucial to develop new methods to eradicate CSCs in tumors. Herein, we develop a photodynamic therapy (PDT) that features bimodal metallacage-loaded nanoparticles (MNPs) for integrated chemotherapy. This platform achieves chemo-photodynamic combinational therapy. Organoplatinum(ii) metallacage-loaded nanoparticles show excellent ability to kill liver CSCs, decreasing their mobility and sphenoid formation ability under near-infrared laser irradiation. Importantly, MNPs can successfully penetrate into 3D tumor spheroids, which display higher drug resistance compared to traditional 2D cultured cells. This destroys CSCs and prevents subsequent tumor formation in vivo. With the excellent combinational therapeutic results in hand, the working mechanisms of MNPs were then studied. MNPs under NIR light irradiation can generate reactive oxygen species (ROS), resulting in damage of mitochondrial membrane and subsequent cell apoptosis with chemotherapeutic platinum. This study proves the great potential of MNPs for combinational cancer therapy, providing a new insight for the next generation of nanomedicines.
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Antineoplásicos/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Nanopartículas del Metal/uso terapéutico , Células Madre Neoplásicas/efectos de los fármacos , Fármacos Fotosensibilizantes/uso terapéutico , Animales , Antineoplásicos/química , Antineoplásicos/efectos de la radiación , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Complejos de Coordinación/química , Complejos de Coordinación/efectos de la radiación , Complejos de Coordinación/uso terapéutico , Humanos , Rayos Infrarrojos , Hígado/patología , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Nanopartículas del Metal/química , Nanopartículas del Metal/efectos de la radiación , Ratones Desnudos , Fotoquimioterapia , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/efectos de la radiación , Platino (Metal)/química , Platino (Metal)/efectos de la radiación , Porfirinas/química , Porfirinas/efectos de la radiación , Porfirinas/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Esferoides Celulares/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
RATIONALE: Lymphangiomas are benign lymphatic malformations that mostly occur in the neck and axillary regions. Abdominal lymphangioma is a rare type of this tumor, and pancreatic lymphangioma accounts for less than 1% of all lymphangiomas. In this report, we firstly reveal the application of ultrasound-guided puncture drainage combined with cell morphological examination for the diagnosis of pancreatic lymphangioma. PATIENT CONCERNS: A 35-year-old male patient was admitted to our hospital with recurrent abdominal pain and general weakness for 1 week. From abdominal ultrasound (US) showed that a large cystic lesion occupied the abdomen, about 30.0cm×25.0cm, leading to suspicion of lymphatic cyst. Computed tomography (CT) was performed for further diagnosis and staging. DIAGNOSES: According to pathological findings in combination with immunohistochemical features, pancreatic lymphangioma was made. INTERVENTIONS: To relieve symptoms of discomfort in the patient, distal pancreatectomy and splenectomy was carried out 1 week after the CT scan. OUTCOMES: The patient recovered to normal status within 19 days after surgery. LESSONS: The abdominal cystic lymphangiomas are difficult to be differential diagnosed from other cystic lesions. And the origin of the tumor is also hard to be detected before operation. We should combine image and pathological examination to clarify a diagnosis. Although lymphangiomas are benign tumours, they can encroach on adjacent organs and grow to an enormous size and that, resection of these invaded organs may be required for a complete excision.
Asunto(s)
Linfangioma Quístico , Pancreatectomía/métodos , Neoplasias Pancreáticas , Esplenectomía/métodos , Succión/métodos , Dolor Abdominal/diagnóstico , Dolor Abdominal/etiología , Adulto , Biopsia con Aguja/métodos , Diagnóstico Diferencial , Humanos , Linfangioma Quístico/diagnóstico , Linfangioma Quístico/patología , Linfangioma Quístico/fisiopatología , Linfangioma Quístico/cirugía , Masculino , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/fisiopatología , Neoplasias Pancreáticas/cirugía , Cirugía Asistida por Computador/métodos , Tomografía Computarizada por Rayos X/métodos , Resultado del Tratamiento , Ultrasonografía/métodosRESUMEN
The high activity of Histone deacetylases (HDACs) in hepatocellular carcinoma (HCC) usually positively correlates with poor prognosis of patients. Accordingly histone deacetylases inhibitors (HDACis) are considered to be potential agents treating patients with HCC. In our study, we evaluated effect of quisinostat alone and in combination with sorafenib in HCC cells via inducing G0/G1 phase arrest through PI3K/AKT/p21 pathway and apoptosis by JNK/c-Jun/caspase3 pathway in vitro and in vivo. The proliferation assay and flow cytometry were used to measure the viability, cell cycle and apoptosis. And Western blot assay was carried out to determine expression alternations of related proteins. Moreover HCCLM3 xenograft was further performed to detect antitumor effect of quisinostat in vivo. Here, we found that quisinostat impeded cell proliferation, and remarkably induced G0/G1 phase arrest and apoptosis in HCC cells in a dose-dependent manner. G0/G1 phase arrest was observed by alterations in PI3K/AKT/p21 proteins. Meanwhile the JNK, c-jun and caspase-3 were activated by quisinostat in a dose-dependent manner. Correspondingly quisinostat facilitated G0/G1 cycle arrest and apoptosis in HCC cells through PI3K/AKT/p21 pathways and JNK/c- jun/caspase3 pathways. Moreover, the potent tumor-suppressive effects facilitated by quisinostat, was significantly potentiated by combination with sorafenib in vitro and vivo. The combination treatment of quisinostat and sorafenib markedly suppressed cell proliferation and induced apoptosis in a synergistic manner. Moreover the therapy of quisinostat combined with sorafenib could apparently decrease tumor volume of a HCCLM3 xenograft model. Our study indicated that quisinostat, as a novel chemotherapy for HCC, exhibited excellent antitumor activity in vitro and vivo, which was even enhanced by the addition of sorafenib, implying combination of quisinostat with sorafenib a promising and alternative therapy for patients with advanced hepatocellular carcinoma.