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BACKGROUND: Among digestive tract tumours, pancreatic ductal adenocarcinoma (PDAC) shows the highest mortality trend. Moreover, although PDAC metastasis remains a leading cause of cancer-related deaths, the biological mechanism is poorly understood. Recent evidence demonstrates that circular RNAs (circRNAs) play important roles in PDAC progression. METHODS: Differentially expressed circRNAs in normal and PDAC tissues were screened via bioinformatics analysis. Sanger sequencing, RNase R and actinomycin D assays were performed to confirm the loop structure of circEIF3I. In vitro and in vivo functional experiments were conducted to assess the role of circEIF3I in PDAC. MS2-tagged RNA affinity purification, mass spectrometry, RNA immunoprecipitation, RNA pull-down assay, fluorescence in situ hybridization, immunofluorescence and RNA-protein interaction simulation and analysis were performed to identify circEIF3I-interacting proteins. The effects of circEIF3I on the interactions of SMAD3 with TGFßRI or AP2A1 were measured through co-immunoprecipitation and western blotting. RESULTS: A microarray data analysis showed that circEIF3I was highly expressed in PDAC cells and correlated with TNM stage and poor prognosis. Functional experiments in vitro and in vivo revealed that circEIF3I accelerated PDAC cells migration, invasion and metastasis by increasing MMPs expression and activity. Mechanistic research indicated that circEIF3I binds to the MH2 domain of SMAD3 and increases SMAD3 phosphorylation by strengthening the interactions between SMAD3 and TGFßRI on early endosomes. Moreover, AP2A1 binds with circEIF3I directly and promotes circEIF3I-bound SMAD3 recruitment to TGFßRI on early endosomes. Finally, we found that circEif3i exerts biological functions in mice similar to those of circEIF3I in humans PDAC. CONCLUSIONS: Our study reveals that circEIF3I promotes pancreatic cancer progression. circEIF3I is a molecular scaffold that interacts with SMAD3 and AP2A1 to form a ternary complex, that facilitates the recruitment of SMAD3 to early endosomes and then activates the TGF-ß signalling pathway. Hence, circEIF3I is a potential prognostic biomarker and therapeutic target in PDAC.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animales , Humanos , Ratones , Carcinoma Ductal Pancreático/genética , Endosomas , Hibridación Fluorescente in Situ , Neoplasias Pancreáticas/genética , ARN Circular , Proteína smad3/genética , Factor de Crecimiento Transformador beta , Neoplasias PancreáticasRESUMEN
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by rapid progression and poor prognosis. Understanding the genetic mechanisms that affect cancer properties and reprogram tumor immune microenvironment will develop new strategies to maximize the benefits for cancer therapies. METHODS: Gene signatures and biological processes associated with advanced cancer and unfavorable outcome were profiled using bulk RNA sequencing and spatial transcriptome sequencing, Caprin-1 was identified as an oncogenesis to expedite pancreatic cancer growth by activating autophagy. The mechanism of Caprin-1 inducing autophagy activation was further explored in vitro and in vivo. In addition, higher level of Caprin-1 was found to manipulate immune responses and inflammatory-related pathways. The immune profiles associated with increased levels of Caprin-1 were identified in human PDAC samples. The roles of CD4+T cells, CD8+T cells and tumor associated macrophages (TAMs) on clinical outcomes prediction were investigated. RESULTS: Caprin-1 was significantly upregulated in advanced PDAC and correlated with poor prognosis. Caprin-1 interacted with both ULK1 and STK38, and manipulated ULK1 phosphorylation which activated autophagy and exerted pro-tumorigenic phenotypes. Additionally, the infiltrated CD4+T cells and tumor associated macrophages (TAMs) were increased in Caprin-1High tissues. The extensive CD4+T cells determined poor clinical outcome in Caprin-1high patients, arguing that highly expressed Caprin-1 may assist cancer cells to escape from immune surveillance. CONCLUSIONS: Our findings establish causal links between the upregulated expression of Caprin-1 and autophagy activation, which may manipulate immune responses in PDAC development. Our study provides insights into considering Caprin-1 as potential therapeutic target for PDAC treatment.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Autofagia/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Inmunidad , Neoplasias Pancreáticas/patología , Proteínas Serina-Treonina Quinasas , Microambiente TumoralRESUMEN
Emerging evidence has indicated that long noncoding RNAs (lncRNAs) are potential biomarkers and play crucial roles in cancer development. However, the functions and underlying mechanisms of lncRNA TPT1-AS1 in pancreatic ductal adenocarcinoma (PDAC) remain elusive. RNAseq data of PDAC tissues and normal tissues were analyzed, and lncRNAs which were associated with PDAC prognosis were identified. The clinical relevance of TPT1-AS1 for PDAC patients was explored, and the effects of TPT1-AS1 in PDAC progression were investigated in vitro and in vivo. LncRNA TPT1-AS1 was highly expressed in PDAC, and high TPT1-AS1 levels predicted a poor prognosis. Moreover, functional experiments revealed that TPT1-AS1 promoted pancreatic cancer cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT) process in vitro and in vivo. Mechanistically, TPT1-AS1 functioned as an endogenous sponge for miR-30a-5p, which increased integrin ß3 (ITGB3) level in pancreatic cancer cells. Conversely, our data revealed that ITGB3 could activate the transcription factor signal transducer and activator of transcription 3 (STAT3), which in turn bound directly to the TPT1-AS1 promoter and affected the expression of TPT1-AS1, thus forming a positive feedback loop with TPT1-AS1. Taken together, our results uncovered a reciprocal loop of TPT1-AS1 and ITGB3 which contributed to pancreatic cancer growth and development, and indicated that TPT1-AS1 might serve as a novel potential diagnostic biomarker and therapeutic target for PDAC patients.
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Carcinoma Ductal Pancreático , MicroARNs , Neoplasias Pancreáticas , ARN Largo no Codificante , Carcinoma Ductal Pancreático/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Retroalimentación , Regulación Neoplásica de la Expresión Génica , Humanos , Integrina beta3/genética , Integrina beta3/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Neoplasias PancreáticasRESUMEN
The main mechanism of hyaluronidase 1(HYAL-1) in the development of postoperative pancreatic fistula (POPF) after pancreatoduodenectomy (PD) was unknown. In this study, a comprehensive inventory of pre-, intra-, and postoperative clinical and biological data of two cohorts (62 pancreatic cancer [PCa] and 111 pancreatic ductal adenocarcinoma [PDAC]) which could induce POPF were retrospectively analyzed. Then, a total of 7644 genes correlated with HYAL-1 was predicted in PDAC tissues and the enriched pathway, kinase targets and biological process of those correlated genes were evaluated. Finally, a mouse pancreatic fistula (PF) model was first built and in vitro studies were performed to investigate the effects of HYAL-1 on PF progression. Our data indicated that preoperative serum HYAL-1 level, pancreatic fibrosis score, and pancreatic duct size were valuable factors for detecting POPF of Grade B and C. The serum HYAL-1 level of 2.07 mg/ml and pancreatic fibrosis score of 2.5 were proposed as the cutoff values for indicating POPF. The bioinformatic analysis and in vitro and in vivo studies demonstrated that HYAL-1 facilitates pancreatic acinar cell autophagy via the dephosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) and signal transducers and activators of transcription 3 (STAT3) signaling pathways, which exacerbate pancreatic secretion and inflammation. In summary, the preoperative serum HYAL-1 was a significant predictor for POPF in patients who underwent PD. Tumor-induced HYAL-1 is one of core risk in accelerating PF and then promoting pancreatic secretion and acute inflammation response through the AMPK and STAT3-induced autophagy.
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Autofagia/fisiología , Hialuronoglucosaminidasa/sangre , Fístula Pancreática/patología , Pancreaticoduodenectomía , Adulto , Anciano , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/cirugía , Femenino , Humanos , Intestinos/patología , Masculino , Persona de Mediana Edad , Páncreas/patología , Fístula Pancreática/diagnóstico , Fístula Pancreática/cirugía , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Pancreaticoduodenectomía/métodos , Estudios Retrospectivos , Factores de Riesgo , Neoplasias PancreáticasRESUMEN
Outflow tract (OFT) anomalies account for about 30% of human congenital heart defects detected at birth. The second heart field (SHF) progenitors contribute to OFT and right ventricle (RV) development, but the process largely remains unknown. WDR1 (WD-repeat domain 1) is a major co-factor of actin depolymerizing factor (ADF)/cofilin that actively disassembles ADF/cofilin-bound actin filaments. Its function in embryonic heart development has been unknown. Using Wdr1 floxed mice and Nkx2.5-Cre, we deleted Wdr1 in embryonic heart (Wdr1F/F;Nkx2.5-Cre) and found that these mice exhibited embryonic lethality, and hypoplasia of OFT and RV. To investigate the role of WDR1 in OFT and RV development, we generated SHF progenitors-specific Wdr1 deletion mice (shfKO). shfKO mice began to die at embryonic day 11.5 (E11.5), and displayed decreased size of the proximal OFT and RV at E10.5. In shfKO embryos, neither the number of SHF cells deployment to OFT nor cell proliferation and the cell number were changed, whereas the cellular organization and myofibrillar assembly of cardiomyocytes were severely disrupted. In the proximal OFT and RV of both shfKO and Wdr1F/F;Nkx2.5-Cre embryos, cardiomyocytes were dissociated from the outer compact myocardial layer and loosely and disorderly arranged into multilayered myocardium. Our results demonstrate that WDR1 is indispensable for normal OFT and RV development, and suggest that WDR1-mediated actin dynamics functions in controlling the size of OFT and RV, which might through regulating the spatial arrangement of cardiomyocytes.
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Ventrículos Cardíacos/embriología , Proteínas de Microfilamentos/fisiología , Actinas/genética , Actinas/metabolismo , Animales , Embrión de Mamíferos/embriología , Desarrollo Embrionario/genética , Desarrollo Embrionario/fisiología , Regulación del Desarrollo de la Expresión Génica/genética , Corazón/embriología , Cardiopatías Congénitas/genética , Ratones , Ratones Noqueados , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Miocardio , Miocitos Cardíacos , Organogénesis , Transducción de Señal , Obstrucción del Flujo Ventricular ExternoRESUMEN
BACKGROUND Acute pancreatitis (AP) is a common digestive disorder. Its management depends on the severity; therefore, it is essential to stratify AP patients early. D-dimer, a coagulation indicator, appears to be associated with the pathogenesis of AP. The aim of this study was to evaluate D-dimer as an early predictor of the severity of AP. MATERIAL AND METHODS This was a single-center retrospective study of 1260 patients diagnosed based on the revised Atlanta classification. Only patients hospitalized within 24 h of onset were included, and 334 patients were enrolled. Blood was collected at admission and 3 times within 48 h of admission. Values at admission and average of the 3 blood samples were evaluated by univariate and multivariate analyses. Furthermore, the area under the receiver-operating characteristic curve (AUC) was used to estimate the validity of the predictor and to define optimal cut-off points for prediction. RESULTS We found that 53.3% of the patients had mild AP (MAP), 24.3% had moderately severe AP (MSAP), and 22.4% had severe AP (SAP). D-dimer at admission and the average D-dimer could distinguish MAP patients from MSAP and SAP patients, with cut-off values of 3.355 mg/L and 4.868 mg/L, respectively. No difference in the parameters at admission was observed in multivariate analysis in distinguishing SAP from MSAP, but the average D-dimer level was significantly different with a cut-off value of 7.268 mg/L by comparing Ranson score, APACHE II score, and D-dimer level. CONCLUSIONS The average value of D-dimer levels could be used as a predictor of severity of AP. In general, patients with an average D-dimer level <4.868 could be diagnosed with MAP, >7.268 would develop into SAP, and between 4.868 and 7.268 would be MSAP.
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Productos de Degradación de Fibrina-Fibrinógeno/análisis , Pancreatitis/metabolismo , APACHE , Enfermedad Aguda , Adulto , China , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Pancreatitis/clasificación , Plasma/química , Valor Predictivo de las Pruebas , Pronóstico , Curva ROC , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: The objective of this study was to evaluate the safety of total thyroidectomy for thyroid disorders and summarise the treatment experience in a less-developed region. METHODS: This was a retrospective observational cohort study using the computerised database of the First Affiliated Hospital of Harbin Medical University. All consecutive thyroidectomy patients from 2003 to 2014 were included in this study. Demographics, surgical procedure, diagnoses, morbidity and mortality were retrospectively reviewed. RESULTS: There were a total of 714 men and 4845 women in this study, with a mean age of 55 (range 9-87) years. A total of 4632 patients underwent total thyroidectomy for primary surgical treatment, and 189 patients previously underwent partial thyroidectomy. A total of 56.2% of the patients had multinodular goitre, including 12.23% who were thyrotoxic. Graves' disease and Hashimoto's disease were diagnosed in 2.82 and 7.23% of the patients, respectively. Papillary thyroid cancer was identified in 1336 patients, 44.99% of whom had papillary microcarcinoma. The total prevalence of permanent complications of first-time and secondary surgeries was 0.35 and 7.41%, respectively. During thyroid surgery, 945 patients underwent parathyroid autotransplantation. CONCLUSIONS: Initial total thyroidectomy can be safely performed for both benign and malignant thyroid diseases in a less-developed region. The morbidity of a secondary surgical procedure after subtotal thyroidectomy is significantly high compared to first-time surgery.
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Países en Desarrollo , Enfermedades de la Tiroides/cirugía , Tiroidectomía/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , China , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/prevención & control , Recurrencia , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: To investigate the effect of utilizing octreotide during perioperative period on pancreatic fistula after pancreaticoduodenectomy (PD). METHODS: Three hundreds and six patients admitted from January 2010 to October 2014, who prepared to undergo pancreaticoduodenectomy (PD) were randomly divided into octreotide group (147 cases) and control group (159 cases). In octreotide group, octreotide was used in subcutaneous injection instantly after PD, each 8 hours until postoperative 10(th) day, and patients in control group were injected with the same volume of saline. Differences of pancreatic fistula (Grade A, Grade B, Grade C), hospitalization days and treatment cost were compared. χ(2) test, t-test and Fisher exact test were used to analyzed to the data, respectively. RESULTS: No statistical significance (P>0.05) between two groups in the incidence of pancreatic fistula after PD (Grade A: 8.8% vs. 10.2%, Grade B: 2.7% vs. 4.4%, Grade C: 0.7% vs. 1.3%; χ(2)=0.197, 0.700, 0.288; P=0.657, 0.403, 0.591), the length of hospitalization((12.1±1.2)days vs. (13.0±1.2)days)(t=1.711, P=0.104) and treatment cost (79 700±6 700 vs. 77 600±5 200)(t=1.378, P=0.185). When accompanied with high risk factors, such as soft texture of pancreas, pancreatic duct size less than 3 mm, BMI≥25 kg/m(2) and diabetes, compared with control group, octreotide group had the lower incidence rate of pancreatic fistula and clinical correlative pancreatic fistula(all P<0.05) after PD. CONCLUSIONS: Generally, octreotide makes no contribution to reduce the incidence of pancreatic fistula after PD. However, for patients who is accompanied with high risk factors, such as soft texture of pancreas, pancreatic duct size less than 3 mm, BMI≥25 kg/m(2) and diabetes, octreotide can effectively prevent pancreatic fistula after PD.
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Octreótido/uso terapéutico , Fístula Pancreática/tratamiento farmacológico , Pancreaticoduodenectomía/efectos adversos , Anastomosis Quirúrgica , Humanos , Incidencia , Páncreas/patología , Pancreatectomía , Conductos Pancreáticos/patología , Periodo Perioperatorio , Estudios ProspectivosRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxic tumor microenvironment (TME), which aids tumor progression, drug resistance, and immune evasion. Dual-specificity phosphatase 2 (DUSP2), a member of the mitogen-activated protein kinase phosphatase family, regulates pancreatic cancer metastasis. However, its role in the hypoxic TME in PDAC remains unknown. We explored the role of DUSP2 by simulating the hypoxic TME. DUSP2 significantly promoted apoptosis in PDAC both in vitro and in vivo, mainly through AKT1 rather than ERK1/2. Mechanistically, DUSP2 competed with AKT1 to bind to casein kinase 2 alpha 1 (CSNK2A1) and inhibited the phosphorylation of AKT1, which plays a crucial role in apoptosis resistance. Interestingly, aberrant activation of AKT1 resulted in an increase in the ubiquitin E3 ligase tripartite motif-containing 21 (TRIM21), which binds to and mediates the ubiquitination-dependent proteasomal degradation of DUSP2. Overall, we identified CSNK2A1 as a novel binding partner of DUSP2 that promotes PDAC apoptosis through CSN2KA1/AKT1 in an ERK1/2-independent manner. Activation of AKT1 also mediated proteasomal degradation of DUSP2 via the AKT1/TRIM21 positive feedback loop. We propose increasing the level of DUSP2 as a potential therapeutic strategy for PDAC.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Fosfatasa 2 de Especificidad Dual/metabolismo , Neoplasias Pancreáticas/patología , Hipoxia , Carcinoma Ductal Pancreático/patología , Apoptosis , Línea Celular Tumoral , Microambiente Tumoral , Proteínas Proto-Oncogénicas c-akt , Neoplasias PancreáticasRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) presents with high mortality and short overall survival. Cancer-associated fibroblasts (CAFs) act as refuge for cancer cells in PDAC. Mechanisms of intracelluar communication between CAFs and cancer cells need to be explored. Long noncoding RNAs (lncRNAs) are involved in the modulation of oncogenesis and tumor progression of PDAC; however, specific lncRNAs and their mechanism of action have not been clarified clearly in tumoral microenvironment. This work aims to identify novel lncRNAs involved in cellular interaction between cancer cells and CAFs in PDAC. To this end, differentially expressed lncRNAs between long-term and short-term survival PDAC patients are screened. Lnc-FSD2-31:1 is found to be significantly increased in long-term survival patients. This work then discovers that tumor-derived lnc-FSD2-31:1 restrains CAFs activation via miR-4736 transported by extracellular vesicles (EVs) in vitro and in vivo. Mechanistically, EVs-derived miR-4736 suppresses autophagy and contributes to CAFs activation by targeting ATG7. Furthermore, blocking miR-4736 suppresses tumor growth in genetically engineered KPC (LSL-KrasG12D/+, LSL-Trp53R172H/+, and Pdx-1-Cre) mouse model of PDAC. This study demonstrates that intratumoral lnc-FSD2-31:1 modulates autophagy in CAFs resulting in their activation through EVs-derived miR-4736. Targeting miR-4736 may be a potential biomarker and therapeutic target for PDAC.
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Fibroblastos Asociados al Cáncer , Carcinoma Ductal Pancreático , MicroARNs , Neoplasias Pancreáticas , ARN Largo no Codificante , Ratones , Animales , Fibroblastos Asociados al Cáncer/patología , ARN Largo no Codificante/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , MicroARNs/genética , Microambiente Tumoral , Neoplasias PancreáticasRESUMEN
Hypertriglyceridemic pancreatitis (HTGP) is featured by higher incidence of complications and poor clinical outcomes. Gut microbiota dysbiosis is associated with pancreatic injury in HTGP and the mechanism remains unclear. Here, we observe lower diversity of gut microbiota and absence of beneficial bacteria in HTGP patients. In a fecal microbiota transplantation mouse model, the colonization of gut microbiota from HTGP patients recruits neutrophils and increases neutrophil extracellular traps (NETs) formation that exacerbates pancreatic injury and systemic inflammation. We find that decreased abundance of Bacteroides uniformis in gut microbiota impairs taurine production and increases IL-17 release in colon that triggers NETs formation. Moreover, Bacteroides uniformis or taurine inhibits the activation of NF-κB and IL-17 signaling pathways in neutrophils which harness NETs and alleviate pancreatic injury. Our findings establish roles of endogenous Bacteroides uniformis-derived metabolic and inflammatory products on suppressing NETs release, which provides potential insights of ameliorating HTGP through gut microbiota modulation.
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Trampas Extracelulares , Microbioma Gastrointestinal , Pancreatitis , Ratones , Animales , Humanos , Trampas Extracelulares/metabolismo , Interleucina-17/metabolismo , Microbioma Gastrointestinal/fisiología , Pancreatitis/metabolismo , Taurina/metabolismoRESUMEN
As a major co-factor of F-actin depolymerization, WD-repeat domain 1 (WDR1) affects the cellular microenvironment by cytoskeleton remodeling, thereby influencing cell molecular behavior. Our previous study showed that WDR1 activates YAP (Yes-associated protein) signaling in non-small-cell lung cancer (NSCLC) cells, but the mechanism remains unclear. We discovered that knockdown WDR1 in NSCLC cells decreased the expression of YAP and the nucleus-to-cytoplasm ratio. Disruption of cortical stress by drugs significantly inhibited YAP nuclear trafficking and enhanced YAP phosphorylation. In WDR1-knockdown NSCLC cells, inhibition of Hippo pathway reduced the nuclear exclusion of YAP and phosphorylated YAP. Our data suggest that WDR1-mediated cortical stress might be involved in regulating YAP signaling, thereby affecting the proliferation and migration of NSCLC cells.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Actinas/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Señalizadoras YAP , Línea Celular Tumoral , Proliferación Celular/fisiología , Microambiente Tumoral , Proteínas de Microfilamentos/fisiologíaRESUMEN
Dissemination of cancer cells is an intricate multistep process that represents the most deadly aspect of cancer. Cancer cells form F-actin-rich protrusions known as invadopodia to invade surrounding tissues, blood vessels and lymphatics. A number of studies have demonstrated the significant roles of invadopodia in cancer. Therefore, the specific cells and molecules involved in invadopodia activity can provide as therapeutic targets. In this review, we included a thorough overview of studies in invadopodia and discussed their functions in cancer metastasis. We then presented the specific cells and molecules involved in invadopodia activity in pancreatic cancer and analyzed their suitability to be effective therapeutic targets. Currently, drugs targeting invadopodia and relevant clinical trials are negligible. Here, we highlighted the significance of potential drugs and discussed future obstacles in implementing clinical trials. This review presents a new perspective on invadopodia-induced pancreatic cancer metastasis and may prosper the development of targeted therapeutics against pancreatic cancer.
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Neoplasias Pancreáticas , Podosomas , Línea Celular Tumoral , Matriz Extracelular , Humanos , Invasividad Neoplásica , Neoplasias Pancreáticas/tratamiento farmacológicoRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease that typically features a dramatic desmoplastic reaction, especially fibroblasts. The roles of cancer-associated fibroblasts (CAFs) in PDAC have received more attention in recent years. As increasing evidence suggests the heterogeneity of CAFs in PDAC, different CAF subtypes have been shown to support tumor growth, while others suppress cancer proliferation. Myofibrotic CAFs (myCAFs) show alpha-smooth muscle actin (α-SMA) high interleukin-6 (IL-6) low myofibroblastic features, are activated by direct contact with tumor cells, and are located in the periglandular region. Inflammatory CAFs (iCAFs) show α-SMA low IL-6 high inflammatory features, are activated by paracrine factors secreted from tumor cells, and are located away from cancer cells. Antigen-presenting CAFs (apCAFs) show major histocompatibility complex II (MHC II) family genes that are highly expressed. CAFs have also been gradually explored as diagnostic and prognostic markers in pancreatic cancer. Targeted therapy of CAFs in PDAC has gradually attracted attention. With the deepening of related studies, some meaningful positive and negative results have surfaced, and CAFs may be the key to unlocking the door to pancreatic cancer treatment. Our review summarizes recent advances in the heterogeneity, function, and markers of CAFs in pancreatic cancer, as well as research and treatment targeting CAFs in pancreatic cancer.
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Chronic pancreatitis (CP) is described as progressive inflammatory fibrosis of pancreas, accompanied with irreversible impaired endocrine and exocrine insufficiency. Pancreatic stellate cells (PSCs) are widely distributed in the stroma of the pancreas and PSCs activation has been shown as one of the leading causes for pancreatic fibrosis. Our previous study has revealed that autophagy is dramatically activated in CP tissues, which facilitates PSCs activation and pancreatic fibrosis. Long non-coding RNAs (LncRNAs) have been recognized as crucial regulators for fibrosis-related diseases. LncRNAs interact with RNA binding protein or construct competitive endogenous RNA (ceRNA) hypothesis which elicited the fibrotic processes. Until now, the effects of lncRNAs on PSCs activation and pancreatic fibrosis have not been clearly explored. In this study, a novel lncRNA named Lnc-PFAR was found highly expressed in mouse and human CP tissues. Our data revealed that Lnc-PFAR facilitates PSCs activation and pancreatic fibrosis via RB1CC1-induced autophagy. Lnc-PFAR reduces miR-141 expression by suppressing pre-miR-141 maturation, which eventually upregulates the RB1CC1 and fibrosis-related indicators expression. Meanwhile, Lnc-PFAR enhanced PSCs activation and pancreatic fibrosis through trigging autophagy. Our study interrogates a novel lncRNA-induced mechanism in promoting the development of pancreatic fibrosis, and Lnc-PFAR is suggested to be a prospective therapeutic target in clinical scenarios.
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Fibrosis/complicaciones , MicroARNs/metabolismo , Pancreatitis Crónica/genética , ARN Largo no Codificante/metabolismo , Animales , Autofagia , Estudios de Casos y Controles , Enfermedad Crónica , Modelos Animales de Enfermedad , Humanos , Ratones , Pancreatitis Crónica/patologíaRESUMEN
The migration, dedifferentiation, and proliferation of vascular smooth muscle cells (VSMCs) are responsible for intimal hyperplasia, but the mechanism of this process has not been elucidated. WD repeat domain 1 (WDR1) promotes actin-depolymerizing factor (ADF)/cofilin-mediated depolymerization of actin filaments (F-actin). The role of WDR1 in neointima formation and progression is still unknown. A model of intimal thickening was constructed by ligating the left common carotid artery in Wdr1 deletion mice, and H&E staining showed that Wdr1 deficiency significantly inhibits neointima formation. We also report that STAT3 promotes the proliferation and migration of VSMCs by directly promoting WDR1 transcription. Mechanistically, we clarified that WDR1 promotes the proliferation and migration of VSMCs and neointima formation is regulated by the activation of the JAK2/STAT3/WDR1 axis.
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Proteínas de Microfilamentos/deficiencia , Animales , Arterias Carótidas/citología , Arterias Carótidas/metabolismo , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Janus Quinasa 2/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas de Microfilamentos/metabolismo , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/metabolismo , Neointima/metabolismo , Neointima/patología , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Repeticiones WD40RESUMEN
Aberrant DNA methylation, especially hypermethylation of tumor suppressor genes, has been associated with many cancers' progression. 5-Aza-2'-deoxycytidine (DAC) can reverse hypermethylation-induced gene silencing via regulating DNA methyltransferases (DNMTs) activity, In addition, low-dose of DAC was proved to exert durable antitumor effects against solid tumor cells. Nevertheless, no clinical effect of DAC has been made when fighting against pancreatic cancer. Hence, it is necessary to raise a novel therapeutic strategy that further enhance the efficacy of DAC but not increase side effect, which impede the utilization of DAC. In the present study, we have discovered that C188-9, a novel signal transduction activator of transcription (STAT) inhibitor, could improve the antitumor effects of low-dose DAC in vivo and in vitro. Further study demonstrated that such improvement was attributed to re-expression of Ras association domain family member 1A (RASSF1A), a well-known tumor suppressor gene. Bisulfite sequencing PCR (BSP) assay showed that C188-9 combined with DAC treatment could significantly reverse the hypermethylation status of RASSF1A promoter, which indicated that C188-9 could enhance the demethylation efficacy of DAC. Our data demonstrated that DNA methyltransferase 1 (DNMT1) was the underlying mechanism that C188-9 regulates the demethylation efficacy of DAC. Overall, these findings provide a novel therapeutic strategy combining low-dose DAC and C188-9 to improve therapeutic efficacy by inhibiting DNMT1-inducing promoter methylation.
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WDR1 is a major cofactor of the actin depolymerizing factor (ADF)/cofilin, accelerating ADF/cofilin-mediated actin disassembly. We had previously showed that WDR1-mediated actin dynamics is required for postnatal myocardial growth and adult myocardial maintenance in mice, in which the detailed phenotypes of adult cardiomyocyte-specific Wdr1 deletion mice had not been analyzed. In this study, we systematically analyzed the role of Wdr1 in adult mouse heart. Adult cardiomyocyte-specific Wdr1 deletion mice (cKO) exhibited cardiac hypertrophy and myocardial fibrosis. Echocardiographic study and electrocardiography revealed impaired contractile function, prolonged QT interval and Tpeak-Tend interval, and abnormal T-wave amplitude in cKO mice. Increased levels of sarcomeric proteins, adherens junction proteins and cofilin, and severe actin filament (F-actin) accumulations were observed in cKO mice heart. Taken together, this finding demonstrates that WDR1 is a critical factor for normal structure and function of adult mouse heart.
Asunto(s)
Cardiomegalia/genética , Proteínas de Microfilamentos/genética , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/patología , Actinas/metabolismo , Animales , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatología , Destrina/metabolismo , Femenino , Corazón/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Microfilamentos/metabolismo , Miocitos Cardíacos/fisiología , OrganogénesisRESUMEN
Currently, preliminary results have confirmed the existence of receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL)-dependent necroptosis of pancreatic acinar cells during early acute pancreatitis (AP), which might be a potential target for the effective regulation of necroinflammatory injury. However, the exact effect of receptor-interacting protein kinase 1 (RIPK1)-dependent regulated acinar cell necrosis on AP is still uncertain. In our study, we first explored the changes in the degree of local and systemic inflammation in AP rats when the activation of acinar cell RIPK1 was inhibited. The RIPK1 inhibitor Nec-1 was used to treat rats, and the levels of related inflammatory markers, necrosis indicators and apoptotic indicators were measured. Changes in pancreatic nuclear factor κB (NF-κB) and aquaporin 8 (AQP8) expression were noted. Next, the expression of AQP8 in AR42J cells was inhibited, and the degree of cell necrosis and inflammatory damage was found to be significantly reduced. Most importantly, we demonstrated that the RIPK1/NF-ĸB/AQP8 axis might be a potential regulatory pathway mediating RIPK1-dependent regulated acinar cell necrosis in early AP. Finally, we used the NF-κB inhibitor PDTC and Nec-1 to treat rats in different groups and measured the degree of pathological pancreatic injury, the activation of RIPK1, and the expression of NF-κB and AQP8. In summary, we hypothesized that there might be a RIPK1/NF-ĸB/AQP8 pathway controlling RIPK1-dependent regulated necrosis of acinar cells in AP, which might be a promising therapeutic target against AP-related injury.