ABSTRACT
Emerging reports demonstrated that long non-coding RNAs (lncRNAs) play a role in the pathogenesis and metastasis of cancers. However, the biological functions and underlying mechanisms of LncRNA CEBPA-AS1 in acute myeloid leukemia (AML) remain largely elusive. The level of CEBPA-AS1 was examined in AML clinical tissues and cell lines via fluorescence in situ hybridization (FISH) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In vivo and in vitro functional tests were applied to identify the pro-oncogenic role of CEBPA-AS1 in AML development. The overexpressed CEBPA-AS1 was linked to poor survival in AML patients. Moreover, the relationships among CEBPA-AS1, Zinc Finger Protein X-Linked (ZFX), and miR-24-3p were predicted by bioinformatics and validated by RNA immunoprecipitation (RIP) and luciferase reporter assays. Our findings unveiled that transcription factor ZFX particularly interacted with the promoter of CEBPA-AS1 and activated CEBPA-AS1 transcription. Downregulation of CEBPA-AS1 inhibited the proliferation and invasion while promoted apoptosis of AML cells in in vitro, as well as in vivo, xenograft tumor growth was modified. However, overexpression of CEBPA-AS1 observed the opposite effects. Furthermore, CEBPA-AS1 acted as a competitive endogenous RNA (ceRNA) of miR-24-3p to attenuate the repressive effects of miR-24-3p on its downstream target CTBP2. Taken together, this study emphasized the pro-oncogenic role of CEBPA-AS1 in AML and illustrated its connections with the upstream transcription factor ZFX and the downstream regulative axis miR-24-3p/CTBP2, providing important insights to the cancerogenic process in AML.
Subject(s)
Leukemia, Myeloid, Acute , MicroRNAs , RNA, Long Noncoding , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , Up-Regulation/genetics , Cell Line, Tumor , In Situ Hybridization, Fluorescence , Leukemia, Myeloid, Acute/genetics , Transcription Factors/genetics , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic/genetics , Cell Movement/genetics , Alcohol Oxidoreductases/genetics , Alcohol Oxidoreductases/metabolism , Co-Repressor Proteins/genetics , Co-Repressor Proteins/metabolism , CCAAT-Enhancer-Binding Proteins/genetics , CCAAT-Enhancer-Binding Proteins/metabolismABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal types of solid tumors, associated with a high prevalence of cachexia (~80%). PDAC-derived cachexia (PDAC-CC) is a systemic disease involving the complex interplay between the tumor and multiple organs. The endocrine organ-like tumor (EOLT) hypothesis may explain the systemic crosstalk underlying the deleterious homeostatic shifts that occur in PDAC-CC. Several studies have reported a markedly heterogeneous collection of cachectic mediators, signaling mechanisms, and metabolic pathways, including exocrine pancreatic insufficiency, hormonal disturbance, pro-inflammatory cytokine storm, digestive and tumor-derived factors, and PDAC progression. The complexities of PDAC-CC necessitate a careful review of recent literature summarizing cachectic mediators, corresponding metabolic functions, and the collateral impacts on wasting organs. The EOLT hypothesis suggests that metabolites, genetic instability, and epigenetic changes (microRNAs) are involved in cachexia development. Both tumors and host tissues can secrete multiple cachectic factors (beyond only inflammatory mediators). Some regulatory molecules, metabolites, and microRNAs are tissue-specific, resulting in insufficient energy production to support tumor/cachexia development. Due to these complexities, changes in a single factor can trigger bi-directional feedback circuits that exacerbate PDAC and result in the development of irreversible cachexia. We provide an integrated review based on 267 papers and 20 clinical trials from PubMed and ClinicalTrials.gov database proposed under the EOLT hypothesis that may provide a fundamental understanding of cachexia development and response to current treatments.
ABSTRACT
Ovarian arterial haemorrhage (OAH), a rare cause of spontaneous retroperitoneal hematoma (SRH), usually occurs in women during pregnancy or in those with a history of repeated pregnancies. The clinical manifestations of OAH are non-specific; hence, proper and timely imaging examinations are extremely important. Contrast Enhanced CT scan is the first choice for clarifying the cause of haemorrhage in patients with SRH. Trans-arterial embolisation (TAE) has become the most common treatment option for OAH. Here, we report a case of SRH in the left ovarian artery region in a patient with a congenital solitary kidney. The patient was initially misdiagnosed as left kidney haemorrhage which was successfully embolised with tissue glue. There are no previous reports of OAH in patients with a congenital solitary kidney. Key Words: Ovarian artery, Spontaneous retroperitoneal hematoma, Congenital solitary kidney, Trans-arterial embolization.
Subject(s)
Embolization, Therapeutic , Solitary Kidney , Pregnancy , Humans , Female , Solitary Kidney/complications , Solitary Kidney/therapy , Postmenopause , Hemorrhage/diagnostic imaging , Hemorrhage/etiology , Hemorrhage/therapy , Hematoma/complications , Hematoma/diagnostic imaging , Embolization, Therapeutic/methods , ArteriesABSTRACT
The food packaging industry is rapidly growing as a consequence of the development of nanotechnology and changing consumers' preferences for food quality and safety. In today's globalization of markets, active packaging has achieved many advantages with the capability to absorb or release substances for prolonging the food shelf life over the traditional one. Therefore, it is critical to developing multifunctional active packaging materials from biodegradable polymers with active agents to decrease environmental challenges. This review article addresses the recent advances in nanocelluloses (NCs)- baseds nanohybrids with new function features in packaging, focusing on the various synthesis methods of NCs-based nanohybrids, and their reinforcing effects as active agents on food packaging properties. The applications of NCs-based nanohybrids as antioxidants, antimicrobial agents, and UV blocker absorbers for prolonging food shelf-life are also reviewed. Overall, these advantages make the CNs-based nanohybrids with versatile properties promising in food and packaging industries, which will impact more readership with concern for future research.
Subject(s)
Cellulose/chemistry , Food Packaging , Nanoparticles/chemistry , Static ElectricityABSTRACT
Background: Single nucleotide polymorphisms (SNPs) of small non-coding RNAs (sncRNAs) can influence sncRNA function and target gene expression to mediate the risk of certain diseases. The aim of the present study was to evaluate the prognostic relevance of sncRNA SNPs for colorectal cancer, which has not been well characterized to date. Methods: We comprehensively examined 31 common SNPs of sncRNAs, and assessed the impact of these variants on survival in a cohort of 188 patients with colorectal cancer. Results: Three SNPs were significantly associated with survival of patients with colorectal cancer after correction for multiple testing, and two of the SNPs (hsa-mir-196a-2 rs11614913 and U85 rs714775) remained significant in multivariate analyses. Additional in silico analysis provided further evidence of this association, since the expression levels of the target genes of the hsa-miR-196a (HOXA7, HOXB8, and AKT1) were significantly correlated with colorectal cancer progression. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that hsa-miR-196a is associated with well-known oncogenic pathways, including cellular protein modification process, mitotic cell cycle, adherens junction, and extracellular matrix receptor interaction pathways. Conclusion: Our results suggest that SNPs of sncRNAs could play a critical role in cancer progression, and that hsa-miR-196a might be a valuable biomarker or therapeutic target for colorectal cancer patients.
Subject(s)
Colorectal Neoplasms/genetics , Genetic Association Studies , Genetic Predisposition to Disease , RNA, Small Untranslated/genetics , Aged , Colorectal Neoplasms/pathology , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Proteins/genetics , Polymorphism, Single Nucleotide , Prognosis , Risk FactorsABSTRACT
Background: MicroRNAs (miRNAs) mediate negative regulation of target genes through base pairing, and aberrant miRNA expression has been described in cancers. We hypothesized that single nucleotide polymorphisms (SNPs) within miRNA target sites might influence clinical outcomes in patients with colorectal cancer. Methods: Sixteen common SNPs within miRNA target sites were identified, and the association between these SNPs and overall survival was assessed in colorectal cancer patients using Kaplan-Meier analysis, Cox regression model, and survival tree analysis. Results: Survival tree analysis identified a higher-order genetic interaction profile consisting of the RPS6KB1 rs1051424 and ZNF839 rs11704 that was significantly associated with overall survival. The 5-year survival rates were 74.6%, 62.7%, and 57.1% for the low-, medium-, and high-risk genetic profiles, respectively (P = 0.006). The genetic interaction profile remained significant even after adjusting for potential risk factors. Additional in silico analysis provided evidence that rs1051424 and rs11704 affect RPS6KB1 and ZNF839 expressions, which in turn is significantly correlated with prognosis in colorectal cancer. Conclusion: Our results suggest that the genetic interaction profiles among SNPs within miRNA target sites might be prognostic markers for colorectal cancer survival.
Subject(s)
Colorectal Neoplasms/genetics , Colorectal Neoplasms/mortality , MicroRNAs/metabolism , Polymorphism, Single Nucleotide , Aged , Binding Sites , Female , Genetic Predisposition to Disease , Humans , Kaplan-Meier Estimate , Male , MicroRNAs/genetics , Middle Aged , Ribosomal Protein S6 Kinases, 70-kDa/genetics , Survival AnalysisABSTRACT
Estrogen and estrogen receptor (ER)-mediated signaling pathways play important roles in the etiology and progression of human breast, endometrial, and ovarian cancers. Attenuating ER activities by natural products and their derivatives is a relatively practical strategy to control and reduce breast, endometrial, and ovarian cancer risk. Here, we found 3-butoxy-1,8,9-trihydroxy-6H-benzofuro[3,2-c]benzopyran-6-one (BTB), a new derivative of wedelolactone, could effectively inhibit the 17-estradiol (E2)-induced ER transactivation and suppress the growth of breast cancer as well as endometrial and ovarian cancer cells. Our results indicate that 2.5 µM BTB effectively suppresses ER-positive, but not ER-negative, breast, endometrial, and ovarian cancer cells. Furthermore, our data indicate that BTB can modulate ER transactivation and suppress the expression of E2-mediated ER target genes (Cyclin D1, E2F1, and TERT) in the ER-positive MCF-7, Ishikawa, and SKOV-3 cells. Importantly, this BTB mediated inhibition of ER activity is selective since BTB does not suppress the activities of other nuclear receptors, including glucocorticoid receptor and progesterone receptor, suggesting that BTB functions as a selective ER signaling inhibitor with the potential to treat breast, endometrial, and ovarian cancers.
Subject(s)
Breast Neoplasms/drug therapy , Coumarins/administration & dosage , Endometrial Neoplasms/drug therapy , Estrogen Receptor alpha/antagonists & inhibitors , Ovarian Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Proliferation/drug effects , Cyclin D1/genetics , Cyclin D1/metabolism , Endometrial Neoplasms/genetics , Endometrial Neoplasms/pathology , Estradiol/administration & dosage , Estrogen Receptor alpha/metabolism , Female , Gene Expression Regulation, Neoplastic , Humans , MCF-7 Cells , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Signal Transduction/drug effectsABSTRACT
Malignant immature ovarian teratomas (IOTs) most often occur in women of reproductive age. It is unclear, however, what roles estrogenic signaling plays in the development of IOT. In this study, we examined whether estrogen receptors (ERα and ß) promote the cellular malignancy of IOT. Estradiol (E2), PPT (propylpyrazole), and DPN (diarylpropionitrile) (ERα- and ß-specific agonists, respectively), as well as ERα- or ERß-specific short hairpin (sh)RNA were applied to PA-1 cells, a well-characterized IOT cell line. Cellular tumorigenic characteristics, for example, cell migration/invasion, expression of the cancer stem/progenitor cell marker CD133, and evidence for epithelial-mesenchymal transition (EMT) were examined. In PA-1 cells that expressed ERα and ERß, we found that ERα promoted cell migration and invasion. We also found that E2/ERα signaling altered cell behavior through non-classical transactivation function. Our data show non-genomic E2/ERα activations of focal adhesion kinase-Ras homolog gene family member A (FAK-RhoA) and ERK governed cell mobility capacity. Moreover, E2/ERα signaling induces EMT and overexpression of CD133 through upregulation micro-RNA 21 (miR21; IOT stem/progenitor promoter), and ERK phosphorylations. Furthermore, E2/ERα signaling triggers a positive feedback regulatory loop within miR21 and ERK. At last, expression levels of ERα, CD133, and EMT markers in IOT tissue samples were examined by immunohistochemistry. We found that cytosolic ERα was co-expressed with CD133 and mesenchymal cell markers but not epithelial cell markers. In conclusion, estrogenic signals exert malignant transformation capacity of cancer cells, exclusively through non-genomic regulation in female germ cell tumors.
Subject(s)
Estrogen Receptor alpha/metabolism , Estrogens/metabolism , Ovarian Neoplasms/metabolism , Teratoma/metabolism , Cell Line, Tumor , Cell Movement/drug effects , Cell Movement/physiology , Estradiol/analogs & derivatives , Estradiol/pharmacology , Estrogen Receptor alpha/genetics , Extracellular Signal-Regulated MAP Kinases/genetics , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Fulvestrant , Gene Expression Regulation, Neoplastic/physiology , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , Neoplasm Invasiveness , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Phosphorylation , Teratoma/genetics , Teratoma/pathology , Tissue Culture Techniques , Tumor Stem Cell AssayABSTRACT
Chronic inflammation is thought to be the leading cause of colorectal cancer, and interleukin-10 (IL10) has been identified as a potent immunomodulatory cytokine that regulates inflammatory responses in the gastrointestinal tract. Although several single nucleotide polymorphisms (SNPs) in IL10 have been associated with the risk of colorectal cancer, their prognostic significance has not been determined. Two hundred and eighty-two colorectal cancer patients were genotyped for two candidate cancer-associated SNPs in IL10. The associations of these SNPs with distant metastasis-free survival and overall survival were evaluated by Kaplan-Meier analysis and Cox regression model. The minor homozygote GG genotype of IL10 rs3021094 was significantly associated with a 3.30-fold higher risk of death compared with the TT+TG genotypes (P=0.011). The patients with IL10 rs3021094 GG genotype also had a poorer overall survival in Kaplan-Meier analysis (log-rank P=0.007) and in multivariate Cox regression model (P=0.044) adjusting for age, gender, carcinoembryonic antigen levels, tumor differentiation, stage, lymphovascular invasion, and perineural invasion. In conclusion, our results suggest that IL10 rs3021094 might be a valuable prognostic biomarker for colorectal cancer patients.
Subject(s)
Colorectal Neoplasms/genetics , Interleukin-10/genetics , Polymorphism, Single Nucleotide , Aged , Alleles , Biomarkers, Tumor/genetics , Carcinoembryonic Antigen/blood , Cell Differentiation , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Female , Genotype , Homozygote , Humans , Kaplan-Meier Estimate , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Staging , Regression AnalysisABSTRACT
Thrombomodulin (TM), a natural anticoagulation factor, maintains circulation homeostasis in endothelial cells. TM has additional roles in modulating inflammation, thrombosis, and carcinogenesis. However, there is little information on the role of TM in the progression and metastasis of ovarian cancer. RNA silencing and cDNA expression vectors were used to manipulate target gene expression in ovarian cancer cells. Cell growth and migration were evaluated by an MTT assay, a wound-healing migration assay, a transwell migration assay, and a biosensor system. In this study, we found that TM silencing may enhance the growth rate of cells. The migratory ability of ovarian cancer cells was enhanced dramatically after TM silencing. TM overexpression in ovarian cells suppressed the proliferation and migration capability. Furthermore, we found that skov-3 cells treated with TM shRNA expressed high levels of fibronectin and vimentin and that the expression of these markers correlated positively with their migratory ability. Our results demonstrate that TM expression may regulate cell growth and migration in ovarian cancer cells. This finding suggests that TM may be a novel prognostic and therapeutic target for ovarian cancer.
Subject(s)
Cell Movement/genetics , Cell Proliferation , RNA Interference , Thrombomodulin/genetics , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Blotting, Western , Cell Line, Tumor , Cell Survival/genetics , Female , Fibronectins/genetics , Fibronectins/metabolism , Gene Expression Regulation, Neoplastic , Humans , Neoplasms, Glandular and Epithelial/genetics , Neoplasms, Glandular and Epithelial/metabolism , Neoplasms, Glandular and Epithelial/pathology , Ovarian Neoplasms/genetics , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Reverse Transcriptase Polymerase Chain Reaction , Thrombomodulin/metabolism , Vimentin/genetics , Vimentin/metabolismABSTRACT
BACKGROUND: Colorectal cancer metastasis is a multistep process involving degradation of extracellular matrix components by proteolytic enzymes. Among them, matrix metalloproteinases (MMPs) are the principal degrading enzymes and their expressions/activities are also correlated with survival. Much research has showed the associations between genetic polymorphisms in MMPs and risk of colorectal cancer; however, their prognostic significance has not been well determined. METHODS: We selected and genotyped 4 cancer-associated single nucleotide polymorphisms (SNPs) in a cohort of 282 colorectal cancer patients. The associations of these SNPs with distant metastasis-free survival and overall survival were evaluated by Kaplan-Meier analysis, Cox regression model, and survival tree analysis. RESULTS: The relative risks of developing distant metastasis after curative surgery were higher in individuals with minor homozygote AA genotype than in those with GG/GA genotypes at MMP2 rs243866 (P = 0.012). Survival tree analysis also identified a higher-order genetic interaction profile consisting of MMP2 rs243866 and MMP2 rs2285053 that was significantly associated with distant metastasis-free survival (P trend = 0.016). After adjusting for possible confounders, the genetic interaction profile remained significant (P trend = 0.050). CONCLUSIONS: These results suggest that genetic variations in the MMP2 might be potential predictors of distant metastasis-free survival after curative surgery.
Subject(s)
Colorectal Neoplasms/enzymology , Matrix Metalloproteinases/genetics , Polymorphism, Single Nucleotide , Aged , Cohort Studies , Colorectal Neoplasms/genetics , Female , Humans , Male , Middle Aged , Treatment OutcomeABSTRACT
Compelling evidence has implicated the Wnt signaling pathway in the pathogenesis of colorectal cancer. We assessed the use of tag single nucleotide polymorphisms (tSNPs) in adenomatous polyposis coli (APC)/ß-catenin (CTNNB1) genes to predict outcomes in patients with colorectal cancer. We selected and genotyped 10 tSNP to predict common variants across entire APC and CTNNB1 genes in 282 colorectal cancer patients. The associations of these tSNPs with distant metastasis-free survival and overall survival were evaluated by Kaplan-Meier analysis, Cox regression model, and survival tree analysis. The 5-year overall survival rate was 68.3%. Survival tree analysis identified a higher-order genetic interaction profile consisting of the APC rs565453, CTNNB1 2293303, and APC rs1816769 that was significantly associated with overall survival. The 5-year survival overall rates were 89.2%, 66.1%, and 58.8% for the low-, medium-, and high-risk genetic profiles, respectively (log-rank Pâ=â0.001). After adjusting for possible confounders, including age, gender, carcinoembryonic antigen levels, tumor differentiation, stage, lymphovascular invasion, perineural invasion, and lymph node involvement, the genetic interaction profile remained significant. None of the studied SNPs were individually associated with distant metastasis-free survival and overall survival. Our results suggest that the genetic interaction profile among Wnt pathway SNPs might potentially increase the prognostic value in outcome prediction for colorectal cancer.
Subject(s)
Adenomatous Polyposis Coli Protein/genetics , Biomarkers, Tumor/genetics , Colorectal Neoplasms/genetics , Polymorphism, Single Nucleotide/genetics , beta Catenin/genetics , Aged , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , DNA, Neoplasm/genetics , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Invasiveness , Neoplasm Staging , Polymerase Chain Reaction , Survival Rate , Wnt Signaling PathwayABSTRACT
Androgen-deprivation therapy (ADT) is the most common therapy for advanced prostate cancer, but the prognosis significantly differs among individuals. In this study, we evaluated recently identified 19 prostate cancer susceptibility variants as prognostic predictors for the survival after ADT. A total of 601 prostate cancer patients treated with ADT were enrolled in this study cohort. The prognostic significance of the prostate cancer risk variants on disease progression, prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) after ADT were assessed by Kaplan-Meier analysis and Cox regression model. Two polymorphisms, rs16901979 and rs7931342, were significantly associated with PCSM (p = 0.005 for rs16901979 and p = 0.038 for rs7931342), and rs16901979 was also associated with ACM (p = 0.003) following ADT. Although the effect of rs7931342 was attenuated after controlling for other known clinical prognostic factors, rs16901979 remained a significant predictor for PCSM and ACM after ADT (p = 0.002). Moreover, the addition of the rs16901979 status in current clinical staging system further enhanced the risk prediction on PCSM and ACM particularly for the high-risk patients with distant metastasis (p < 0.017). In conclusion, this is the first study showing that prostate cancer risk variants, such as rs16901979, might improve outcome prediction following ADT, thus allowing identification of high-risk patients who might benefit from appropriate adjuvant therapy.
Subject(s)
Androgen Antagonists/therapeutic use , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Prostatic Neoplasms/genetics , Aged , Humans , Male , Middle Aged , Prognosis , Proportional Hazards Models , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/mortalityABSTRACT
UV irradiation is one of the major external insults to cells and can cause skin aging and cancer. In response to UV light-induced DNA damage, the nucleotide excision repair (NER) pathways are activated to remove DNA lesions. We report here that testicular nuclear receptor 4 (TR4), a member of the nuclear receptor family, modulates DNA repair specifically through the transcription-coupled (TC) NER pathway but not the global genomic NER pathway. The level of Cockayne syndrome B protein (CSB), a member of the TC-NER pathway, is 10-fold reduced in TR4-deficient mouse tissues, and TR4 directly regulates CSB at the transcriptional level. Moreover, restored CSB expression rescues UV hypersensitivity of TR4-deficient cells. Together, these results indicate that TR4 modulates UV sensitivity by promoting the TC-NER DNA repair pathway through transcriptional regulation of CSB. These results may lead to the development of new treatments for UV light-sensitive syndromes, skin cancer, and aging.
Subject(s)
DNA Helicases/metabolism , DNA Repair Enzymes/metabolism , Gene Expression Regulation , Nuclear Receptor Subfamily 2, Group C, Member 2/metabolism , Animals , Cell Line , DNA Damage , DNA Repair , Humans , Mice , Mice, Transgenic , Neoplasms/metabolism , Poly-ADP-Ribose Binding Proteins , Signal Transduction , Transcription, Genetic , Ultraviolet RaysABSTRACT
The estimated incidence of mitochondrial diseases in humans is approximately 1:5000 to 1:10,000, whereas the molecular mechanisms for more than 50% of human mitochondrial disease cases still remain unclear. Here we report that mice lacking testicular nuclear receptor 4 (TR4(-/-)) suffered mitochondrial myopathy, and histological examination of TR4(-/-) soleus muscle revealed abnormal mitochondrial accumulation. In addition, increased serum lactate levels, decreased mitochondrial ATP production, and decreased electron transport chain complex I activity were found in TR4(-/-) mice. Restoration of TR4 into TR4(-/-) myoblasts rescued mitochondrial ATP generation capacity and complex I activity. Further real-time PCR quantification and promoter studies found TR4 could modulate complex I activity via transcriptionally regulating the complex I assembly factor NDUFAF1, and restoration of NDUFAF1 level in TR4(-/-) myoblasts increased mitochondrial ATP generation capacity and complex I activity. Together, these results suggest that TR4 plays vital roles in mitochondrial function, which may help us to better understand the pathogenesis of mitochondrial myopathy, and targeting TR4 via its ligands/activators may allow us to develop better therapeutic approaches.
Subject(s)
Electron Transport Complex I/deficiency , Mitochondrial Myopathies/metabolism , Receptors, Steroid/deficiency , Receptors, Thyroid Hormone/deficiency , Adenosine Triphosphate/biosynthesis , Aminoimidazole Carboxamide/analogs & derivatives , Aminoimidazole Carboxamide/pharmacology , Animals , Cells, Cultured , Electron Transport Complex I/genetics , Electron Transport Complex I/metabolism , Gene Expression Regulation/drug effects , Humans , Lactic Acid/blood , Metformin/pharmacology , Mice , Mitochondria/drug effects , Mitochondria/metabolism , Mitochondria/pathology , Mitochondria/ultrastructure , Mitochondrial Myopathies/blood , Mitochondrial Myopathies/complications , Mitochondrial Myopathies/pathology , Muscle Weakness/blood , Muscle Weakness/complications , Muscle Weakness/metabolism , Muscle Weakness/pathology , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Muscle, Skeletal/ultrastructure , Myoblasts/drug effects , Myoblasts/metabolism , Myoblasts/pathology , NADH Dehydrogenase/genetics , NADH Dehydrogenase/metabolism , Physical Conditioning, Animal , Receptors, Steroid/metabolism , Receptors, Thyroid Hormone/metabolism , Ribonucleotides/pharmacologyABSTRACT
OBJECTIVE: TR4 is a nuclear receptor without clear pathophysiological roles. We investigated the roles of hepatic TR4 in the regulation of lipogenesis and insulin sensitivity in vivo and in vitro. RESEARCH DESIGN AND METHODS: TR4 activity and phosphorylation assays were carried out using hepatocytes and various TR4 wild-type and mutant constructs. Liver tissues from TR4 knockout, C57BL/6, and db/db mice were examined to investigate TR4 target gene stearoyl-CoA desaturase (SCD) 1 regulation. RESULTS: TR4 transactivation is inhibited via phosphorylation by metformin-induced AMP-activated protein kinase (AMPK) at the amino acid serine 351, which results in the suppression of SCD1 gene expression. Additional mechanistic dissection finds TR4-transactivated SCD1 promoter activity via direct binding to the TR4-responsive element located at -243 to -255 on the promoter region. The pathophysiological consequences of the metforminâAMPKâTR4âSCD1 pathway are examined via TR4 knockout mice and primary hepatocytes with either knockdown or overexpression of TR4. The results show that the suppression of SCD1 via loss of TR4 resulted in reduced fat mass and increased insulin sensitivity with increased ß-oxidation and decreased lipogenic gene expression. CONCLUSIONS: The pathway from metforminâAMPKâTR4âSCD1âinsulin sensitivity suggests that TR4 may function as an important modulator to control lipid metabolism, which sheds light on the use of small molecules to modulate TR4 activity as a new alternative approach to battle the metabolic syndrome.
Subject(s)
Liver/metabolism , Metformin/pharmacology , Receptors, Steroid/metabolism , Receptors, Thyroid Hormone/metabolism , Stearoyl-CoA Desaturase/metabolism , AMP-Activated Protein Kinases/metabolism , Animals , Blotting, Western , Electrophoresis, Polyacrylamide Gel , Glucose Tolerance Test , Immunoprecipitation , Insulin/pharmacology , Liver/drug effects , Liver/enzymology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Phosphorylation/drug effects , Receptors, Steroid/genetics , Receptors, Thyroid Hormone/genetics , Stearoyl-CoA Desaturase/genetics , Sterol Regulatory Element Binding Protein 1/genetics , Sterol Regulatory Element Binding Protein 1/metabolismABSTRACT
Early studies suggest that TR4 nuclear receptor is a key transcriptional factor regulating various biological activities, including reproduction, cerebella development, and metabolism. Here we report that mice lacking TR4 (TR4(-/-)) exhibited increasing genome instability and defective oxidative stress defense, which are associated with premature aging phenotypes. At the cellular level, we observed rapid cellular growth arrest and less resistance to oxidative stress and DNA damage in TR4(-/-) mouse embryonic fibroblasts (MEFs) in vitro. Restoring TR4 or supplying the antioxidant N-acetyl-l-cysteine (NAC) to TR4(-/-) MEFs reduced the DNA damage and slowed down cellular growth arrest. Focused qPCR array revealed alteration of gene profiles in the DNA damage response (DDR) and anti-reactive oxygen species (ROS) pathways in TR4(-/-) MEFs, which further supports the hypothesis that the premature aging in TR4(-/-) mice might stem from oxidative DNA damage caused by increased oxidative stress or compromised genome integrity. Together, our finding identifies a novel role of TR4 in mediating the interplay between oxidative stress defense and aging.
Subject(s)
Aging, Premature/genetics , Antioxidants/metabolism , Immune System/metabolism , Oxidative Stress/genetics , Receptors, Steroid/genetics , Receptors, Thyroid Hormone/genetics , Aging, Premature/metabolism , Animals , Antioxidants/physiology , Cells, Cultured , Cellular Senescence/genetics , Cellular Senescence/physiology , DNA Damage/genetics , DNA Damage/physiology , Female , Genomic Instability/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Oxidative Stress/physiology , Phenotype , Reactive Oxygen Species/metabolismABSTRACT
PURPOSE: Recent evidence indicates that small noncoding RNA molecules, known as microRNAs (miRNAs), are involved in cancer initiation and progression. We hypothesized that genetic variations in miRNAs and miRNA target sites could be associated with the efficacy of androgen-deprivation therapy (ADT) in men with prostate cancer. EXPERIMENTAL DESIGN: We systematically evaluated 61 common single nucleotide polymorphisms (SNPs) inside miRNAs and miRNA target sites in a cohort of 601 men with advanced prostate cancer treated with ADT. The prognostic significance of these SNPs on disease progression, prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) after ADT were assessed by Kaplan-Meier analysis and Cox regression model. RESULTS: Four, seven, and four SNPs were significantly associated with disease progression, PCSM, and ACM, respectively, after ADT in univariate analysis. KIF3C rs6728684, CDON rs3737336, and IFI30 rs1045747 genotypes remained as significant predictors for disease progression; KIF3C rs6728684, PALLD rs1071738, GABRA1 rs998754, and SYT9 rs4351800 remained as significant predictors for PCSM; and SYT9 rs4351800 remained as a significant predictor for ACM in multivariate models that included clinicopathologic predictors. Moreover, strong combined genotype effects on disease progression and PCSM were also observed. Patients with a greater number of unfavorable genotypes had a shorter time to progression and worse prostate cancer-specific survival during ADT (P for trend < 0.001). CONCLUSION: SNPs inside miRNAs and miRNA target sites have a potential value to improve outcome prediction in prostate cancer patients receiving ADT.
Subject(s)
Androgen Antagonists/therapeutic use , Gonadotropin-Releasing Hormone/agonists , MicroRNAs/genetics , Polymorphism, Single Nucleotide , Prostatic Neoplasms/diagnosis , Aged , Genetic Association Studies , Genotype , Humans , Kaplan-Meier Estimate , Male , MicroRNAs/metabolism , Orchiectomy , Prostatic Neoplasms/genetics , Prostatic Neoplasms/mortality , Prostatic Neoplasms/therapy , RNA Interference , Treatment OutcomeABSTRACT
OBJECTIVE: To investigate the association of RUNX1 rs2253319 with clinicopathological characteristics of prostate cancer (PCa) and disease recurrence after radical prostatectomy (RP). PATIENTS AND METHODS: Taking advantage of the systematic stage and grade for each tumor in a cohort of 314 patients with localized PCa receiving RP, we evaluated the associations of RUNX1 rs2253319 with age at diagnosis, preoperative prostate-specific antigen (PSA) level, Gleason score, surgical margin, pathologic stage, status of lymph node metastasis, and PSA recurrence after RP. RESULTS: The minor allele, T, and the minor homozygote TT genotype of RUNX1 rs2253319 were significantly associated with a 1.49- to 2.76-fold higher risk for advanced pathologic stage and a 3.35- to 9.52-fold higher risk for lymph node metastasis. RUNX1 rs2253319 TT genotype was also associated with poorer PSA-free survival compared with the major homozygote CC genotype in Kaplan-Meier analysis (log-rank test, P= 0.038) and multivariate Cox proportional hazards model adjusting for age and PSA concentration (P= 0.045). CONCLUSION: RUNX1 rs2253319 is associated with adverse clinicopathological features and might be a prognostic factor for the recurrence of PSA in patients with PCa receiving RP.
Subject(s)
Core Binding Factor Alpha 2 Subunit/genetics , Neoplasm Recurrence, Local/genetics , Polymorphism, Single Nucleotide/genetics , Prostatic Neoplasms/genetics , Aged , Alleles , Epidemiologic Methods , Humans , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Prostatectomy , Prostatic Neoplasms/pathology , Prostatic Neoplasms/surgeryABSTRACT
BACKGROUND: Recent genome-wide association studies have identified several independent single nucleotide polymorphisms (SNPs) strongly associated with prostate cancer (PCa) risk. However, their individual and cumulative associations with clinicopathologic characteristics of the disease remain inconclusive. METHODS: We systematically evaluated 20 PCa risk SNPs in a cohort of 320 localized PCa patients receiving radical prostatectomy, and the associations of these variants with age at diagnosis, preoperative prostate-specific antigen concentration, Gleason score, pathologic stage, surgical margin, and lymph node metastasis were evaluated. RESULTS: Eight SNPs, rs10486567 at 7p15, rs6465657 at 7q21, rs6983267, rs1447295, and rs4242382 at 8q24, 10993994 at 10q11, rs4430796 at 17q12, and rs266849 at 19q13, were significantly (P< or =0.048) associated with some specific clinicopathologic features. In combination of these 8 SNPs, men who carried 4 or 5, or more than 5 unfavorable alleles had an increasing likelihood of adverse clinicopathologic features, as compared with men who carried fewer than 4 unfavorable alleles (P for trend, 0.031, <0.001, 0.006, and 0.003, for Gleason scores 8-10, advanced pathologic stage, positive surgical margin, and lymph node metastasis, respectively). CONCLUSIONS: Our results suggested that loci associated with PCa risk might also have a cumulative and significant association with disease aggressiveness.