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INTRODUCTION: Hepatitis B Virus (HBV) is widely recognized as a "metabolic virus" that disrupts hepatic metabolic homeostasis, rendering it one of the foremost risk factors for hepatocellular carcinoma (HCC). Except for antiviral therapy, the fundamental principles underlying HBV- and HBV+ HCC have remained unchanged, limiting HCC treatment options. OBJECTIVES: In this study, we aim to identify the distinctive metabolic profile of HBV-associated HCC, with the promise of identifying novel metabolic targets that confer survival advantages and ultimately impede cancer progression. METHODS: We employed a comprehensive methodology to evaluate metabolic alterations systematically. Initially, we analyzed transcriptomic and proteomic data obtained from a public database, subsequently validating these findings within our test cohort at both the proteomic and transcriptomic levels. Additionally, we conducted a comprehensive analysis of tissue metabolomics profiles, lipidomics, and the activity of the MAPK and AKT signaling pathway to corroborate the abovementioned changes. RESULTS: Our multi-omics approach revealed distinct metabolic dysfunctions associated with HBV-associated HCC. Specifically, we observed upregulated steroid hormone biosynthesis, primary bile acid metabolism, and sphingolipid metabolism in HBV-associated HCC patients' serum. Notably, metabolites involved in primary bile acid and sphingolipids can activate the MAPK/mTOR pathway. Tissue metabolomics and lipidomics analyses further validated the serum metabolic alterations, particularly alterations in lipid composition and accumulation of unsaturated fatty acids. CONCLUSION: Our findings emphasize the pivotal role of HBV in HCC metabolism, elucidating the activation of a unique MAPK/mTOR signaling axis by primary bile acids and sphingolipids. Moreover, the hyperactive MAPK/mTOR signaling axis transduction leads to significant reprogramming in lipid metabolism within HCC cells, further triggering the activation of the MAPK/mTOR pathway in turn, thereby establishing a self-feeding circle driven by primary bile acids and sphingolipids.
Subject(s)
Carcinoma, Hepatocellular , Hepatitis B virus , Liver Neoplasms , TOR Serine-Threonine Kinases , Humans , Carcinoma, Hepatocellular/virology , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/virology , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , TOR Serine-Threonine Kinases/metabolism , Hepatitis B virus/physiology , Lipid Metabolism , Male , Lipids/blood , Signal Transduction , MAP Kinase Signaling System , Hepatitis B/complications , Hepatitis B/virology , Hepatitis B/metabolism , Middle Aged , FemaleABSTRACT
OBJECTIVES: Drug-eluting beads transarterial chemoembolization (DEB-TACE) has shown promise as a treatment modality for primary liver cancer and colorectal cancer liver metastasis. However, its role in pancreatic cancer liver metastasis (PCLM) remains uncertain. This study aimed to investigate the efficacy and safety of DEB-TACE in PCLM patients. METHODS: A retrospective study included 10 PCLM patients who underwent DEB-TACE using CalliSpheres® microspheres as the chemoembolization material. Treatment response, survival outcomes, adverse events, and liver function indexes were comprehensively assessed. RESULTS: Among the patients, complete response, partial response, stable disease, and progressive disease rates were 0.0%, 40.0%, 30.0%, and 30.0%, respectively. The objective response rate was 40.0%, and the disease-control rate was 70.0%. The median progression-free survival (PFS) was 12.0 months (95% CI: 0.0-26.7), with a 1-year PFS rate of 48.0%. The median overall survival (OS) was 18.0 months (95% CI: 6.0-30.0), with a 1-year OS rate of 80.0%. Additionally, no significant differences were observed in any of the liver function indexes, including alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, etc., between pre- and posttreatment evaluations. Adverse events included pain, grade 1-2 vomiting, fever, and transient liver dysfunction. CONCLUSIONS: DEB-TACE demonstrates a promising treatment response, favorable survival profile, and satisfactory safety in PCLM patients. ADVANCES IN KNOWLEDGE: This study adds to the current research by providing novel evidence on the efficacy, safety, and favorable survival outcomes of DEB-TACE in treating PCLM, highlighting its potential as an effective therapeutic option in this specific population.
Subject(s)
Chemoembolization, Therapeutic , Liver Neoplasms , Microspheres , Pancreatic Neoplasms , Humans , Chemoembolization, Therapeutic/methods , Male , Liver Neoplasms/secondary , Liver Neoplasms/therapy , Female , Retrospective Studies , Middle Aged , Pancreatic Neoplasms/therapy , Pancreatic Neoplasms/pathology , Aged , Treatment Outcome , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , AdultABSTRACT
Pancreatic cancer represents a malignant neoplasm originating from pancreatic cells. The optimal approach to cancer treatment remains uncertain, lacking a definitive consensus. Here, we present a compelling case of a 49-year-old female with pancreatic head cancer with liver metastases, as identified by CT and confirmed by biopsy. PET-CT indicated widespread metastatic involvement. TACE therapy with gemcitabine and cisplatin was initiated, yielding a stable disease response. The patient's high PD-L1 expression prompted TACE-PD-1 monoclonal antibody combination therapy. Subsequent treatments, including ablation, sustained PD-1 immunotherapy, and consolidation TACE, culminated in a complete response, as evidenced by imaging and tumor marker dynamics. Our case underscores the potential of multifaceted strategies in managing aggressive pancreatic cancer.
Subject(s)
Chemoembolization, Therapeutic , Liver Neoplasms , Pancreatic Neoplasms , Female , Humans , Middle Aged , Positron Emission Tomography Computed Tomography , Programmed Cell Death 1 Receptor , Chemoembolization, Therapeutic/methods , Liver Neoplasms/secondary , Pancreatic Neoplasms/therapy , Pancreatic Neoplasms/pathology , Immunotherapy , Pancreatic NeoplasmsABSTRACT
OBJECTIVES: Most patients with intrahepatic cholangiocarcinoma (ICC) present with locally advanced or metastatic disease. We report the combined potency of transarterial chemoembolization (TACE), lenvatinib and programmed cell death-1 (PD-1) inhibitors in patients with advanced and metastatic ICC. METHODS: This retrospective study enrolled 32 patients with advanced or metastatic ICC between January 2017 and August 2021. Eligible patients had received gemcitabine-based TACE combined with lenvatinib with or without PD-1 inhibitor in any line of treatment. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Risk factors associated with OS were assessed using univariate and multivariate Cox regression analyses. RESULTS: Eighteen patients received a combination of TACE and lenvatinib (TL group) and 14 patients received TACE and lenvatinib plus aPD-1 inhibitor (TLP group). The median follow-up time was 19.8 months (range 1.8-37.8). The median OS was 25.3 months (95% CI 18.5-32.1) and the median PFS was 7.3 months (95% CI 4.9-9.7). Partial response was achieved in 10 patients (31.3%), and stable disease in 13 (40.6 %) with disease control rate of 71.9%. The median OS was comparable in the TL and TLP groups (22.4 vs 27.3 months, respectively; hazard ratio: 1.245, 95% CI 0.4245-3.653; p = 0.687). The regression analysis revealed that, regardless of treatment group, a favorable independent prognostic factor for OS was HBV/HCV infection (HR: 0.063, 95% CI 0.009-0.463; p = 0.007). There were no treatment-related deaths and 81.3% of study participants experienced adverse events (AEs), the majority of which were of moderate severity (71.8% Grade 1-2). CONCLUSIONS: Gemcitabine-based TACE plus lenvatinib with or without aPD-1 inhibitor was well tolerated and provided promising therapeutic outcomes for patients with advanced and metastatic ICC. ADVANCES IN KNOWLEDGE: Monotherapy with TACE, or Lenvatinib, or PD-1 inhibitors has shown limited efficacy over standard first-line chemotherapy in advanced and metastatic ICC. This work suggested the combined potency of these treatments and well-tolerance.
Subject(s)
Bile Duct Neoplasms , Carcinoma, Hepatocellular , Chemoembolization, Therapeutic , Cholangiocarcinoma , Liver Neoplasms , Humans , Immune Checkpoint Inhibitors , Retrospective Studies , Carcinoma, Hepatocellular/therapy , Liver Neoplasms/therapy , Cholangiocarcinoma/therapy , Gemcitabine , Bile Duct Neoplasms/therapy , Bile Ducts, IntrahepaticABSTRACT
BACKGROUND: Gallbladder carcinoma is the most common cancer of the biliary tract, and the immune checkpoint blockade showed promising efficacy in the treatment of advanced gallbladder carcinoma. However, the underlying mechanisms remain unknown. METHODS: Single-cell RNA sequencing was used to reveal immune cell dynamics in an anti-PD-1 responder with gallbladder carcinoma liver metastases. Gene set variation analysis, pseudotime analysis, single-cell regulatory network inference and clustering analysis, and CellChat analysis were used to identify the functions of each cell cluster. Immunohistochemistry and multicolored immunohistochemistry analysis were applied to confirm the intratumoral cell types, and the prognostic value of CXCL13+CD8+T cells in patients with gallbladder carcinoma liver metastases with immunotherapy was evaluated. Four biliary tract carcinoma and 3 immunotherapy bulk RNA-seq datasets were analyzed to investigate the prognostic value of CXCL13+CD8+T cells and SPP1+TAMs. RESULT: A total of 19,648 high-quality single-cell transcriptome data were obtained from liver metastasis before and after aPD-1 therapy. We discovered improved cytotoxic activity in CD8+T cells and enhanced proinflammatory phenotypes in myeloid cells. The identified SPP1+TAMs were related to poor prognosis. The increased effector/memory T cells represented characteristics similar to exhausted T cells in transitory status after aPD-1therapy, which may play a crucial role in the antitumor immune response. We further revealed that CXCL13+T cells in a high subtype of biliary tract carcinoma were characterized as a 'hot tumor' profile with high immune scores, correlated to the immunostimulatory context with favorable survival, and can predict effective responses to immunotherapy. CONCLUSIONS: Our study provided an overview of immune cell dynamics in gallbladder carcinoma liver metastases after aPD-1 treatment and highlighted the importance of CXCL13+T cells in biliary tract carcinoma and effective responses to immunotherapy, which would advance the understanding and treatment of the disease.
Subject(s)
Carcinoma , Gallbladder Neoplasms , Liver Neoplasms , Humans , Carcinoma/metabolism , CD8-Positive T-Lymphocytes , Gallbladder Neoplasms/drug therapy , Gallbladder Neoplasms/genetics , Gallbladder Neoplasms/metabolism , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Single-Cell Gene Expression Analysis , Programmed Cell Death 1 Receptor/antagonists & inhibitorsABSTRACT
PURPOSE: To evaluate the anticancer activities of lenvatinib in ICC and its possible molecular mechanisms. METHODS: Patients-derived xenograft (PDX) model and cell line-derived xenograft (CDX) model were both used for the in vivo study. For in vivo work, ICC cell lines were applied to analyze the effect of Lenvatinib on cell proliferation, cell cycle progression, apoptosis, and the molecular mechanism. RESULTS: In the present study, we found that lenvatinib dramatically hindered in vivo tumor growth in ICC patient-derived xenograft models. In addition, by using in vitro experiments in ICC cell lines, we found that lenvatinib dose- and time-dependently inhibited the proliferation of ICC cells and induced cell cycle arrest in the G0/G1 phase. Transcriptional profiling analysis further applied indicated that lenvatinib might inhibit cell proliferation through the induction of cell-cycle arrestment via activating of Gadd45a, it was evidenced by that the knockout of Gadd45a significantly attenuated the cycle arrest induced by lenvatinib, as well as the inhibitory effect of lenvatinib on ICC. CONCLUSION: Our work first found that lenvatinib exerted an excellent antitumor effect on ICC, mainly via inducing Gadd45a-mediated cell cycle arrest. Our work provides evidence and a rationale for the future use of lenvatinib in the treatment of ICC.
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To develop a superior diagnostic approach for pancreatic adenocarcinoma (PAAC), the present study prospectively included 338 PAAC patients, 294 normal healthy volunteers (NHV), 122 chronic pancreatitis (CP) patients and 100 patients with non-PAAC malignancies. In the identification phase, HuProt Human Proteome Microarray, comprising 21 065 proteins, was used to identify serum tumor-associated autoantibodies (TAAbs) candidates differentiating PAAC (n = 30) from NHV (n = 30). A PAAC-focused array containing 165 differentially expressed TAAbs identified was subsequently adopted in the validation phase (n = 712) for specificity and sensitivities. The multivariate TAAbs signature for differentiation PAAC from controls (NHV + CP) identified five candidates, namely the IgG-type TAAbs against CLDN17, KCNN3, SLAMF7, SLC22A11 and OR51F2. Multivariate logistic performance model of y = (22.893 × CA19-9 + 0.68 × CLDN17 - 4.012) showed a significant better diagnostic accuracy than that of CA19-9 and CLDN17 in differentiating PAAC from controls (NHV + CP) (AUC = 0.97, 0.92 and 0.82, respectively, P-value < .0001). We further tested the autoantigen level of CLDN17 by ELISA in 82 sera samples from PAAC (n = 42), CP (n = 24) and NHV (n = 16). Similarly, the model showed superior diagnostic performance than that of CA19-9 and CLDN17 (AUC = 0.93, 0.83 and 0.81, respectively, P-value < .0001) in differentiating PAAC from controls. In conclusion, our study is the first to characterize the circulating TAAbs signatures in PAAC. The results showed that CLDN17 combined with CA19-9 provided potentially clinical value and may serve as noninvasive novel biomarkers for PAAC diagnosis.
Subject(s)
Adenocarcinoma , Pancreatic Neoplasms , Pancreatitis, Chronic , Humans , Pancreatic Neoplasms/pathology , Autoantibodies , Adenocarcinoma/diagnosis , Biomarkers, Tumor , CA-19-9 Antigen , Pancreatitis, Chronic/diagnosis , Pancreatic NeoplasmsABSTRACT
The co-delivery of multiple drugs using nanocarriers has been recognized as a promising strategy for cancer treatment to enhance therapeutic efficacy. In this study, a monodisperse mesoporous silica nanoparticle (mSiO2) is prepared and functionalized into high-efficiency loaded Lenvatinib and Bufalin for targeted delivery to Cholangiocarcinoma (CCA). mSiO2 was synthesized on solid silica nanoparticles by oil-water interface method, and highly monodisperse mSiO2 with uniform morphology was obtained. mSiO2 was then sequentially modified by polyethylene glycol (PEG) and the targeting molecule folic acid (FA). mSiO2-FA was designed as co-delivery system for Lenvatinib (Le) and Bufalin (Bu) to increase drug availability and highly target tumor cells. Compared with unfunctionalized mSiO2, mSiO2-FA can more efficiently enter human CCA cell lines (9810 cells) and enhance intracellular drug delivery. Moreover, drug-loaded mSiO2-FA (Le/Bu@mSiO2-FA) significantly inhibited the viability, migration and invasion of 9810 cells. In vivo, the nanocomplex significantly reduced the tumor load in CCA tumor-bearing mouse models compared to Le or Bu alone. The current work provides a useful strategy for highly targeted and multidrug-resistance reversal therapy for CCA.
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Background: The immune checkpoint inhibitor (ICIs) therapy has been proven effective in a range of solid tumors including hepatocellular carcinoma (HCC), non-small cell lung carcinoma and metastatic melanoma. However, only a subset of approximately 20% of patients shows an objective response to anti-PD-1 therapy in HCC. Furthermore, the response to anti-PD-1 therapy is not correlated with programmed cell death 1 ligand expression in tumor tissue. Therefore, it is urgent to identify a biomarker to predict the response of anti-PD-1 therapy. Methods: This retrospective study was conducted at the Fudan University Shanghai Cancer Center from December 2019 to June 2021. The monocyte-to-lymphocyte ratio (MLR) was analyzed using a receiver operating characteristic (ROC) curve. A Cox regression model and the log-rank test were used to analyze the relationship between the MLR value and the time to progression (TTP). Results: A total of 34 advanced HCC patients were enrolled in this study. The cut-off point for the MLR at baseline was 0.35. Univariate and multivariate Cox regression models showed that the MLR at baseline was significantly correlated with the TTP (P<0.05). Consistent results were found for disease progression. The log-rank test showed that patients in the low MLR group had a longer TTP (P=0.0027). At the time of disease progression, the median TTP in the low and high MLR groups were 33 and 18 weeks, respectively (P=0.0047). Conclusions: The MLR can predict the response to anti-PD-1 therapy, and a high MLR is correlated with a short TTP in anti-PD-1-treated HCC patients.
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BACKGROUND: To investigate the effects of the Lenvatinib@H-MnO2-FA administration system on the proliferation and apoptosis of Intrahepatic cholangiocarcinoma (ICC) and the underlying molecular mechanism. MATERIALS AND METHODS: In this research, hollow MnO2 (H-MnO2) was synthesized via the modified Stöber method, and H-MnO2 was modified with polyethylene glycol-bis (Amine) (NH2-PEG-NH2) and folic acid (FA) to obtain H-MnO2-PEG-FA (H-MnO2-FA). Lenvatinib was coated in the hollow cavity of H-MnO2-PEG-FA to further form a nanometre drug-carrying system (Lenvatinib@H-MnO2-PEG-FA). Lenvatinib@H-MnO2-FA was characterized through transmission electron microscopy (TEM) and scanning electron microscopy (SEM). Fourier transform infrared spectroscopy (FT-IR) was used to verify that Lenvatinib was loaded on nanoparticles. Functionally, confocal laser scanning microscopy (CLSM), 2-(4-Amidinophenyl)-6-indolecarbamidine dihydrochloride (DAPI) staining, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay were performed to determine the effect of Lenvatinib@H-MnO2-FA on the proliferation and apoptosis of ICC cells (9810 cells). Finally, the protein levels of Raf-1MEK1/2-ERK1/2 signalling pathway components were detected through Western blotting analysis. RESULTS: We successfully synthesised a Lenvatinib@H-MnO2-PEG-FA administration system. The resulting nanomaterials had excellent biological stability and improved targeting effects. Functionally, Lenvatinib@ H-MnO2-FA inhibited the proliferation of 9810 cells. The Bcl-2 protein level was significantly downregulated, and the caspase-3 protein level was significantly upregulated, indicating that Lenvatinib@H-MnO2- PEG- FA promoted the apoptosis of 9810 cells. Mechanistically, Lenvatinib@H-MnO2-FA increased the phosphorylation levels of Raf, MEK1/2, and ERK1/2. CONCLUSION: H-MnO2-FA can more effectively deliver Lenvatinib to inhibit proliferation and promote apoptosis in ICC, which could be the promising drug delivery nano-vehicles for delivery drugs.
Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Nanoparticles , Bile Ducts, Intrahepatic , Cell Line, Tumor , Cholangiocarcinoma/drug therapy , Drug Carriers/chemistry , Drug Delivery Systems , Folic Acid/chemistry , Humans , Manganese Compounds/pharmacology , Nanoparticles/chemistry , Oxides/pharmacology , Phenylurea Compounds , Polyethylene Glycols/chemistry , Quinolines , Spectroscopy, Fourier Transform InfraredABSTRACT
OBJECTIVES: To retrospectively compare the survival outcomes of thermal ablation plus chemotherapy to those of chemotherapy alone in patients with unresectable intrahepatic cholangiocarcinoma (ICC). METHODS: 189 patients with unresectable ICC who received thermal ablation plus chemotherapy or chemotherapy alone as the initial treatment were identified . To avoid potential bias, 1:1 matching between groups was performed through propensity score matching. Overall survival (OS) was the primary endpoint. Clinical and tumor factors related to OS were analyzed through univariate and multivariate analyses. RESULTS: Of the enrolled patients, 55 received ablation plus chemotherapy, and 134 received chemotherapy alone. The median OS was 16.267 months for patients treated with combined therapy and 6.067 months for patients treated with chemotherapy alone (p = 0.000). The benefit of ablation plus chemotherapy was also preserved in the matched cohort, with a median OS of 15.233 months in the combined treatment group and 7.967 months in the chemotherapy group (p = 0.009). Univariate and multivariate analyses indicated that the type of treatment was an independent factor of OS (p < 0.05). CONCLUSIONS: The combination of thermal ablation and systemic chemotherapy provides an opportunity to improve the prognosis of patients with unresectable ICC.
Subject(s)
Ablation Techniques , Antineoplastic Agents/therapeutic use , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/surgery , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/surgery , Aged , Bile Duct Neoplasms/mortality , Cholangiocarcinoma/mortality , Combined Modality Therapy , Female , Humans , Male , Middle Aged , Propensity Score , Retrospective Studies , Survival Rate , Treatment OutcomeABSTRACT
Pancreatic cancer is a highly aggressive cancer with an exceedingly low rate of response to treatments, which calls for comprehensive molecular characterization of pancreatic cancer cell lines (PCCLs). We screened multi-layer molecular data of 36 PCCLs, including gene mutation, gene expression, microRNA (miRNA) expression, and protein profiles. Our comparative analysis of genomic mutations found that PCCLs recapitulated genomic alterations of the primary tumor and suggested potential therapeutic strategies for clinical interventions. The panel of 36 PCCLs was classified into 2 subgroups based on transcriptomic mRNA expression, wherein the C1 subgroup was characterized with differentiation, whereas C2 cell lines were featured with immunity, angiogenesis, epidermis, and proliferation. Transcriptomic classification was further recapitulated by miRNA and protein expression. Additionally, the differential proteins between C1 and C2 subgroups were prominently involved in epidermal growth factor receptor (EGFR) signaling, phosphatidylinositol 3-kinase (PI3K) signaling, and mitogen-activated protein kinase (MAPK) signaling pathways. Tumor samples from different subgroups exhibited distinct infiltration of CD4 naive cells and monocytes. Remarkably, patients in subgroups C1 showed longer survival, whereas those in C2 had worse clinical outcome. Further integrative analysis revealed that temozolomide and NVP-TAE684 showed higher sensitivity in the C1 subgroup, whereas the C2 cell lines were more sensitive to SR1001 and SRT-1720. Our results also showed that PCCLs with mutations in CDKN2A, TP53, and SMAD4 were more sensitive to certain anti-cancer drugs. Our integrative analysis identified molecular features of pancreatic cancer that were associated with clinical significance and drug sensitivity, providing potentially effective strategies for precision treatments of patients with pancreatic cancer.
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Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor patient prognosis. A cellular stress response mechanism called the unfolded protein response (UPR) has been implicated in PDAC progression. More recently, nucleobindin 1 (NUCB1), a calcium-binding protein, has been shown to control the UPR but its precise role in PDAC has not been explored. Here, we found that downregulation of NUCB1 was associated with poor prognosis in patients with PDAC. Functionally, NUCB1 overexpression suppressed pancreatic cancer cell proliferation and showed additive effects with gemcitabine (GEM) in vitro and in vivo. Moreover, by controlling ATF6 activity, NUCB1 overexpression suppressed GEM-induced UPR and autophagy. Last but not least, we uncovered METTL3-mediated m6A modification on NUCB1 5'UTR via the reader YTHDF2 as a mechanism for NUCB1 downregulation in PDAC. Taken together, our study revealed crucial functions of NUCB1 in suppressing proliferation and enhancing the effects of gemcitabine in pancreatic cancer cells and identified METTL3-mediated m6A modification as a mechanism for NUCB1 downregulation in PDAC.
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BACKGROUND: Lysophosphatidic acid (LPA) is known to promote cancer cell invasiveness through LPA1, but the downstream signaling cascades are still not fully clarified. The CKLF-like MARVEL transmembrane domain-containing (CMTM) family regulates aggressive phenotype in many cancers. METHODS: We performed LPA1 co-immunoprecipitation combined with mass spectrometry to search for LPA1-associated proteins. The role of CMTM8 in mediating the pro-invasive activity of LPA was investigated in pancreatic cancer. RESULTS: We identified CMTM8 as an LPA1-interacting protein. LPA1 and CMTM8 were co-localized in pancreatic cancer cells. LPA treatment led to stabilization of CMTM8 protein, which was impaired by knockdown of LPA1. Depletion of CMTM8 significantly suppressed the migration and invasion of pancreatic cancer cells. Conversely, ectopic expression of CMTM8 enhanced the migratory and invasive capacity of pancreatic cancer cells. CMTM8 depletion blocked the formation of metastatic lesions in the lung. Knockdown of CMTM8 attenuated LPA-induced migration and invasion in pancreatic cancer cells. CMTM8 overexpression stimulated ß-catenin activation through reduction of GSK3ß. In addition, knockdown of ß-catenin dramatically antagonized CMTM8-mediated migration and invasion in pancreatic cancer cells. CONCLUSIONS: CMTM8 serves as a key mediator of LPA-induced invasiveness in pancreatic cancer. The interaction between CMTM8 and LPA1 leads to activation of oncogenic ß-catenin signaling. CMTM8 represents a potential therapeutic target for pancreatic cancer.
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BACKGROUND: Elevated expression of family with sequence similarity 83 member D (Fam83D) has been found in various cancers; however, its role in pancreatic adenocarcinoma (PDAC) remains unclear. The current study was designed to elucidate the roles of Fam83D in pancreatic cancer. METHOD: The level of Fam83D was detected in PDAC tissues and adjacent no-tumorous tissues. Effects of Fam83D on proliferation, glycolysis and gemcitabine (GEM) sensitivity of pancreatic cancer cells were examined. RESULTS: Fam83D was overexpressed in PDAC and associated with clinical stage, metastatic status and survival rates of PDAC patients. Function study showed that Fam83D knockdown (KD) caused inhibited proliferation, suppressed mitochondrial respiration capacity, reduced aerobic glycolysis, and down-regulation of nuclear ß-catenin, proto-oncogene C-Myc, and lactate dehydrogenase A (LDHA). Fam83D KD enhanced the sensitivity of PDAC cells to GEM in vitro and in vivo. On the contrary, Fam83D overexpression displayed reverse effects on PDAC cells. Moreover, the Wnt/ß-catenin inhibitor abolished the effects of Fam83D overexpression in PDAC cells. CONCLUSIONS: the current data suggest that enhanced Fam83D expression contributes to PDAC progression and the development of chemoresistance through the Wnt/ß-catenin signaling.
Subject(s)
Adenocarcinoma/metabolism , Carcinogenesis/metabolism , Cell Cycle Proteins/biosynthesis , Deoxycytidine/analogs & derivatives , Microtubule-Associated Proteins/biosynthesis , Pancreatic Neoplasms/metabolism , Wnt Signaling Pathway/physiology , Adenocarcinoma/drug therapy , Aged , Animals , Carcinogenesis/drug effects , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/physiology , Female , Humans , Male , Mice , Mice, Nude , Middle Aged , Pancreatic Neoplasms/drug therapy , Wnt Signaling Pathway/drug effects , Xenograft Model Antitumor Assays/methods , GemcitabineABSTRACT
Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP), a histidine phosphatase, plays an important role in tumor progression and metastasis as a tumor suppressor. Here, we investigate the effect of LHPP in intrahepatic cholangiocarcinoma (ICC). We discovered that LHPP was downregulated in tumor tissues and low levels of LHPP predicted poor survival. LHPP inhibited ICC cell growth, cell invasion and epithelial-mesenchymal transition (EMT) in vitro and in vivo. Mechanically, LHPP deactivated transforming growth factorbeta (TGFß) signaling pathway, and low level LHPP upregulated the expression of TGFß and phosphorylation of smad2/3. Moreover, inhibition of this pathway reversed the biofunction of LHPP. In summary, these findings demonstrated that LHPP suppressed ICC through inhibiting the activation of TGFß/smad signaling. Our results indicated that LHPP is a potential therapeutic target in ICC.
Subject(s)
Bile Duct Neoplasms/pathology , Cholangiocarcinoma/pathology , Inorganic Pyrophosphatase/metabolism , Signal Transduction , Smad Proteins/metabolism , Transforming Growth Factor beta/metabolism , Carcinogenesis , Cell Line, Tumor , Cell Proliferation , Epithelial-Mesenchymal Transition , Gene Expression Regulation, Neoplastic , Humans , Up-RegulationABSTRACT
Objectives: To retrospectively assess the efficacy of combined ablation-chemotherapy in comparison to that of chemotherapy alone in patients with liver metastasized pancreatic ductal adenocarcinoma (lmPDAC).Methods: In total 104 patients with hepatic oligo metastasized PDAC were identified; among them, 74 patients underwent combined thermal ablation-chemotherapy, and 30 patients underwent chemotherapy alone. Through propensity score matching, 1:1 matching of the combined ablation-chemotherapy group and chemotherapy group was achieved. The primary endpoint of this study was overall survival (OS). Clinical and tumor-related factors affecting OS were also analyzed through univariate and multivariate analyses using the Cox risk model.Results: For patients treated with combined ablation-chemotherapy, the median OS was 10.77 months, while it was 5.77 months for patients treated with chemotherapy alone (P = 0.011). The survival benefit for patients treated with combined ablation-chemotherapy was still preserved in the matched cohort, with a median OS of 8.17 months compared to 5.77 months in the chemotherapy group. Univariate and multivariate analyses in the matched population also showed treatment with combined ablation-chemotherapy was an independent prognostic factor (P < 0.05).Conclusions: For patients with liver metastases from pancreatic cancer, the combined use of thermal ablation and systemic chemotherapy offers a chance for a better survival outcome.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Pancreatic Ductal/therapy , Liver Neoplasms/therapy , Pancreatic Neoplasms/pathology , Radiofrequency Ablation , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/secondary , Combined Modality Therapy , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Drug Combinations , Female , Humans , Kaplan-Meier Estimate , Liver Neoplasms/pathology , Liver Neoplasms/secondary , Male , Microwaves/therapeutic use , Middle Aged , Oxonic Acid/administration & dosage , Propensity Score , Radiofrequency Ablation/adverse effects , Retrospective Studies , Survival Rate , Tegafur/administration & dosage , Tumor Burden , GemcitabineABSTRACT
BACKGROUND: Tumor mutation burden (TMB) has an important association with immunotherapy responses. TMB in the Chinese population has not been well established. Finding differences between the Chinese and Caucasian populations and elucidating the underlying biological mechanisms of high TMB might help develop more precise and effective means for TMB and immunotherapy response prediction. METHODS: Chinese cancer patients fresh tissue (n=2,177), formalin-fixed, paraffin-embed (FFPE) specimens (n=3,294), and pleural fluid (n=189) were profiled using a 295- or 520-gene next-generation sequencing (NGS) panel. The association of the TMB status with a series of molecular features and biological pathways was determined using bootstrapping. RESULTS: TMB, measured by 295- or 520-cancer-related gene panels, was correlated with whole-exome sequencing (WES) TMB based on the in silico simulation in The Cancer Genome Atlas cohort. The median TMB of our data was slightly higher than that from the Foundation Medicine Inc. (FMI) dataset. TMB was also slightly different within the same cancer type between the Chinese and Caucasian population. We discovered that the underlying pathways of TMB status varied greatly and sometimes had an opposite association with TMB across different cancer types. Moreover, we developed a 23-gene and a 16-gene signature to predict TMB prediction for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), respectively, indicating a histology-specific mechanism for driving high-TMB in lung cancer. CONCLUSIONS: TMB varies among different ethnic populations. Our findings extend the knowledge of the underlying biological mechanisms for high TMB and might be helpful for developing more precise and accessible TMB assessment panels and algorithms in more cancer types.
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BACKGROUND: Heat shot protein 90 (HSP90) AA1 functions as an onco-protein to regulate the assembly, manipulation, folding and degradation of its client proteins, including c-MYC. However, little is known about the mechanism of HSP90AA1 regulation. METHODS: Transcriptome RNA-sequencing data of hepatocellular carcinoma (HCC) samples were used to detect the mRNA expression of FBXL6. Immunoprecipitation/Mass Spectrum (IP/MS) method was used to identify the interacting proteins of FBXL6. The co-immunoprecipitation assay was used to determine the interaction between FBXL6 and HSP90AA1. The in vivo ubiquitination assay was performed to determine the regulation of HSP90AA1 by FBXL6. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to determine the transcriptional regulation of FBXL6 by c-MYC. Immunohistochemical (IHC) staining was performed to study the correlation of FBXL6 and HSP90AA1 protein expression in 87 HCC samples. Cell counting and colony formation assays were implemented to detect the biological effects of FBXL6 on the growth of HCC cells in vitro. The effect of FBXL6 on HCC tumor growth in vivo was studied in a tumor xenograft model in mice. RESULTS: Here, we identified the orphan F-box protein FBXL6, a substrate recognition subunit of an SCF (Skp1-Cul1-F-box protein) complex, as the ubiquitin ligase for HSP90AA1. FBXL6 promoted K63-dependent ubiquitination of HSP90AA1 to stabilize it. Through analysis of the TCGA dataset, we found that FBXL6 was significantly increased in HCC tissues and positively correlated with c-MYC pathway. FBXL6 accumulation in HCC causes the stabilization and activation of c-MYC by preventing HSP90AA1 degradation. The activated c-MYC directly binds to the promoter region of FBXL6 to induce its mRNA expression. CONCLUSION: Collectively, our data revealed an unknown FBXL6-HSP90AA1-c-MYC axis which might contribute to the oncogenesis of HCC, and we propose that inhibition of FBXL6 might represent an effective therapeutic strategy for HCC treatment. Video abstract.
Subject(s)
Carcinoma, Hepatocellular/metabolism , F-Box Proteins/metabolism , HSP90 Heat-Shock Proteins/metabolism , Liver Neoplasms/metabolism , Proto-Oncogene Proteins c-myc/metabolism , Ubiquitination , Animals , Carcinogenesis/genetics , Carcinogenesis/pathology , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , F-Box Proteins/genetics , Gene Expression Regulation, Neoplastic , HEK293 Cells , Humans , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Lysine/metabolism , Mice, Inbred BALB C , Mice, Nude , Protein Stability , Proto-Oncogene Proteins c-myc/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Transcription, GeneticABSTRACT
The present study aimed to screen the immune-related genes (IRGs) in patients with liver hepatocellular carcinoma (LIHC) and construct a synthetic index for indicating the prognostic outcomes. The bioinformatic analysis was performed on the data of 374 cancer tissues and 50 normal tissues, which were downloaded from TCGA database. We observed that 17 differentially expressed IRGs were significantly associated with survival in LIHC patients. These LIHC-specific IRGs were validated with function analysis and molecular characteristics. Cox analysis was applied for constructing a RiskScore for predicting the survival. The RiskScore involved six IRGs and corresponding coefficients, which was calculated with the following formula: RiskScore = [Expression level of FABP5 *(0.064)] + [Expression level of TRAF3 * (0.198)] + [Expression level of CSPG5 * (0.416)] + [Expression level of IL17D * (0.197)] + [Expression level of STC2 * (0.036)] + [Expression level of BRD8 * (0.140)]. The RiskScore was positively associated with the poor survival, which was verified with the dataset from ICGC database. Further analysis revealed that the RiskScore was independent of any other clinical feature, while it was linked with the infiltration levels of six types of immune cells. Our study reported the survival-associated IRGs in LIHC and then constructed IRGs-based RiskScore as prognostic indicator for screening patients with high risk of short survival. Both the screened IRGs and IRGs-based RiskScore were clinically significant, which may be informative for promoting the individualized immunotherapy against LIHC.