ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with dismal prognosis due to distant metastasis, even in the early stage. Using RNA sequencing and multiplex immunofluorescence, here we find elevated expression of mixed lineage kinase domain-like pseudo-kinase (MLKL) and enhanced necroptosis pathway in PDAC from early liver metastasis T-stage (T1M1) patients comparing with non-metastatic (T1M0) patients. Mechanistically, MLKL-driven necroptosis recruits macrophages, enhances the tumor CD47 'don't eat me' signal, and induces macrophage extracellular traps (MET) formation for CXCL8 activation. CXCL8 further initiates epithelial-mesenchymal transition (EMT) and upregulates ICAM-1 expression to promote endothelial adhesion. METs also degrades extracellular matrix, that eventually supports PDAC liver metastasis. Meanwhile, targeting necroptosis and CD47 reduces liver metastasis in vivo. Our study thus reveals that necroptosis facilitates PDAC metastasis by evading immune surveillance, and also suggest that CD47 blockade, combined with MLKL inhibitor GW806742X, may be a promising neoadjuvant immunotherapy for overcoming the T1M1 dilemma and reviving the opportunity for radical surgery.
Subject(s)
CD47 Antigen , Carcinoma, Pancreatic Ductal , Epithelial-Mesenchymal Transition , Extracellular Traps , Liver Neoplasms , Macrophages , Necroptosis , Pancreatic Neoplasms , Protein Kinases , Humans , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/immunology , Liver Neoplasms/secondary , Liver Neoplasms/metabolism , Animals , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/immunology , Carcinoma, Pancreatic Ductal/genetics , Mice , Macrophages/metabolism , Macrophages/immunology , Cell Line, Tumor , CD47 Antigen/metabolism , CD47 Antigen/genetics , Protein Kinases/metabolism , Extracellular Traps/metabolism , Intercellular Adhesion Molecule-1/metabolism , Intercellular Adhesion Molecule-1/genetics , Male , Signal Transduction , Female , Acrylamides , SulfonamidesABSTRACT
Patients with concurrent intrahepatic cholangiocarcinoma (ICC) and hepatolithiasis generally have poor prognoses. Hepatolithiasis is once considered the primary cause of ICC, although recent insights indicate that bacteria in the occurrence of hepatolithiasis can promote the progression of ICC. By constructing in vitro and in vivo ICC models and patient-derived organoids (PDOs), it is shown that Escherichia coli induces the production of a novel RNA, circGLIS3 (cGLIS3), which promotes tumor growth. cGLIS3 binds to hnRNPA1 and G3BP1, resulting in the assembly of stress granules (SGs) and suppression of hnRNPA1 and G3BP1 ubiquitination. Consequently, the IKKα mRNA is blocked in SGs, decreasing the production of IKKα and activating the NF-κB pathway, which finally results in chemoresistance and produces metastatic phenotypes of ICC. This study shows that a combination of Icaritin (ICA) and gemcitabine plus cisplatin (GP) chemotherapy can be a promising treatment strategy for ICC.
Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Disease Progression , Escherichia coli , NF-kappa B , Stress Granules , Animals , Humans , Mice , Bile Duct Neoplasms/metabolism , Bile Duct Neoplasms/genetics , Bile Duct Neoplasms/pathology , Cholangiocarcinoma/metabolism , Cholangiocarcinoma/genetics , Cholangiocarcinoma/pathology , Disease Models, Animal , DNA Helicases , Escherichia coli/genetics , Escherichia coli/metabolism , Gemcitabine , NF-kappa B/metabolism , NF-kappa B/genetics , Poly-ADP-Ribose Binding Proteins/metabolism , Poly-ADP-Ribose Binding Proteins/genetics , RNA Helicases , RNA Recognition Motif Proteins/metabolism , RNA Recognition Motif Proteins/genetics , Signal Transduction/genetics , Stress Granules/metabolism , Stress Granules/geneticsABSTRACT
Intrahepatic cholangiocarcinoma (ICC) is characterized by its dense fibrotic microenvironment and highly malignant nature, which are associated with chemotherapy resistance and very poor prognosis. Although circRNAs have emerged as important regulators in cancer biology, their role in ICC remains largely unclear. Herein, a circular RNA, cPKM is identified, which is upregulated in ICC and associated with poor prognosis. Silencing cPKM in ICC cells reduces TGFB1 release and stromal fibrosis, inhibits STMN1 expression, and suppresses ICC growth and metastasis, moreover, it also leads to overcoming paclitaxel resistance. This is regulated by the interactions of cPKM with miR-199a-5p or IGF2BP2 and by the ability of cPKM to stabilize STMN1/TGFB1 mRNA. Based on these findings, a Trojan horse nanotherapy strategy with co-loading of siRNA against cPKM (si-cPKM) and paclitaxel (PTX) is developed. The siRNA/PTX co-loaded nanosystem (Trojan horse) efficiently penetrates tumor tissues, releases si-cPKM and paclitaxel (soldiers), promotes paclitaxel sensitization, and suppresses ICC proliferation and metastasis in vivo. Furthermore, it alleviates the fibrosis of ICC tumor stroma and reopens collapsed tumor vessels (opening the gates), thus enhancing the efficacy of the standard chemotherapy regimen (main force). This novel nanotherapy provides a promising new strategy for ICC treatment.
Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Humans , Cell Line, Tumor , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/genetics , RNA, Small Interfering , Paclitaxel/therapeutic use , Bile Ducts, Intrahepatic/metabolism , Bile Ducts, Intrahepatic/pathology , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/genetics , Fibrosis , Tumor Microenvironment , Transforming Growth Factor beta1/metabolism , RNA-Binding Proteins , Stathmin/metabolismABSTRACT
BACKGROUND: Prostate cancer (PCa) is the most common malignancy seen in men and the second leading cause of cancer-related death in males. The incidence and mortality associated with PCa has been rapidly increasing in China recently. METHODS: Multiple diagnostic models of human PCa were developed based on Taylor database by combining the artificial neural networks (ANNs) to enhance the ability of PCa diagnosis. Genetic algorithm (GA) is used to select feature genes as numerical encoded parameters that reflect cancer, metastatic, or normal samples. Back propagation (BP) neural network and learning vector quantization (LVQ) neural network were used to build different Cancer/Normal, Primary/Metastatic, and Gleason Grade diagnostic models. RESULTS: The performance of these modeling approaches was evaluated by predictive accuracy (ACC) and area under the receiver operating characteristic curve (AUC). By observing the statistically significant parameters of the three training sets, our Cancer/Normal, Primary/Metastatic, and Gleason Grade models' with ACC and AUC can be drawn (97.33%, 0.9832), (99.17%, 0.9952), and (90.48%, 0.8742), respectively. CONCLUSION: These results indicated that our diagnostic models of human PCa based on Taylor database combining the feature gene expression profiling data and artificial intelligence algorithms might act as a powerful tool for diagnosing PCa. Gleason Grade diagnostic models were used as novel prognostic diagnosis models for biochemical recurrence-free survival and overall survival, which might be helpful in the prognostic diagnosis of PCa in patients.
Subject(s)
Neural Networks, Computer , Prostatic Neoplasms/diagnosis , Aged , Databases, Factual , Gene Expression Profiling , Humans , Male , Middle Aged , Neoplasm Grading , Prostatic Neoplasms/mortality , Prostatic Neoplasms/pathologyABSTRACT
BACKGROUND: FK506 binding protein 9 (FKBP9) has been reported and identified for a long time, but its relationship with cancer is rarely studied. For example, the role of FK506 binding protein 9 in prostate cancer (PCa) is still unclear. Therefore, we decided to detect the expression level of FKBP9 in PCa and explore its clinical significance. METHODS: The expression level of FKBP9 protein was detected by immunohistochemistry. In addition, it was demonstrated by high-throughput sequencing of mRNA levels in the TCGA (cancer genome atlas) dataset of 499 patients. Kaplan-meier analysis and Cox proportional hazard regression model were used to evaluate the relationship between FKBP9 expression and survival in prostate cancer patients. RESULTS: The expression of FKBP9 was localized in the cytoplasm, which in normal prostate tissues was obviously lower than that in PCa tissues (Pâ¯=â¯0.001). High expression of FKBP9 was related with lymph node metastasis (Pâ¯=â¯0.022) and distant metastasis (Pâ¯=â¯0.028). Kaplan-Meier survival analysis revealed that the BCR-free survival of PCa patients with high FKBP9 level was significantly shortened (P=0.041). CONCLUSIONS: FKBP9 may be a cancer promoter that enhances PCa progression, and the level of FKBP9 may be used as an independent precursor of PCa patients.
Subject(s)
Gene Expression Regulation, Neoplastic/genetics , Prostate/metabolism , Prostatic Neoplasms/metabolism , Tacrolimus Binding Proteins/metabolism , Aged , Disease Progression , Humans , Lymphatic Metastasis/pathology , Male , Middle Aged , Prognosis , Proportional Hazards Models , Prostate/pathology , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathologyABSTRACT
BACKGROUND: This study aimed to analyze the dynamic changes of the scientific research innovation efficiency of Guangzhou Institute of Respiratory Diseases (GIRD) during the year 2009-2013 to explore the reason for these changes and give some suggestions on how to improve the overall efficiency of the Institute. METHODS: The panel data used in this study were taken from 19 research teams of GIRD during 2009 to 2013. Data envelopment analysis (DEA) based on Malmquist index (MI) was used to analyze the performance of each research team in terms of productivity changes over time. Data were analyzed using DEAP 2.1 software. RESULTS: The annual average increase rate of total factor productivity (TFP), technological progress, technical efficiency, pure technical efficiency, and scale efficiency was 30.4%, 22.5%, 6.4%, 0.9%, and 5.4%, respectively from 2009 to 2013. The scientific research innovation efficiency of the GIRD was generally high and kept on growing. The increase of TFP was mainly caused by the progress of tech, the descending of TFP in some teams should be mainly attributable to the declining pure technical efficiency, and scale efficiency on the whole, maintaining a stable growth at a low speed. CONCLUSIONS: To achieve higher scientific research innovation, GIRD not only needs to further improve the management level and introduce advanced management mode, but also needs to focus on optimization of resource allocation, as well as to strengthen the talent introduction, and continue to maintain the absorption of new technologies and innovation.
ABSTRACT
BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) is a member of the spindle assembly checkpoint protein family, which has been proven to be associated with many kinds of cancers. The aim of this study was to investigate whether BUB1B was correlated with progression and prognosis in patients with prostate cancer (PCa) and how BUB1B regulated the proliferation, migration, and invasion of PCa cell lines. Compared to benign prostate cells and tissues, both messenger RNA and protein expressions of BUB1B were statistically increased in PCa cell lines and tumor tissues. In vitro studies revealed that BUB1B overexpression enhanced the proliferation, migration, and invasion ability of PCa cell lines, whereas depletion of BUB1B did not affect the cell functions. Microarray analysis showed the positive staining of BUB1B was upregulated in the higher Gleason score group, which also correlated with advanced clinicopathological stage, higher serum prostate-specific antigen, metastasis, overall survival, and prostate-specific antigen failure. Furthermore, the survival analysis indicated that high expression of BUB1B was an independent predictor for shorter biochemical recurrence-free survival, which had no effect on overall survival. BUB1B plays an important role in tumor growth and progression, which can lead to its use as a potential biomarker for the diagnosis and prognosis of PCa.
ABSTRACT
Increased expression of E2F1 has been reported to be associated with tumor growth and cell survival of prostate cancer (PCa). However, its roles and mechanisms on PCa have not been fully elucidated. The present study found that E2F1 overexpression in PCa tissues was significantly associated with high Gleason score (P=0.01) and advanced pathological stage (P=0.02). In addition, PCa patients with high E2F1 expression more frequently had shorter biochemical recurrence-free survival (P=0.047) than those with low E2F1 expression. Then, we confirmed that the knock-down of E2F1 expression was able to inhibit cell cycle progression, invasion and migration of PCa cell lines in vitro, along with tumor xenograft growth and epithelial-to-mesenchymal transition (EMT) in vivo. Moreover, we identified CD147 as a novel interaction partner for E2F1 through bio-informatic binding site prediction, combined with chromatin immunoprecipitation-PCR (ChIP-PCR) and western blot analysis. Taken together, our data delineate an as yet unrecognized function of E2F1 as enhancer of tumor invasion and migration of PCa via regulating the expression of CD147 in PCa. Importantly, E2F1 may function as a biomarker that can differentiate patients with biochemical recurrent and non-biochemical recurrent disease following radical prostatectomy, highlighting its potential as a therapeutic target.
Subject(s)
Basigin/metabolism , E2F1 Transcription Factor/metabolism , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Animals , Basigin/genetics , Binding Sites , Cell Line, Tumor , Cell Movement , E2F1 Transcription Factor/chemistry , Epithelial-Mesenchymal Transition , Gene Expression Regulation, Neoplastic , Humans , Male , Mice , Neoplasm Grading , Neoplasm Invasiveness , Prognosis , Prostatic Neoplasms/genetics , Survival AnalysisABSTRACT
Dual-specificity phosphatase 5 (DUSP5), which specifically inactivates the extracellular signal-regulated kinase (ERK) 1/2 within the mitogen-activated protein kinase (MAPK) signaling, has recently been considered to be a tumor suppressor. However, its role in prostate cancer is still elusive. In this study, we performed immunohistochemistry analysis on human tissue microarray (TMA) to detect the DUSP5 protein expression pattern. The results indicated that DUSP5 was down-regulated in the human prostate cancer relative to the adjacent benign tissues (IRS: PCa = 4.29 ± 1.72 versus Benign = 4.89 ± 1.58, P = 0.04). In addition, when we linked the DUSP5 protein levels to the clinicopathological features of the patients, we found that the downregulation of DUSP5 was significantly associated with advanced pathological stage (P = 0.004) and high Gleason score (P = 0.009). Moreover, we attempted to validate these findings and investigate the prognostic value of DUSP5 in a publicly available microarray-based Taylor Dataset. Statistic analysis demonstrated that the downregulation of DUSP5 was closely correlated with high Gleason score (P = 0.011), positive metastasis (P < 0.001) and biochemical recurrence (BCR) (P = 0.016). More importantly, Kaplan-Meier analysis revealed that significant differences between patients with high and low DUSP5 expression level in regard to the BCR-free survival of overall (P = 0.009), non-metastatic (P = 0.006) and patients with Gleason score 7 (P = 0.044). Multivariate analysis by Cox regression indicated that DUSP5 could be an independent predictor for the risk of BCR (HR: 0.41, 95% CI: 0.2-0.82; P = 0.012). In summary, our findings disclose that DUSP5 may be an important tumor suppressor that inhibits the progression of PCa. The downregulation of DUSP5 may accurately predict poor prognosis in PCa patients.
ABSTRACT
PURPOSE: To investigate the involvement of hsa-miRNA-195-5p (miR-195) in progression and prognosis of human prostate cancer. EXPERIMENTAL DESIGN: qRT-PCR was performed to detect miR-195 expression in both prostate cancer cell lines and clinical tissue samples. Its clinical significance was statistically analyzed. The roles of miR-195 and its candidate target gene, ribosomal protein S6 kinase, 70 kDa, polypeptide 1 (RPS6KB1) in prostate cancer progression were confirmed on the basis of both in vitro and in vivo systems. RESULTS: miR-195 downregulation in prostate cancer tissues was significantly associated with high Gleason score (P = 0.001), positive metastasis failure (P < 0.001), and biochemical recurrence (BCR, P < 0.001). Survival analysis identified miR-195 as an independent prognostic factor for BCR-free survival of prostate cancer patients (P = 0.022). Then, we confirmed the tumor suppressive role of miR-195 through prostate cancer cell invasion, migration, and apoptosis assays in vitro, along with tumor xenograft growth, angiogenesis, and invasion in vivo according to both gain-of-function and loss-of-function experiments. In addition, RPS6KB1 was identified as a novel direct target of miR-195 through proteomic expression profiling combined with bioinformatic target prediction and luciferase reporter assay. Moreover, the reexpression and knockdown of RPS6KB1 could respectively rescue and imitate the effects induced by miR-195. Importantly, RPS6KB1 expression was closely correlated with aggressive progression and poor prognosis in prostate cancer patients as opposed to miR-195. Furthermore, we identified MMP-9, VEGF, BAD, and E-cadherin as the downstream effectors of miR-195-RPS6KB1 axis. CONCLUSION: The newly identified miR-195-RPS6KB1 axis partially illustrates the molecular mechanism of prostate cancer progression and represents a novel potential therapeutic target for prostate cancer treatment.
Subject(s)
MicroRNAs/genetics , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , RNA Interference , Ribosomal Protein S6 Kinases, 70-kDa/genetics , 3' Untranslated Regions , Animals , Apoptosis/genetics , Base Sequence , Binding Sites , Cadherins/genetics , Cadherins/metabolism , Cell Line, Tumor , Cell Movement/genetics , Disease Models, Animal , Disease Progression , Gene Expression Regulation, Neoplastic , Humans , Male , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , Mice , MicroRNAs/chemistry , Neovascularization, Pathologic/genetics , Prognosis , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/mortality , Proteomics/methods , RNA, Messenger/chemistry , RNA, Messenger/genetics , Ribosomal Protein S6 Kinases, 70-kDa/chemistry , Tumor Burden/genetics , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism , Xenograft Model Antitumor Assays , bcl-Associated Death Protein/genetics , bcl-Associated Death Protein/metabolismABSTRACT
OBJECTIVE: To screen and verify differentially expressed genes in prostate cancer. METHODS: Using DNA microarray, we screened differentially expressed genes in prostate cancer tissue and its adjacent tissue followed by verification by PCR. RESULTS: A total of 1 444 genes were found to be differentially expressed (differentiation ≥ 1.5-fold; P≤ 0.05) in the prostate cancer tissue, of which 769 (53%) were up-regulated and 675 (47%) down-regulated. Fifty percent of the differentially expressed genes showed a 1.5- to 2-fold differentiation, including 396 up-regulated and 182 down-regulated ones. Additionally, 308 up-regulated and 334 down-regulated genes exhibited a >2- to 5-fold, 46 up-regulated and 78 down-regulated genes a > 5- to 10-fold, and 19 up-regulated and 81 down-regulated genes a > 10-fold differentiation. Verification by subjecting 15 most significantly up-regulated and another 15 most markedly down-regulated genes to quantitative real-time PCR (qRT-PCR) showed that most of the genes had a transcriptional profile similar to that in the microarray data, with a Pearson correction coefficient of 0.83 between the microarray data and qRT-PCR results. Totally, 10 significantly differentially expressed genes were identified. CONCLUSION: DNA microarray analysis provides reliable information on differentially expressed genes in prostate cancer and benign tissues. The 10 significantly differentially expressed genes verified by qRT-PCR could possibly become new bio-markers and specific molecules for tumor identification.
Subject(s)
Gene Expression , Prostatic Neoplasms/genetics , Cell Differentiation , Down-Regulation , Gene Expression Regulation, Neoplastic , Humans , Male , Oligonucleotide Array Sequence Analysis , Polymerase Chain Reaction , Transcriptional Activation , Up-RegulationABSTRACT
BACKGROUND AND AIM: CC chemokine ligand 18 (CCL18) promotes malignant behaviors of various human cancer types. However, its involvement in human prostate cancer has not been fully elucidated. The aim of this study was to investigate the role of CCL18 in PCa. METHODS: Expression of CCL18 at mRNA and protein levels was detected using real-time qRT-PCR and immunohistochemistry analysis. We analyzed the associations of CCL18 expression with clinical features of human PCa. The effects of PCa cell migration, invasion, and apoptosis were tested. The efficiency of CCL18 on prostate tumor growth was assessed in a subcutaneous xenograft model. RESULTS: CCL18 expression was upregulated (both P < 0.01) in PCa tissues compared with those in noncancerous prostate tissues. CCL18 upregulation was correlated with high Gleason score (P = 0.034) of patients with PCa. rCCL18 stimulation in PCa cells promoted cell migration and invasion but decreased DU145 cells apoptosis rate. Furthermore, subcutaneous homografts models showed the increased tumor growth and tumor vascularization with the CCL18 stimulation, and the expression of Ki67, PCNA, and CD31 in CCL18 stimulation mice was also significantly increased. CONCLUSIONS: Our data offer the convincing evidence that the upregulation of CCL18 may be involved in the malignant progression of PCa.
Subject(s)
Chemokines, CC/metabolism , Disease Progression , Prostatic Neoplasms/pathology , Aged , Allografts , Animals , Apoptosis/genetics , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation , Chemokines, CC/genetics , Gene Expression Regulation, Neoplastic , Humans , Male , Mice, Inbred C57BL , Middle Aged , Neoplasm Invasiveness , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/pathology , Prostatic Neoplasms/blood supply , Prostatic Neoplasms/genetics , Protein Transport , RNA, Messenger/genetics , RNA, Messenger/metabolism , Real-Time Polymerase Chain ReactionABSTRACT
Suppressors of cytokine signaling (SOCS) proteins have been identified as negative feedback regulators of cytokine-mediated signaling in various tissues, and demonstrated to play critical roles in tumorigenesis and tumor development of different cancers. The involvement of SOCSs in human prostate cancer (PCa) has not been fully elucidated. Thus, the aim of this study is to investigate the expression patterns and the clinical significance of SOCSs in PCa. The expression changes of SOCSs at mRNA and protein levels in human PCa tissues compared with adjacent benign prostate tissues were, respectively, detected by using real-time quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) and immunohistochemistry analyses. The associations of SOCSs expression with clinicopathological features and clinical outcome of PCa patients were further statistically analyzed. Among SOCSs, both QRT-PCR and immunohistochemistry analyses found that SOCS2 expression was upregulated (at mRNA level: change ratio = 1.98, P = 0.031; at protein level: 5.12 ± 0.60 vs. 2.68 ± 0.37, P = 0.016) and SOCS6 expression was downregulated (at mRNA level: change ratio = -1.65, P = 0.008; at protein level: 3.03 ± 0.32 vs. 4.0.72 ± 0.39, P = 0.004) in PCa tissues compared with those in non-cancerous prostate tissues. In addition, the upregulation of SOCS2 in PCa tissues was correlated with the lower Gleason score (P < 0.001), the absence of metastasis (P < 0.001) and the negative PSA failure (P = 0.009); the downregulation of SOCS6 tended to be found in PCa tissues with the higher Gleason score (P = 0.016), the advanced pathological stage (P = 0.007), the positive metastasis (P = 0.020), and the positive PSA failure (P = 0.032). Furthermore, both univariate and multivariate analyses showed that the downregulation of SOCS2 was an independent predictor of shorter biochemical recurrence-free survival. Our data offer the convincing evidence for the first time that the dysregulation of SOCS2 and SOCS6 may be associated with the aggressive progression of PCa. SOCS2 may be potential markers for prognosis in PCa patients.