ABSTRACT
BACKGROUND: Lung cancer is the most prevalent cancer worldwide, with non-small cell lung cancer (NSCLC) accounting for 85% of all cases. Circular RNAs(circRNA) play crucial roles in regulating the progression of lung cancer. Despite the identification of a large number of circRNAs, their expression patterns, functions, and mechanisms of action in NSCLC development remain unclear.This study aims to investigate the transcriptional expressions, functions, and potential mechanisms of circRNA hsa_circ_0050386 in NSCLC. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized for the analysis of hsa_circ_0050386 expression. Cell proliferation was detected using the IncuCyte Live Cell Analysis System and clone formation assays. Migration and invasion of NSCLC cells were evaluated through Transwell assays. Flow cytometry was performed to assay cell cycle and apoptosis. Western blot was used to investigate protein expression. Protein binding analysis was conducted by employing pull-down assays, RNA immunoprecipitation (RIP), and mass spectrometry. The role of hsa_circ_0050386 in vivo was evaluated through the use of a xenograft model. RESULTS: The study discovered that hsa_circ_0050386 displayed lower expression levels in NSCLC tissues when compared to adjacent normal tissues. Patients exhibiting lower levels of hsa_circ_0050386 expression exhibited an inverse correlation with the Clinical Stage, T-stage, and M-stage of NSCLC. Functionally, hsa_circ_0050386 suppressed the proliferation and invasion of NSCLC cells both in vitro and in vivo. A comprehensive examination exposed the interaction between hsa_circ_0050386 and RNA binding protein Serine and arginine-rich splicing factor 3 (SRSF3), resulting in the down-regulation of Fibronectin 1 (FN1) expression, which inhibits the progression of NSCLC. CONCLUSIONS: Our study shows that hsa_circ_0050386 suppresses the malignant biological behavior of NSCLC cells by down-regulating the expression of FN1, and may serve as a potential biomarker and therapeutic target for NSCLC treatment.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , MicroRNAs , Humans , Carcinoma, Non-Small-Cell Lung/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Fibronectins , Gene Expression Regulation, Neoplastic , Lung Neoplasms/genetics , RNA/genetics , RNA, Circular/genetics , Serine-Arginine Splicing FactorsABSTRACT
Cancer cells often encounter hypoxic and hypo-nutrient conditions, which force them to make adaptive changes to meet their high demands for energy and various biomaterials for biomass synthesis. As a result, enhanced catabolism (breakdown of macromolecules for energy production) and anabolism (macromolecule synthesis from bio-precursors) are induced in cancer. This phenomenon is called "metabolic reprogramming," a cancer hallmark contributing to cancer development, metastasis, and drug resistance. HCC and cholangiocarcinoma (CCA) are 2 different liver cancers with high intertumoral heterogeneity in terms of etiologies, mutational landscapes, transcriptomes, and histological representations. In agreement, metabolism in HCC or CCA is remarkably heterogeneous, although changes in the glycolytic pathways and an increase in the generation of lactate (the Warburg effect) have been frequently detected in those tumors. For example, HCC tumors with activated ß-catenin are addicted to fatty acid catabolism, whereas HCC tumors derived from fatty liver avoid using fatty acids. In this review, we describe common metabolic alterations in HCC and CCA as well as metabolic features unique for their subsets. We discuss metabolism of NAFLD as well, because NAFLD will likely become a leading etiology of liver cancer in the coming years due to the obesity epidemic in the Western world. Furthermore, we outline the clinical implication of liver cancer metabolism and highlight the computation and systems biology approaches, such as genome-wide metabolic models, as a valuable tool allowing us to identify therapeutic targets and develop personalized treatments for liver cancer patients.
Subject(s)
Bile Duct Neoplasms , Carcinoma, Hepatocellular , Liver Neoplasms , Non-alcoholic Fatty Liver Disease , Humans , Liver Neoplasms/metabolism , Carcinoma, Hepatocellular/pathology , Bile Duct Neoplasms/pathology , Bile Ducts, Intrahepatic/pathologyABSTRACT
Despite the continuous advancement of surgical resection techniques, postoperative tumor recurrence and metastasis remain a huge challenge. Here, we constructed an injectable curcumin/doxorubicin-loaded nanoparticle (NanoCD) hydrogel, which could effectively inhibit tumor regrowth and metastasis via reshaping the tumor immune microenvironment (TIME) for highly effective postsurgical cancer treatment. NanoCD was prepared by the controlled assembly of curcumin (CUR) and doxorubicin (DOX) via π-π stacking and hydrogen bonding in the presence of human serum albumin. To facilitate prolonged treatment of postsurgical tumors, NanoCD was further incorporated into the temperature-sensitive Poloxamer 407 gel (NanoCD@Gel) for intracavity administration. Mechanistically, DOX induced the generation of intracellular reactive oxygen species (ROS) and CUR reduced the ROS metabolism by inhibiting thioredoxin reductase (TrxR). The synergy of DOX and CUR amplified intracellular ROS levels and thus resulted in enhanced immunogenic cell death (ICD) of tumor cells. Upon being injected into the tumor cavity after resection, the in situ-generated NanoCD@Gel allowed the local release of CUR and DOX in a controlled manner to induce local chemotherapy and persistently activate the antitumor immune response, thereby achieving enhanced immunogenic chemotherapy with reduced systemic toxicity. Our work provides an elegant strategy for persistently stimulating effective antitumor immunity to prevent postsurgical tumor recurrence and metastasis.
Subject(s)
Curcumin , Nanoparticles , Humans , Curcumin/pharmacology , Hydrogels , Reactive Oxygen Species , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/prevention & control , Cell Line, Tumor , Doxorubicin , Tumor MicroenvironmentABSTRACT
Transcription activation by cyclic AMP (cAMP) receptor protein (CAP) is the classic paradigm of transcription regulation in bacteria. CAP was suggested to activate transcription on class-II promoters via a recruitment and isomerization mechanism. However, whether and how it modifies RNA polymerase (RNAP) to initiate transcription remains unclear. Here, we report cryo-electron microscopy (cryo-EM) structures of an intact Escherichia coli class-II CAP-dependent transcription activation complex (CAP-TAC) with and without de novo RNA transcript. The structures reveal two distinct architectures of TAC and raise the possibility that CAP binding may induce substantial conformational changes in all the subunits of RNAP and transiently widen the main cleft of RNAP to facilitate DNA promoter entering and formation of the initiation open complex. These structural changes vanish during further RNA transcript synthesis. The observations in this study may reveal a possible on-pathway intermediate and suggest a possibility that CAP activates transcription by inducing intermediate state, in addition to the previously proposed stabilization mechanism.
Subject(s)
Cyclic AMP Receptor Protein/chemistry , Escherichia coli Proteins/chemistry , Cryoelectron Microscopy , Cyclic AMP Receptor Protein/metabolism , DNA-Directed RNA Polymerases/chemistry , DNA-Directed RNA Polymerases/metabolism , Data Visualization , Escherichia coli Proteins/metabolism , Models, Molecular , Multiprotein Complexes/chemistry , Protein Conformation , RNA/chemistry , RNA/metabolism , Sigma Factor/chemistry , Sigma Factor/metabolism , Transcription, GeneticABSTRACT
The Mre11/Rad50/NBS1 (MRN) complex maintains genomic stability by bridging DNA ends and initiating DNA damage signaling through activation of the ATM kinase. Mre11 possesses DNA nuclease activities that are highly conserved in evolution but play unknown roles in mammals. To define the functions of Mre11, we engineered targeted mouse alleles that either abrogate nuclease activities or inactivate the entire MRN complex. Mre11 nuclease deficiency causes a striking array of phenotypes indistinguishable from the absence of MRN, including early embryonic lethality and dramatic genomic instability. We identify a crucial role for the nuclease activities in homology-directed double-strand-break repair and a contributing role in activating the ATR kinase. However, the nuclease activities are not required to activate ATM after DNA damage or telomere deprotection. Therefore, nucleolytic processing by Mre11 is an essential function of fundamental importance in DNA repair, distinct from MRN control of ATM signaling.
Subject(s)
DNA Repair Enzymes/metabolism , DNA Repair , DNA-Binding Proteins/metabolism , Genomic Instability , Amino Acid Sequence , Animals , Ataxia Telangiectasia Mutated Proteins , Cell Cycle Proteins/metabolism , Cell Line, Transformed , Cell Proliferation , DNA Breaks, Double-Stranded , DNA Damage , DNA Repair Enzymes/chemistry , DNA-Binding Proteins/chemistry , Fibroblasts/metabolism , MRE11 Homologue Protein , Mice , Protein Serine-Threonine Kinases/metabolism , Recombination, Genetic , Telomere/metabolism , Tumor Suppressor Proteins/metabolismABSTRACT
Objective: The heightened prevalence of pulmonary nodules (PN) has escalated its significance as a public health concern. While the precise identification of high-risk PN carriers for malignancy remains an ongoing challenge, genetic variants hold potentials as determinants of disease susceptibility that can aid in diagnosis. Yet, current understanding of the genetic loci associated with malignant PN (MPN) risk is limited. Methods: A frequency-matched case-control study was performed, comprising 247 MPN cases and 412 benign NP (BNP) controls. We genotyped 11 established susceptibility loci for lung cancer in a Chinese cohort. Loci associated with MPN risk were utilized to compute a polygenic risk score (PRS). This PRS was subsequently incorporated into the diagnostic evaluation of MPNs, with emphasis on serum tumor biomarkers. Results: Loci rs10429489G>A, rs17038564A>G, and rs12265047A>G were identified as being associated with an increased risk of MPNs. The PRS, formulated from the cumulative risk effects of these loci, correlated with the malignant risk of PNs in a dose-dependent fashion. A high PRS was found to amplify the MPN risk by 156% in comparison to a low PRS [odds ratio (OR)=2.56, 95% confidence interval (95% CI), 1.40-4.67]. Notably, the PRS was observed to enhance the diagnostic accuracy of serum carcinoembryonic antigen (CEA) in distinguishing MPNs from BPNs, with diagnostic values rising from 0.716 to 0.861 across low- to high-PRS categories. Further bioinformatics investigations pinpointed rs10429489G>A as an expression quantitative trait locus. Conclusions: Loci rs10429489G>A, rs17038564A>G, and rs12265047A>G contribute to MPN risk and augment the diagnostic precision for MPNs based on serum CEA concentrations.
ABSTRACT
BACKGROUND & AIMS: Promoted by pancreatitis, oncogenic KrasG12D triggers acinar cells' neoplastic transformation through acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia. Anterior gradient 2 (Agr2), a known inhibitor of p53, is detected at early stage of pancreatic ductal adenocarcinoma (PDAC) development. RNA polymerase II (RNAPII) is a key nuclear enzyme; regulation of its nuclear localization in mammalian cells represents a potential therapeutic target. METHODS: A mouse model of inflammation-accelerated KrasG12D-driven ADM and pancreatic intraepithelial neoplasia development was used. Pancreas-specific Agr2 ablation was performed to access its role in pancreatic carcinogenesis. Hydrophobic hexapeptides loaded in liposomes were developed to disrupt Agr2-RNAPII complex. RESULTS: We found that Agr2 is up-regulated in ADM-to-pancreatic intraepithelial neoplasia transition in inflammation and KrasG12D-driven early pancreatic carcinogenesis. Genetic ablation of Agr2 specifically blocks this metaplastic-to-neoplastic process. Mechanistically, Agr2 directs the nuclear import of RNAPII via its C-terminal nuclear localization signal, undermining the ATR-dependent p53 activation in ADM lesions. Because Agr2 binds to the largest subunit of RNAPII in a peptide motif-dependent manner, we developed a hexapeptide to interfere with the nuclear import of RNAPII by competitively disrupting the Agr2-RNAPII complex. This novel hexapeptide leads to dysfunction of RNAPII with concomitant activation of DNA damage response in early neoplastic lesions; hence, it dramatically compromises PDAC initiation in vivo. Moreover, the hexapeptide sensitizes PDAC cells and patient-derived organoids harboring wild-type p53 to RNAPII inhibitors and first-line chemotherapeutic agents in vivo. Of note, this therapeutic effect is efficient across various cancer types. CONCLUSIONS: Agr2 is identified as a novel adaptor protein for nuclear import of RNAPII in mammalian cells. Also, we provide genetic evidence defining Agr2-dependent nuclear import of RNAPII as a pharmaceutically accessible target for prevention and treatment in PDAC in the context of wild-type p53.
Subject(s)
Carcinoma in Situ/enzymology , Carcinoma, Pancreatic Ductal/enzymology , Mucoproteins/metabolism , Oncogene Proteins/metabolism , Pancreatic Neoplasms/enzymology , RNA Polymerase II/metabolism , Tumor Suppressor Protein p53/metabolism , Active Transport, Cell Nucleus , Animals , Antineoplastic Agents/pharmacology , Carcinoma in Situ/drug therapy , Carcinoma in Situ/genetics , Carcinoma in Situ/pathology , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Gene Expression Regulation, Neoplastic , Metaplasia , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , Mucoproteins/genetics , Mutation , Oligopeptides/pharmacology , Oncogene Proteins/genetics , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Proto-Oncogene Proteins p21(ras)/genetics , RNA Polymerase II/genetics , Tumor Suppressor Protein p53/geneticsABSTRACT
Selenomethionine (SeMet) did not prevent prostate cancer in the SELECT trial and in two hormone-driven rat models. However, we have shown that daily oral bolus administration of next-generation selenium forms, methylseleninic acid (MSeA) and Se-methylselenocysteine (MSeC) at 3 mg Se/kg body weight, inhibits prostate carcinogenesis in the TRAMP and pten-deficient mouse models and In Vivo growth of human prostate cancer cells. Here, we determined whether these Se forms prevent prostate cancer in a chemically induced-androgen promoted carcinogenesis rat model in which SeMet was not preventive. WU rats were treated with methylnitrosourea, and one week later, slow-release testosterone implants when they were randomized to groups fed AIN-93M diet supplemented with 3 ppm selenium as MSeA or MSeC or control diet. Mean survival, tumor incidence in all accessory sex glands combined (dorsolateral and anterior prostate plus seminal vesicle) and the incidence of tumors confined to dorsolateral and/or anterior prostate were not statistically significantly different among the groups. Thus, MSeA and MSeC feeding was not preventive in this model. The contrast with the inhibitory effects of MSeA and MSeC in mouse models may be due to differences in carcinogenic mechanisms, selenium dosage, delivery mode, and pharmacokinetics or fundamental rat-mouse differences in selenium metabolism.
Subject(s)
Prostatic Neoplasms , Selenium , Androgens/metabolism , Animals , Antioxidants/metabolism , Carcinogenesis/chemically induced , Carcinogens , Diet , Disease Models, Animal , Humans , Male , Mice , Organoselenium Compounds , Prostate/metabolism , Prostatic Neoplasms/chemically induced , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/prevention & control , Rats , Selenium/metabolism , Selenium/pharmacology , Selenocysteine/analogs & derivatives , Selenocysteine/metabolism , Selenocysteine/pharmacology , Selenomethionine/metabolism , Selenomethionine/pharmacologyABSTRACT
Circular RNAs (circRNAs) have been shown to play a functional role in a variety of cancers. However, few studies on circRNAs in estrogen receptor-positive breast cancer have been conducted. Here, we investigated the role of circRNA circTP63 in estrogen receptor-positive breast cancer progression and malignant behaviors. First, we observed increased expression of circTP63 in MCF7 cells relative to normal human mammary epithelial cell lines, such as DU4475 and MCF-10A, and the changed oncogenicity of MCF7 cells correlated with circTP63 overexpression and downregulation. Interestingly, a series of gain- and loss-of-function assays revealed that a higher level of FOXM1 was closely associated with MCF7 malignant behaviors induced by circTP63 overexpression. Further investigations showed that circTP63 sponged to miR-873-3p, which targeted FOXM1 mRNA and inhibited its expression. Mechanistically, circTP63 binds to miR-873-3p and prevents the targeting of FOXM1, thus inducing the progression and malignant behaviors of estrogen receptor-positive breast cancer, such as cell proliferation, cell cycle dysregulation, invasion, migration and even tumor growth. CircTP63 might be a potential biomarker or target to treat estrogen receptor-positive breast cancer patients in the future.
Subject(s)
Breast Neoplasms/pathology , Forkhead Box Protein M1/metabolism , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , RNA, Circular/genetics , Receptors, Estrogen/metabolism , Transcription Factors/genetics , Tumor Suppressor Proteins/genetics , Animals , Apoptosis , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Cycle , Cell Proliferation , Epithelial-Mesenchymal Transition , Female , Forkhead Box Protein M1/genetics , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Invasiveness , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Long non-coding RNAs (lncRNAs) could regulate growth and metastasis of hepatocellular carcinoma (HCC). In this study, we aimed to investigate the mechanism of lncRNA F11-AS1 in hepatitis B virus (HBV)-related HCC. The relation of lncRNA F11-AS1 expression in HBV-related HCC tissues to prognosis was analysed in silico. Stably HBV-expressing HepG2.2.15 cells were established to explore the regulation of lncRNA F11-AS1 by HBx protein, as well as to study the effects of overexpressed lncRNA F11-AS1 on proliferation, migration, invasion and apoptosis in vitro. Subsequently, the underlying interactions and roles of lncRNA F11-AS1/miR-211-5p/NR1I3 axis in HBV-related HCC were investigated. Additionally, the influence of lncRNA F11-AS1 and miR-211-5p on tumour growth and metastasis capacity of HepG2.2.15 cells were studied on tumour-bearing nude mice. Poor expression of lncRNA F11-AS1 was correlated with poor prognosis in patients with HBV-related HCC, and its down-regulation was caused by the HBx protein. lncRNA F11-AS1 was proved to up-regulate the NR1I3 expression by binding to miR-211-5p. Overexpression of lncRNA F11-AS1 reduced the proliferation, migration and invasion, yet induced apoptosis of HepG2.2.15 cells in vitro, which could be abolished by overexpression of miR-211-5p. Additionally, either lncRNA F11-AS1 overexpression or miR-211-5p inhibition attenuated the tumour growth and metastasis capacity of HepG2.2.15 cells in vivo. Collectively, lncRNA F11-AS1 acted as a modulator of miR-211-5p to positively regulate the expression of NR1I3, and the lncRNA F11-AS1/miR-211-5p/NR1I3 axis participated in HBV-related HCC progression via interference with the cellular physiology of HCC.
Subject(s)
Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/virology , Disease Progression , Hepatitis B virus/physiology , Liver Neoplasms/genetics , MicroRNAs/metabolism , RNA, Long Noncoding/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Apoptosis/genetics , Base Sequence , Carcinoma, Hepatocellular/pathology , Cell Movement/genetics , Cell Proliferation/genetics , Constitutive Androstane Receptor , Female , Gene Expression Regulation, Neoplastic , Hep G2 Cells , Humans , Liver Neoplasms/pathology , Liver Neoplasms/virology , Male , MicroRNAs/genetics , Middle Aged , Models, Biological , Neoplasm Invasiveness , Neoplasm Metastasis , Prognosis , Protein Binding , RNA, Long Noncoding/genetics , Trans-Activators/metabolism , Up-Regulation/genetics , Viral Regulatory and Accessory Proteins/metabolismABSTRACT
BACKGROUND: There is a need to develop novel therapies which could be beneficial to patients with prostate cancer (CaP) including those who are predisposed to poor outcome, such as African-Americans. This study investigates the role of ROBO1-pathway in predicting outcome and race-based disparity in patients with CaP. METHODS AND RESULTS: Aided by RNA sequencing-based DECIPHER-testing and immunohistochemical (IHC) analysis of tumors we show that ROBO1 is lost during the progressive stages of CaP, a prevalent feature in African-Americans. We show that the loss of ROBO1 predicts high-risk of recurrence, metastasis and poor outcome of androgen-deprivation therapy in radical prostatectomy-treated patients. These data identified an aggressive ROBO1deficient /DOCK1+ve sub-class of CaP. Combined genetic and IHC data showed that ROBO1 loss is accompanied by DOCK1/Rac1 elevation in grade-III/IV primary-tumors and Mets. We observed that the hypermethylation of ROBO1-promoter contributes to loss of expression that is highly prevalent in African-Americans. Because of limitations in restoring ROBO1 function, we asked if targeting the DOCK1 could be an ideal strategy to inhibit progression or treat ROBO1deficient metastatic-CaP. We tested the pharmacological efficacy of CPYPP, a selective inhibitor of DOCK1 under in vitro and in vivo conditions. Using ROBO1-ve and ROBO1+ve CaP models, we determined the median effective concentration of CPYPP for growth. DOCK1-inhibitor treatment significantly decreased the (a) Rac1-GTP/ß-catenin activity, (b) transmigration of ROBO1deficient cells across endothelial lining, and (c) metastatic spread of ROBO1deficient cells through the vasculature of transgenicfl Zebrafish model. CONCLUSION: We suggest that ROBO1 status forms as predictive biomarker of outcome in high-risk populations such as African-Americans and DOCK1-targeting therapy has a clinical potential for treating metastatic-CaP.
Subject(s)
Black or African American/genetics , Nerve Tissue Proteins/genetics , Prostatic Neoplasms/ethnology , Prostatic Neoplasms/genetics , Receptors, Immunologic/genetics , rac GTP-Binding Proteins/genetics , Animals , Cell Line, Tumor , DNA Methylation , Health Status Disparities , Humans , Immunohistochemistry , Male , Neoplasm Metastasis , Nerve Tissue Proteins/biosynthesis , Nerve Tissue Proteins/deficiency , Promoter Regions, Genetic , Prostatectomy , Prostatic Neoplasms/pathology , Prostatic Neoplasms/surgery , Receptors, Immunologic/biosynthesis , Receptors, Immunologic/deficiency , White People/genetics , Zebrafish , rac GTP-Binding Proteins/antagonists & inhibitors , rac GTP-Binding Proteins/metabolism , rac1 GTP-Binding Protein/genetics , rac1 GTP-Binding Protein/metabolism , Roundabout ProteinsABSTRACT
Inhibiting the disease progression in KRAS-driven cancers after diagnosis has been a difficult task for clinicians to manage due to the lack of effective intervention/preventive therapies. KRAS-driven cancers depend on sustained KRAS signaling. Although developing inhibitors of KRAS signaling has proven difficult in the past, the quest for identifying newer agents has not stopped. Based on studies showing terpenoids as modulators of KRAS-regulated downstream molecular pathways, we asked if this chemical family has an affinity of inhibiting KRAS protein activity. Using crystal structure as a bait in silico, we identified 20 terpenoids for their KRAS protein-binding affinity. We next carried out biological validation of in silico data by employing in situ, in vitro, patient-derived explant ex vivo, and KPC transgenic mouse models. In this report, we provide a comprehensive analysis of a lup-20(29)-en-3b-ol (lupeol) as a KRAS inhibitor. Using nucleotide exchange, isothermal titration calorimetry, differential scanning fluorimetry, and immunoprecipitation assays, we show that lupeol has the potential to reduce the guanosine diphosphate/guanosine triphosphate exchange of KRAS protein including mutant KRASG12V . Lupeol treatment inhibited the KRAS activation in KRAS-activated cell models (NIH-panel, colorectal, lung, and pancreatic intraepithelial neoplasia) and patient tumor explants ex vivo. Lupeol reduced the three-dimensional growth of KRAS-activated cells. The pharmacokinetic analysis showed the bioavailability of lupeol after consumption via oral and intraperitoneal routes in animals. Tested under prevention settings, the lupeol consumption inhibited the development of pancreatic intraepithelial neoplasia in LSL-KRASG12D/Pdx-cre mice (pancreatic ductal adenocarcinoma progression model). These data suggest that the selected members of the triterpene family (such as lupeol) could be exploited as clinical agents for preventing the disease progression in KRAS-driven cancers which however warrants further investigation.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Cell Transformation, Neoplastic/drug effects , Disease Models, Animal , Pancreatic Neoplasms/drug therapy , Pentacyclic Triterpenes/pharmacology , Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors , Animals , Apoptosis , Cell Proliferation , Cell Transformation, Neoplastic/pathology , Disease Progression , Female , Humans , In Vitro Techniques , Mice , Mice, Inbred C57BL , Mice, Transgenic , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Signal Transduction , Tumor Cells, Cultured , Xenograft Model Antitumor Assays , Pancreatic NeoplasmsABSTRACT
At the present time, COVID-19 is spreading rapidly [1]. The global prevention and control of COVID-19 is focused on the estimation of the relevant incubation period, basic reproduction number (R0), effective reproduction number (Rt) and death risk. Although the prevention and control of COVID-19 requires a reliable estimation of the relevant incubation period, R0, Rt and death risk. Another key epidemiological parameter-asymptomatic ratio that provides strength and range for social alienation strategies of COVID-19, which is widely defined as the proportion of asymptomatic infections among all disease infections. In fact, the ratio of asymptomatic infection is a useful indicator of the burden of disease and a better measurement of the transmissibility of the virus. So far, people have not paid enough attention to asymptomatic carriers. The asymptomatic carriers discussed in this study are recessive infections, that is, those who have never shown symptoms after onset of infection. We will discuss three aspects: detection, infectivity and proportion of healthy carriers.
Subject(s)
Asymptomatic Infections/epidemiology , Coronavirus Infections/transmission , Pneumonia, Viral/transmission , COVID-19 , China/epidemiology , Contact Tracing , Coronavirus Infections/epidemiology , Female , Humans , Male , Pandemics , Pneumonia, Viral/epidemiologyABSTRACT
BACKGROUND: At present, the relationship between serum homocysteine and microalbuminuria (MAU) in systemic lupus erythematosus (SLE) patients is still unclear. Therefore, the aim of our study was to analyze the association between serum homocysteine and MAU in SLE patients. METHODS: The study analyzed 150 patients with SLE at Affiliated Hospital of Youjiang Medical University for Nationalities retrospectively, and we collected for clinical and laboratory data. RESULTS: We found a positive correlation between serum homocysteine and MAU in SLE patients (r = 0.430, p < 0.001). We found that serum homocysteine levels were increased in SLE patients with MAU positive compared to those who were MAU negative (p < 0.001). After adjusting for multiple confounding factors, we found that serum homocysteine maintained a positive correlation with MAU in patients with SLE in multivariate correlation analysis (p = 0.253, r = 0.002). The receiver operating characteristic (ROC) curve with an area under the curve of 0.730, and serum homocysteine had 72.2% sensitivity and 61.9% specificity with cutoff values 9.0 to identify the SLE patients with MAU positive. CONCLUSIONS: The current results found a correlation between serum homocysteine and MAU in SLE patients, suggesting that elevated serum homocysteine levels might be an adverse factor for SLE patients with kidney injury.
Subject(s)
Lupus Erythematosus, Systemic , Albuminuria/diagnosis , Homocysteine , Humans , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/diagnosis , ROC Curve , Retrospective StudiesABSTRACT
OBJECTIVES: The present study was committed to investigate the role of miR-148a-3p in HCC infected with hepatitis C virus (HCV) and the regulatory mechanism of miR-148a-3p/c-Jun/MAPK signalling pathway. METHODS: Differential analysis and GSEA analysis were performed with R packages. QRT-PCR and Western blot were used to detect RNA or protein level, respectively. The targeted relationship between miR-148a-3p and c-Jun was predicted by TargetScan database and determined by double luciferase reporter assay. MTT assay and flow cytometry were used to evaluate cell proliferation, cell cycle and cell apoptosis, respectively. RESULTS: C-Jun was up-regulated, and MAPK signalling pathway was activated in HCV-infected HCC cells. C-Jun expression regulated inflammation-related gene expression and had an influence on cell proliferation, cell cycle and cell apoptosis. MiR-148a-3p, down-regulated in HCV-infected HCC cells, could target c-Jun mRNA to suppress c-Jun protein expression. CONCLUSIONS: MiR-148a-3p suppressed the proliferation of HCC cells infected with HCV through targeting c-Jun mRNA.
Subject(s)
Carcinoma, Hepatocellular/genetics , Hepatitis C/genetics , Liver Neoplasms/genetics , MicroRNAs/genetics , Adult , Apoptosis/genetics , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/virology , Cell Cycle/genetics , Cell Proliferation/genetics , Disease Progression , Female , Gene Expression Regulation, Neoplastic/genetics , Hepacivirus/genetics , Hepacivirus/pathogenicity , Hepatitis C/pathology , Hepatitis C/virology , Humans , JNK Mitogen-Activated Protein Kinases/genetics , Liver Neoplasms/pathology , Liver Neoplasms/virology , MAP Kinase Signaling System/genetics , Male , Neoplasm Proteins/genetics , RNA, Messenger/geneticsABSTRACT
The study aimed to identify the long noncoding RNAs (lncRNAs) biomarkers for occurrence and prognosis of patients with hepatocellular carcinoma (HCC), and simultaneously to investigate the potential role of lncRNAs in the oncogenesis of HCC. The lncRNAs expression data and the corresponding clinical information of HCC samples were extracted from The Cancer Genome Atlas (TCGA) database. The differentially expressed genes and lncRNAs were identified and the correlation networks were constructed. In this study, we identified 212 differentially expressed lncRNAs and 7,577 differentially expressed genes between liver HCC tumor tissues and normal tissue samples. And then, combining with clinical information, a total of 11 lncRNAs and 162 genes as HCC biomarkers were identified by comprehensive bioinformatics analysis. Further, through coexpress network analysis, we confirmed four lncRNAs (lncRNA_ANKRD10.IT1, lncRNA_CTD.2583A14.8, lncRNA_RP11.404P21.3, and lncRNA_RP11.488L18.10), which can serve as prognostic biomarkers for HCC. The four lncRNAs identified in this study may serve as a potential therapy target for HCC.
Subject(s)
Biomarkers, Tumor/genetics , Carcinoma, Hepatocellular/genetics , Liver Neoplasms/genetics , RNA, Long Noncoding/genetics , Aged , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/therapy , Female , Gene Expression Regulation, Neoplastic , Gene Regulatory Networks , Humans , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Liver Neoplasms/therapy , Male , Middle Aged , Prognosis , TranscriptomeABSTRACT
Long noncoding RNA (lncRNA) differentiation antagonizing nonprotein coding RNA (DANCR) has been identified as an oncogene in several cancers. However, the biological function and role of DANCR in hepatocellular carcinoma (HCC) remain unclear. Our current study aimed to investigate the detailed mechanism of DANCR in HCC. We found that DANCR was significantly upregulated in HCC cell lines in comparison to LO2 cells. Then, we observed that knockdown of DANCR could greatly inhibit Huh7 and HepG2 cell proliferation. In addition, HCC cell apoptosis was increased by silence of DANCR and meanwhile, cell cycle progression was blocked in G1 phase. Apart from these, downregulation of DANCR repressed HCC cell migration and invasion ability obviously. As predicted by the bioinformatics analysis, microRNA-216a-5p (miR-216a-5p) could serve as a direct target of DANCR. MiR-216a-5p has been reported to be involved in many cancers. Here, the correlation between miR-216a-5p and DANCR was confirmed using dual-luciferase reporter assay and radioimmunoprecipitation assay. Subsequently, Kruppel-like factor 12 (KLF12) exerts an important role in different tumor types. KLF12 can function as a downstream target of miR-216a-5p. Finally, the in vivo experiments were used and the data proved that DANCR also strongly suppressed HCC tumor growth in vivo via targeting miR-216a-5p and KLF12. In conclusion, our study indicated that DANCR might provide a new perspective for HCC treatment.
Subject(s)
Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Kruppel-Like Transcription Factors/metabolism , Liver Neoplasms/genetics , Liver Neoplasms/pathology , MicroRNAs/metabolism , RNA, Long Noncoding/metabolism , Animals , Apoptosis/genetics , Base Sequence , Carcinogenesis/genetics , Carcinogenesis/pathology , Cell Cycle/genetics , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Down-Regulation/genetics , Gene Expression Regulation, Neoplastic , Gene Silencing , Humans , Kruppel-Like Transcription Factors/genetics , Mice, Inbred BALB C , Mice, Nude , MicroRNAs/genetics , Neoplasm Invasiveness , RNA, Long Noncoding/geneticsABSTRACT
Smart nanoparticles are increasingly important in a variety of applications such as cancer therapy. However, it is still a major challenge to develop light-responsive nanoparticles that can maximize the potency of synergistic thermo-chemotherapy under light irradiation. Here, spatially confined cyanine-anchored silica nanochannels loaded with chemotherapeutic doxorubicin (CS-DOX-NCs) for light-driven synergistic cancer therapy are introduced. CS-DOX-NCs possess a J-type aggregation conformation of cyanine dye within the nanochannels and encapsulate doxorubicin through the π-π interaction with cyanine dye. Under near-infrared light irradiation, CS-DOX-NCs produce the enhanced photothermal conversion efficiency through the maximized nonradiative transition of J-type Cypate aggregates, trigger the light-driven drug release through the destabilization of temperature-sensitive π-π interaction, and generate the effective intracellular translocation of doxorubicin from the lysosomes to cytoplasma through reactive oxygen species-mediated lysosomal disruption, thereby causing the potent in vivo hyperthermia and intracellular trafficking of drug into cytoplasma at tumors. Moreover, CS-DOX-NCs possess good resistance to photobleaching and preferable tumor accumulation, facilitating severe photoinduced cell damage, and subsequent synergy between photothermal and chemotherapeutic therapy with tumor ablation. These findings provide new insights of light-driven nanoparticles for synergistic cancer therapy.
Subject(s)
Doxorubicin/therapeutic use , Hyperthermia, Induced , Indoles/chemistry , Light , Nanoparticles/chemistry , Propionates/chemistry , Silicon Dioxide/chemistry , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Doxorubicin/pharmacology , Drug Liberation , Endocytosis/drug effects , Mice , Nanoparticles/ultrastructure , Singlet Oxygen/metabolism , Tissue Distribution/drug effects , Tumor Burden/drug effectsABSTRACT
While translational regulation of p53 by the internal ribosome entry site (IRES) at its 5'-untranslated region following DNA damage has been widely accepted, the detailed mechanism underlying the translational control of p53 by its IRES sequence is still poorly understood. In this review, we will focus on the latest progress in identifying novel regulatory proteins of the p53 IRES and in uncovering the functional connection between defective IRES-mediated p53 translation and tumorigenesis. We will also discuss how these findings may lead to a better understanding of the process of oncogenesis and open up new avenues for cancer diagnosis and therapeutics.
Subject(s)
DNA Damage , Gene Expression Regulation, Neoplastic , Internal Ribosome Entry Sites , Neoplasms/genetics , Tumor Suppressor Protein p53/genetics , 5' Untranslated Regions , Animals , Carcinogenesis/genetics , Humans , Neoplasms/diagnosis , Protein Biosynthesis , RNA, Messenger/geneticsABSTRACT
[This corrects the article DOI: 10.1186/s12935-016-0280-y.].