ABSTRACT
BACKGROUND: This study aimed to investigate the safety and efficacy of laparoscopic anatomical left hemihepatectomy guided by the middle hepatic vein (MHV) for the treatment of patients with hepatolithiasis who had a history of upper abdominal surgery. METHODS: Retrospective data analysis was performed on patients who underwent laparoscopic left hepatectomy for hepatolithiasis and with previous upper abdominal surgery at the Second Affiliated Hospital of Nanchang University from January 2018 to April 2022. According to the different surgical approaches, patients were divided into laparoscopic anatomical left hepatectomy guided by the MHV group (MHV-AH group) and laparoscopic traditional anatomical left hepatectomy not guided by the MHV group (non-MHV-AH group). RESULTS: This study included 81 patients, with 37 and 44 patients in the MHV-AH and non-MHV-AH groups, respectively. There was no significant difference in the basic information between the two groups. Five cases were converted to laparotomy, and the remaining were successfully completed under laparoscopy. Compared to the non-MHV-AH group, the MHV-AH group had a slightly longer operation time (319.30 min vs 273.93 min, P = 0.032), lower bile leakage rate (5.4% vs 20.5%, P = 0.047), stone residual rate (2.7% vs 20.5%, P = 0.015), stone recurrence rate (5.4% vs 22.7%, P = 0.028), and cholangitis recurrence rate (2.7% vs 22.7%, P = 0.008).There were no significant differences in the results of other observation indices between the groups. CONCLUSIONS: Laparoscopic anatomical left hepatectomy guided by the MHV is safe and effective in the treatment of left hepatolithiasis with a history of upper abdominal surgery. It does not increase intraoperative bleeding and reduces the risk of postoperative bile leakage, residual stones, stone recurrence, and cholangitis recurrence.
Subject(s)
Calculi , Cholangitis , Laparoscopy , Lithiasis , Liver Diseases , Humans , Hepatectomy/methods , Liver Diseases/surgery , Lithiasis/surgery , Retrospective Studies , Hepatic Veins , Treatment Outcome , Calculi/surgery , Laparoscopy/methods , Cholangitis/etiologyABSTRACT
At present, the extent of lymph node dissection (LND) for radical gallbladder cancer (GBC) is still controversial, and there is no evidence that LND improves prognosis, however, the latest guidelines for GBC recommend that removal of more than 6 lymph nodes facilitates staging of regional lymph nodes. The aim of this study is to investigate the effect of different LND methods on the number of lymph nodes detected and assess the prognostic factors during radical resection of GBC. This study retrospectively analyzed 133 patients (46 men and 87 women; average age: 64.01, range: 40-83 years) who underwent radical resection of GBC in a single center between July 2017 and July 2022, of which 41 underwent fusion lymph node dissection (FLND) and 92 underwent standard lymph node dissection (SLND). Baseline data, surgical results, number of LNDs, and follow-up data were analyzed. Each patient was followed up every 3 months. The total number of lymph nodes detected after the operation was 12.00 ± 6.95 versus 6.10 ± 4.71 (P < .05). The number of positive lymph nodes detected was (mean) 1.85 versus 0.78 and (percentage) 15.45% versus 12.83% (P < .05). Postoperative complications (8 vs 23, P > .05). The progression-free survival was 13 versus 8 months, the median survival time was 17 versus 9 months (P < .05). This study concluded that FLND can increase the detection rate of total lymph nodes and positive lymph nodes after surgery, which can prolong the survival time of patients.
Subject(s)
Carcinoma in Situ , Gallbladder Neoplasms , Male , Humans , Female , Adult , Middle Aged , Aged , Aged, 80 and over , Gallbladder Neoplasms/surgery , Retrospective Studies , Lymph Node Excision , Lymph Nodes/surgery , PrognosisABSTRACT
Background: The DNA binding protein NABP2 (nucleic acid binding protein 2) is a member of the SSB (single-stranded DNA-binding) protein family, which is involved in DNA damage repair. Its prognostic significance and relationship with immune infiltration in hepatocellular carcinoma (HCC), however, remain unknown. Methods: The purpose of this study was to estimate the prognostic value of NABP2 and to investigate its possible immune function in HCC. By applying multiple bioinformatics methods, we gathered and analysed data from The Cancer Genome Atlas (TCGA), Cancer Cell Lineage Encyclopedia (CCLE), and Gene Expression Omnibus (GEO) to investigate the potential oncogenic and cancer-promoting role of NABP2, including the differential expression, prognostic value, immune cell infiltration association, and drug sensitivity of NABP2 in HCC. Immunohistochemistry and Western blotting were used to validate the expression of NABP2 in HCC. The knockdown of NABP2 expression by siRNA was further used to validate its role in hepatocellular carcinoma. Results: Our findings indicated that NABP2 was overexpressed in HCC samples and was related to poor survival, clinical stage, and tumour grade in HCC patients. Analysis of functional enrichment indicated that NABP2 was potentially involved in the cell cycle, DNA replication, G2M checkpoint, E2F targets, apoptosis, P53 signalling, TGFA signalling via NF-κB, and so on. NABP2 was shown to be significantly linked to immune cell infiltration and immunological checkpoints in HCC. Analyses of drug sensitivity predict a number of drugs that could potentially be used to target NABP2. Moreover, in vitro experiments verified the promoting effect of NABP2 on the migration and proliferation of hepatocellular carcinoma cells. Conclusion: Based on these findings, NABP2 appears to be a candidate biomarker for HCC prognosis and immunotherapy.
ABSTRACT
Gallbladder cancer (GBC) and cholangiocarcinoma are common cancers of the biliary system and are associated with a poor prognosis. Surgery and chemotherapy provide limited benefit to patients with advanced biliary tract carcinoma. Novel immunotherapies and molecularly targeted therapies are more effective options; however, few patients benefit and drug resistance is a concern. Here, we report five cases of advanced GBC with either high programmed death-ligand 1 (PD-L1) expression or a high tumor mutation burden (TMB-H). The patients were treated with a combination therapy of tislelizumab and S-1. The tumors were effectively controlled in most patients. One patient developed immune-related pneumonia (irP) during treatment, which resolved after hormone therapy, and the patient underwent surgery. Tislelizumab and S-1 were administered again after surgery; however, recurrent irP required discontinuation, and the tumor progressed after drug withdrawal. These cases demonstrate that combined therapy of anti-programmed cell death protein-1 (PD-1) antibodies and S-1 is a safe and effective regimen with few side effects for GBC patients, especially for sensitive populations (patients with TMB-H, microsatellite instability, deficient mismatch repair, or high expression of PD-L1). To our knowledge, this is the first time that tislelizumab in combination with S-1 has been used to treat patients with advanced GBC.
Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Gallbladder Neoplasms , Humans , Gallbladder Neoplasms/drug therapy , B7-H1 Antigen , Antibodies, Monoclonal, Humanized/therapeutic use , Cholangiocarcinoma/drug therapy , Bile Duct Neoplasms/drug therapy , Bile Ducts, IntrahepaticABSTRACT
BACKGROUND: Laparoscopic transcystic common bile duct exploration (LTCBDE) is used to treat cholecystolithiasis and choledocholithiasis. This study aimed to investigate the safety, effectiveness and generalisability of LTCBDE in patients with cholecystolithiasis and choledocholithiasis based on our LTCBDE experience within 8 years. METHODS: Four hundred patients with cholecystolithiasis and choledocholithiasis (including 62 of cholecystolithiasis and choledocholithiasis with common bile duct no-dilatation) treated with LTCBDE at a single centre from January 2014 to February 2022 were retrospectively evaluated. They were divided into the first 200 and last 200 LTCBDE cases. The disease characteristics, cystic duct incision methods, surgical outcomes and follow-up data were analysed retrospectively. Each patient was followed up for > 3 months. RESULTS: Four hundred patients underwent LTCBDE, including 188 males and 212 females aged from 15 to 91 years (average age: 56 years). LTCBDE was successful in 377 (94.3%) patients, while treatment was converted to laparoscopic choledocholithotomy with T-tube drainage in 23 (5.8%), owing to intraoperative choledochoscope insertion failure. The CBD diameter (10.89 ± 1.76 vs 9.97 ± 2.39, P < 0.05), cystic duct diameter (4.62 ± 1.03 vs 5.03 ± 1.29, P < 0.05), and operation time (164.60 ± 24.30 vs 135.34 ± 30.00, P < 0.05). Residual stones were found in six (1.5%) patients and removed during the second operation; post-operative bile leakage was found in one (0.3%) patient, who was discharged safely after the second operation. CONCLUSIONS: Phase I LTCBDE is safe and effective in treating cholecystolithiasis and choledocholithiasis. With continuous technological advances, LTCBDE has been effectively promoted and applied.
Subject(s)
Cholecystectomy, Laparoscopic , Cholecystolithiasis , Choledocholithiasis , Laparoscopy , Male , Female , Humans , Middle Aged , Adolescent , Young Adult , Adult , Aged , Aged, 80 and over , Choledocholithiasis/surgery , Choledocholithiasis/etiology , Retrospective Studies , Cholecystolithiasis/complications , Cholecystolithiasis/surgery , Cholecystectomy, Laparoscopic/adverse effects , Cholecystectomy, Laparoscopic/methods , Treatment Outcome , Common Bile Duct/surgery , Laparoscopy/methodsABSTRACT
Salient Object Detection (SOD) simulates the human visual perception in locating the most attractive objects in the images. Existing methods based on convolutional neural networks have proven to be highly effective for SOD. However, in some cases, these methods cannot satisfy the need of both accurately detecting intact objects and maintaining their boundary details. In this paper, we present a Multiresolution Boundary Enhancement Network (MRBENet) that exploits edge features to optimize the location and boundary fineness of salient objects. We incorporate a deeper convolutional layer into the backbone network to extract high-level semantic features and indicate the location of salient objects. Edge features of different resolutions are extracted by a U-shaped network. We designed a Feature Fusion Module (FFM) to fuse edge features and salient features. Feature Aggregation Module (FAM) based on spatial attention performs multiscale convolutions to enhance salient features. The FFM and FAM allow the model to accurately locate salient objects and enhance boundary fineness. Extensive experiments on six benchmark datasets demonstrate that the proposed method is highly effective and improves the accuracy of salient object detection compared with state-of-the-art methods.
Subject(s)
Neural Networks, Computer , Visual Perception , Humans , Attention , Semantics , BenchmarkingABSTRACT
Background: Periampullary carcinoma, which includes ampullary carcinoma, pancreatic head cancer, distal common bile duct cancer, and duodenal papillary cancer, is a relatively rare malignancy with uncertain therapeutic options. Although several studies have investigated the efficacy of multiple adjuvant chemotherapy regimens for periampullary carcinoma treatment, the optimal regimen remains to be determined. The inherent heterogeneity of the mucosal origin divides periampullary carcinoma into intestinal and pancreaticobiliary types. Therefore, the selection of chemotherapy regimens based on pathological type may have potential therapeutic significance. Case Presentation: A 72-year-old woman with moderately differentiated periampullary adenocarcinoma experienced disease progression after receiving FOLFOX regimen. Subsequently, the sample was subtyped first by H&E evaluation and then by the evaluation of an IHC panel composed of CK20, CDX2, MUC1, MUC2, and MUC5AC. The pathologists concluded that the patient's sample was of the pancreaticobiliary (PB) subtype. The subsequent change to gemcitabine plus S-1 adjuvant therapy achieved remission of liver metastases based on the pathological classification of the cancer. Conclusion: Based on the pathological classification, adjuvant chemotherapy with gemcitabine may be beneficial for patients with PB subtype periampullary carcinoma. 5-Fu-based adjuvant chemotherapy may be beneficial for patients with intestinal subtype periampullary carcinoma.
ABSTRACT
The disruption of tumour cell metabolism can inhibit tumour metastasis, indicating that aerobic glycolysis is central to tumour development. However, the key factors responsible for mediating aerobic glycolysis in hepatocellular carcinoma (HCC) remain unknown. Here, we observed that RBCK1 expression was significantly upregulated in HCC tissues. Our clinical study revealed that high RBCK1 expression is significantly correlated with poor tumour survival and distant invasion. Functional assays revealed that RBCK1 promotes migration and invasion by enhancing GLUT1-mediated aerobic glycolysis. Furthermore, RBCK1-induced HCC cell migration and aerobic glycolysis via activation of WNT/ß-catenin/GLUT1 pathway, which was dependent on the destruction of the PPARγ/PGC1α complex. Mechanistically, RBCK1 promotes PPARγ ubiquitination and degradation, and RBCK1 overexpression enhances the transcriptional activity of WNT/ß-catenin, thus to upregulate the expression of GLUT1-mediated aerobic glycolysis in HCC cells. Altogether, our findings identify a mechanism used by HCC cells to survive the nutrient-poor tumour microenvironment and provide insight into the role of RBCK1 in HCC cellular adaptation to metabolic stresses.
ABSTRACT
ATG4D, a member of autophagy-related protein 4 (ATG4) family, plays an interplay role between autophagy and apoptosis in cancers. However, the role of ATG4D in hepatocellular carcinoma (HCC) has not been defined. Herein, this study aimed to investigate the role and the underlying mechanism of ATG4D in regulating HCC cell apoptosis. ATG4D was silenced in MHCC-97L HCC cells, and then cell proliferation and apoptosis were examined. ATG4D expression was significantly upregulated in HCC tissues when compared with paired non-tumor tissues. In vitro assays revealed that silencing of ATG4D significantly suppressed cell proliferation, promoted cell apoptosis, and enhanced sensitivity to cisplatin of MHCC-97L cells. Furthermore, silencing of ATG4D decreased the phosphorylation of Akt and increased the protein level of caspase-3. Taken together, ATG4D may play an oncogenic role in HCC progression. These findings suggest that ATG4D may serve as a therapeutic target for HCC therapy.
Subject(s)
Autophagy-Related Proteins/metabolism , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Caspase 3/metabolism , Cisplatin/pharmacology , Cysteine Endopeptidases/metabolism , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Autophagy/drug effects , Carcinoma, Hepatocellular/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Liver Neoplasms/metabolismABSTRACT
BACKGROUND: Laparoscopic transcystic common bile duct exploration (LTCBDE) is the minimally traumatic surgical method for the treatment of choledocholithiasis secondary to cholecystolithiasis with dilated common bile duct (CBD). However, no report exists concerning LTCBDE in patients with nondilated CBD. The purpose of this study was thus to explore the safety, efficacy, and feasibility of LTCBDE in patients with choledocholithiasis secondary to cholecystolithiasis with nondilatation of the CBD. METHODS: We retrospectively analyzed 47 patients with choledocholithiasis secondary to cholecystolithiasis who were treated with LTCBDE at the Second Affiliated Hospital of Nanchang University from January 2017 to August 2021 (all the patients had undergone endoscopic retrograde cholangio-pancreatography treatment, but this failed due to various reasons). Clinical data on disease characteristics, methods for cystic duct incision and CBD stone extraction, and surgical outcomes were collected and reviewed. Each patient was followed up for more than 3 months. RESULTS: There were 47 patients in this study, including 21 females and 26 males, with their ages ranging from 15 to 82 years (51±15 years). All patients were treated with surgery, and the CBD stones were removed successfully. Among these patients, 45 underwent LTCBDE for the removal of stones in the CBD, with failure occurring in 2 patients who then accepted laparoscopic common bile duct stone removal (LCBDE) + T tube drainage. The diameter of the cystic duct was 0.30-0.73 cm (0.60±0.07 cm), the diameter of the CBD was 0.60-0.80 cm (0.73±0.05 cm), the operation time was 75-220 minutes (159±33 minutes), and the postoperative hospital stay was 2-13 days (6±2 days). None of the patients experience any serious postoperative complications, and all were discharged safely. During the follow-up, no postoperative biliary stenosis, bile leakage, or other complications occurred. CONCLUSIONS: LTCBDE is feasible to treat patients with choledocholithiasis secondary to cholecystolithiasis with nondilatation of the CBD. This choice of treatment plan reduces the length of hospital stay and the occurrence of postoperative complications. However, it is recommended that this be attempted on the basis of the experience of LTCBDE with dilated CBD.
Subject(s)
Choledocholithiasis , Laparoscopy , Adolescent , Adult , Aged , Aged, 80 and over , Choledocholithiasis/surgery , Common Bile Duct/surgery , Cystic Duct , Female , Humans , Length of Stay , Male , Middle Aged , Retrospective Studies , Young AdultABSTRACT
Pancreatic cancer is one of the most fatal cancers in humans. While it thrives in a state of malnutrition, the mechanism by which pancreatic cancer cells adapt to metabolic stress through metabolic reprogramming remains unclear. Here, we showed that UBR5, an E3 ubiquitin ligase, was significantly upregulated in pancreatic cancer patient samples compared to the levels in adjacent normal tissues. Levels of UBR5 were closely related to a malignant phenotype and shorter survival among pancreatic cancer patients. Multivariate analyses also revealed that UBR5 overexpression was an independent predictor of poor outcomes among patients with pancreatic cancer. Functional assays revealed that UBR5 contributes to the growth of pancreatic cancer cells by inducing aerobic glycolysis. Furthermore, we demonstrated that UBR5 knockdown increased levels of fructose-1,6-bisphosphatase (FBP1), an important negative regulator in the process of aerobic glycolysis in many cancers. We found a significant negative correlation between levels of UBR5 and FBP1, further demonstrating that UBR5-induced aerobic glycolysis is dependent on FBP1 in pancreatic cancer cells. Mechanistically, UBR5 regulates FBP1 expression by modulating C/EBPα, directly binding to C/EBPα, and promoting its ubiquitination and degradation. Together, these results identify a mechanism used by pancreatic cancer cells to survive the nutrient-poor tumour microenvironment and also provide insight regarding the role of UBR5 in pancreatic cancer cell adaptation to metabolic stresses.
Subject(s)
Biomarkers, Tumor/metabolism , CCAAT-Enhancer-Binding Protein-alpha/chemistry , Gene Expression Regulation, Neoplastic , Glycolysis , Pancreatic Neoplasms/pathology , Ubiquitin-Protein Ligases/metabolism , Animals , Apoptosis , Biomarkers, Tumor/genetics , CCAAT-Enhancer-Binding Protein-alpha/genetics , CCAAT-Enhancer-Binding Protein-alpha/metabolism , Cell Proliferation , Fructose-Bisphosphatase/genetics , Fructose-Bisphosphatase/metabolism , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Protein Stability , Tumor Cells, Cultured , Ubiquitin-Protein Ligases/genetics , Xenograft Model Antitumor AssaysABSTRACT
The dysregulation of deubiquitinating enzymes (DUBs), which regulate the stability of most cellular proteins, has been implicated in many human diseases, including cancers. Thus, DUBs can be considered potential therapeutic targets for many cancers. However, the role of deubiquitinase ubiquitin-specific protease 18 (USP18) in pancreatic cancer remains unknown. Here, we found that the deubiquitinase ubiquitin-specific protease 18 (USP18) is significantly upregulated in pancreatic cancer and is correlated with a shorter median overall and relapse-free survival. A functional assay demonstrated that overexpression of USP18 resulted in increased proliferation of pancreatic cancer cells. Conversely, these phenomena were reversed after USP18 was silenced in pancreatic cancer cells. Further investigation revealed that USP18 promoted cell progression by increasing c-Myc expression, which has been reported to control pancreatic cancer progression, and our data demonstrated that c-Myc is key for USP18-mediated pancreatic cancer cell progression in vitro and in vivo. Moreover, we found that USP18 promoted pancreatic cancer progression via upregulation of Notch-1-dependent c-Myc. Mechanistically, USP18 interacts with and removes K48-linked ubiquitin chains from Notch1, thereby stabilizing Notch1 and promoting the Notch1-c-Myc pathway. Our work identifies and validates USP18 as a pancreatic cancer oncogene and provides a potential druggable target for this intractable disease.
ABSTRACT
Transforming growth factor-ß-activated kinase 1 (TAK1)-binding protein 3 (TAB3) and the proviral integration site for Moloney murine leukaemia virus 1 (PIM1) are implicated in cancer development. In this study, we investigated the relationship between TAB3 and PIM1 in colorectal cancer (CRC) and determined the potential role and molecular mechanism of TAB3 in PIM1-mediated CRC growth. We found that TAB3 and PIM1 expression levels were positively correlated in CRC tissues. The knockdown of TAB3 significantly decreased PIM1 expression and inhibited CRC proliferation in vitro and in vivo. The upregulation of PIM1 rescued the decreased cell proliferation induced by TAB3 knockdown, whereas PIM1 knockdown decreased TAB3-enhanced CRC proliferation. Additionally, TAB3 regulates PIM1 expression through the STAT3 signalling pathway and confirmed a positive correlation between TAB3 and phosphorylated-STAT3 expression in CRC tissues. Patients with high expression of TAB3 and phosphorylated-STAT3 had the worst prognosis. Mechanistically, TAB3 regulates PIM1 expression by promoting STAT3 phosphorylation and activation through the formation of the TAB3-TAK1-STAT3 complex. Overall, a novel CRC regulatory circuit involving the TAB3-TAK1-STAT3 complex and PIM1 was identified, the dysfunction of which may contribute to CRC tumorigenesis.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Colorectal Neoplasms/genetics , Gene Expression Regulation, Neoplastic , MAP Kinase Kinase Kinases/genetics , Proto-Oncogene Proteins c-pim-1/genetics , STAT3 Transcription Factor/genetics , Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Adaptor Proteins, Signal Transducing/metabolism , Animals , Cell Line, Tumor , Cell Movement , Cell Proliferation , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/mortality , Colorectal Neoplasms/surgery , Female , Humans , MAP Kinase Kinase Kinases/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Phosphorylation , Prognosis , Proto-Oncogene Proteins c-pim-1/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction , Survival Analysis , Tumor Burden , Xenograft Model Antitumor AssaysABSTRACT
Ring finger protein 6 (RNF6), a RING-domain E3 ubiquitin Ligase, functions as a potential tumor promoter in several caners. However, the function and clinical significance of RNF6 in hepatocellular carcinoma (HCC) remains unclear. Here, we found that high RNF6 expression was detected frequently in primary HCC tissues, and was closely associated with malignant phenotype and shorter survival among the HCC patients. Multivariate analyses also revealed that RNF6 overexpression was independent prognostic factors for poor outcome of patients with HCC. Further, RNF6 knockdown notably inhibited the metastasis abilities of HCC in vivo and in vitro. RNF6 silence also suppressed the epithelial-mesenchymal transition (EMT) and radioresistance in HCC. Mechanistically, our results demonstrated that RNF6 directly bound and ubiquitylated Forkhead box protein A1 (FoxA1), an important transcriptional repressor of EMT process. Additionally, our data shown that the oncogenic effect of RNF6 in HCC is partially dependent on FoxA1 degradation. Collectively, our data suggest that RNF6 plays a crucial oncogenic role in HCC tumorigenesis, and we provide a novel evidence that RNF6 may be serve as a prognostic and therapeutic target for HCC progression.
Subject(s)
Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , DNA-Binding Proteins/metabolism , Hepatocyte Nuclear Factor 3-alpha/metabolism , Radiation Tolerance , Ubiquitination , Animals , Cell Line, Tumor , DNA-Binding Proteins/genetics , Epithelial-Mesenchymal Transition/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Mice, Inbred BALB C , Mice, Nude , Middle Aged , Multivariate Analysis , Neoplasm Invasiveness , Neoplasm Metastasis , Polyubiquitin/metabolism , Prognosis , Protein Binding , Proteolysis , RNA, Messenger/genetics , RNA, Messenger/metabolism , Survival AnalysisABSTRACT
Ubiquitin-specific peptidase 18 (USP18) is closely related with hepatitis B virus (HBV), which has been involved in tumourigenesis. However, there has been little research into the role of USP18 on the progression of hepatocellular carcinoma (HCC), especially in HBV-related HCC. In present study, we found that USP18 expression was aberrantly elevated in HCC tissues than adjacent non-tumour tissues. Importantly, USP18 expression was higher in HBV-related HCC cell lines (HepG2.2.15 and Hep3B) than HBV-unrelated HCC cell lines. Furthermore, knockdown of USP18 significantly suppressed tumour cell proliferation in vitro and tumour growth in vivo, whereas overexpression of USP18 promoted HCC cells growth. Moreover, our experimental data revealed that USP18 silencing obviously blocked cell cycle at G1 phase and increased cell apoptosis. Finally, BCL2L1, a member of BCL2 family protein, was identified as a downstream gene of USP18. Mechanistically, we found that USP18 directly bind to BCL2L1 and positively regulated its expression in HCC cells. Overall, our results suggested that USP18 has a crucial role in regulating diverse aspects of the pathogenesis of HCC, indicating that it might be a potential therapeutic target.
Subject(s)
Apoptosis/physiology , Carcinoma, Hepatocellular/metabolism , Endopeptidases/metabolism , Hepatitis B virus , Liver Neoplasms/metabolism , bcl-X Protein/metabolism , Apoptosis/genetics , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/virology , Cell Cycle/physiology , Cell Line, Tumor , Cell Proliferation/physiology , Down-Regulation , Hepatitis B virus/isolation & purification , Humans , Liver Neoplasms/pathology , Liver Neoplasms/virology , Signal Transduction/physiology , Ubiquitin ThiolesteraseABSTRACT
Ubiquitin specific protease 39 (USP39) is one of the deubiquitinating enzymes without ubiquitin protease activity, which has been implicated in the progression of several cancers. However, the role of USP39 in pancreatic cancer (PC) is largely unknown. In present study, we found that USP39 expression was elevated in PC tissues than adjacent non-tumor tissues. Importantly, we demonstrated that overexpression of USP39 is closely correlated with tumor progression and poor survival in PC patients. Furthermore, high USP39 expression was observed in PC cell lines and ectopic expression of USP39 significantly enhanced in vitro cell proliferation and promoted in vivo tumor growth, whereas silencing USP39 suppressed growth of PC cells. Besides, our experimental data revealed that knockdown of USP39 induced cell apoptosis through inhibition of AKT signaling pathway in PC cells. Moreover, USP39 was a direct target of miR-133a, a microRNA that has been reported to be involved in progression of PC. Taken together, our data provide a novel PC regulatory axis that is miR-133a/USP39, the dysfunction of which drives diverse aspects of the progression of PC.
Subject(s)
Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , Pancreatic Neoplasms/genetics , Proto-Oncogene Proteins c-akt/genetics , Signal Transduction/genetics , Ubiquitin-Specific Proteases/genetics , Animals , Apoptosis/genetics , Blotting, Western , Cell Line , Cell Line, Tumor , Cell Proliferation/genetics , Disease Progression , Female , Humans , Kaplan-Meier Estimate , Male , Mice, Inbred BALB C , Mice, Nude , Middle Aged , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Proto-Oncogene Proteins c-akt/metabolism , RNA Interference , Reverse Transcriptase Polymerase Chain Reaction , Transplantation, Heterologous , Ubiquitin-Specific Proteases/metabolismABSTRACT
Rho-associated kinase 2 (Rock2) is known to promote tumorigenesis in hepatocellular carcinoma (HCC). CCAAT/enhancer-binding protein delta (CEBPD) functions as a tumor suppressor. In this study, we found that the expression of Rock2 and CEBPD are inversely correlated. Knockdown of Rock2 increased CEBPD expression and inhibited the proliferation of HCC cells in vitro and in vivo. Mechanistically, we found that Rock2 regulates CEBPD expression through the p-GSK3ß/ß-catenin pathway. Taken together, we identified a novel Rock2-p-GSK3ß/ß-catenin-CEBPD regulatory circuitry, the dysfunction of which may contribute to the tumorigenic characteristic of HCC.
Subject(s)
CCAAT-Enhancer-Binding Protein-delta/metabolism , Cell Proliferation , Glycogen Synthase Kinase 3/metabolism , Signal Transduction , beta Catenin/metabolism , rho-Associated Kinases/metabolism , Animals , Blotting, Western , CCAAT-Enhancer-Binding Protein-delta/genetics , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Glycogen Synthase Kinase 3 beta , Hep G2 Cells , Humans , Mice, Nude , Phosphorylation , RNA Interference , Reverse Transcriptase Polymerase Chain Reaction , Xenograft Model Antitumor Assays/methods , rho-Associated Kinases/geneticsABSTRACT
Rho-associated coiled-coil-containing protein kinase 2 (Rock2) is a downstream effector of Rho that plays an important role in the tumorigenesis and progression of hepatocellular carcinoma (HCC). Matrix metalloproteinase 2 (MMP2) is a master regulator of tumor metastasis. In this study, we investigated the collections of Rock2 and MMP2 in HCCs and determined the potential role and molecular mechanism of Rock2 in MMP2-mediated invasiveness and metastasis. We found that Rock2 and MMP2 were markedly overexpressed in HCCs compared with the corresponding adjacent tissues, where a positive correlation in their expression was found. The knockdown of Rock2 significantly decreased MMP2 expression and inhibited the invasion and metastasis of HCC in vitro and in vivo. Additionally, the upregulation of MMP2 rescued the decreased migration and invasion induced by the knockdown of Rock2, whereas the knockdown of MMP2 decreased Rock2-enhanced HCC migration and invasion. Mechanistically, Rock2 stabilized MMP2 by preventing its ubiquitination and degradation. Together, our results link two drivers of invasion and metastasis in HCC and identify a novel pathway for MMP2 control.
Subject(s)
Carcinoma, Hepatocellular/enzymology , Carcinoma, Hepatocellular/secondary , Liver Neoplasms/enzymology , Matrix Metalloproteinase 2/metabolism , rho-Associated Kinases/metabolism , Animals , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Movement/genetics , Cell Movement/physiology , Gene Knockdown Techniques , Hep G2 Cells , Heterografts , Humans , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Matrix Metalloproteinase 2/genetics , Mice , Mice, Nude , Neoplasm Invasiveness/genetics , Neoplasm Invasiveness/pathology , Neoplasm Invasiveness/physiopathology , Proteolysis , Signal Transduction , Ubiquitination , Up-Regulation , rho-Associated Kinases/antagonists & inhibitors , rho-Associated Kinases/geneticsABSTRACT
Tetramethylpyrazine (TMPZ) is one of the active compounds extracted from the traditional Chinese medicinal herb Chuanxiong and several studies have shown it to possess anticancer properties. However, its effectiveness in gastric cancer and its cellular mechanisms are relatively unknown. The present study aimed to investigate the effect of TMPZ on SGC7901 cells, and it was demonstrated that a high dose of TMPZ inhibited cell viability and induced apoptosis by stimulating AMP-activated protein kinase (AMPK) through the generation of reactive oxygen species (ROS). Furthermore, TMPZ-induced apoptosis resulted in the sequential events beginning with the translocation of Bax, the collapse of mitochondrial membrane potential (ΔΨm), the release of cytochrome c and the activation of caspase-9 and -3. Each of these events was inhibited by compound C, a pharmacological inhibitor of AMPK. To the best of our knowledge, these results demonstrate for the first time that the induction of apoptosis by TMPZ in gastric cancer cells is associated with the activation of the ROS/AMPK pathway. AMPK activation induces apoptosis through the mitochondrial apoptotic pathway. In addition, these results raise the possibility that TMPZ may have a future therapeutic role in gastric cancer.