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BACKGROUND@#Findings on the association of genetic factors and colorectal cancer (CRC) survival are limited and inconsistent, and revealing the mechanism underlying their prognostic roles is of great importance. This study aimed to explore the relationship between functional genetic variations and the prognosis of CRC and further reveal the possible mechanism.@*METHODS@#We first systematically performed expression quantitative trait locus (eQTL) analysis using The Cancer Genome Atlas (TCGA) dataset. Then, the Kaplan-Meier analysis was used to filter out the survival-related eQTL target genes of CRC patients in two public datasets (TCGA and GSE39582 dataset from the Gene Expression Omnibus database). The seven most potentially functional eQTL single nucleotide polymorphisms (SNPs) associated with six survival-related eQTL target genes were genotyped in 907 Chinese CRC patients with clinical prognosis data. The regulatory mechanism of the survival-related SNP was further confirmed by functional experiments.@*RESULTS@#The rs71630754 regulating the expression of endoplasmic reticulum aminopeptidase 1 ( ERAP1 ) was significantly associated with the prognosis of CRC (additive model, hazard ratio [HR]: 1.43, 95% confidence interval [CI]: 1.08-1.88, P = 0.012). The results of dual-luciferase reporter assay and electrophoretic mobility shift assay showed that the A allele of the rs71630754 could increase the binding of transcription factor 3 (TCF3) and subsequently reduce the expression of ERAP1 . The results of bioinformatic analysis showed that lower expression of ERAP1 could affect the tumor immune microenvironment and was significantly associated with severe survival outcomes.@*CONCLUSION@#The rs71630754 could influence the prognosis of CRC patients by regulating the expression of the immune-related gene ERAP1 .@*TRIAL REGISTRATION@#No. NCT00454519 ( https://clinicaltrials.gov/ ).
Subject(s)
Humans , Prognosis , Genotype , Polymorphism, Single Nucleotide/genetics , Quantitative Trait Loci , Colorectal Neoplasms , Tumor Microenvironment , Aminopeptidases/metabolism , Minor Histocompatibility Antigens/geneticsABSTRACT
Drastic surges in intracellular reactive oxygen species (ROS) induce cell apoptosis, while most chemotherapy drugs lead to the accumulation of ROS. Here, we constructed an organic compound, arsenical N-(4-(1,3,2-dithiarsinan-2-yl)phenyl)acrylamide (AAZ2), which could prompt the ROS to trigger mitochondrial-dependent apoptosis in gastric cancer (GC). Mechanistically, by targeting pyruvate dehydrogenase kinase 1 (PDK1), AAZ2 caused metabolism alteration and the imbalance of redox homeostasis, followed by the inhibition of phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and leading to the activation of B-cell lymphoma 2 (Bcl2)/Bcl2-associated X (Bax)/caspase-9 (Cas9)/Cas3 cascades. Importantly, our in vivo data demonstrated that AAZ2 could inhibit the growth of GC xenograft. Overall, our data suggested that AAZ2 could contribute to metabolic abnormalities, leading to mitochondrial-dependent apoptosis by targeting PDK1 in GC.
Subject(s)
Humans , Signal Transduction , Stomach Neoplasms/drug therapy , Reactive Oxygen Species/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Apoptosis , Proto-Oncogene Proteins c-bcl-2 , Cell Line, TumorABSTRACT
Objective To investigate the effect of Sema6D knockdown on the proliferation, migration, invasion and angiogenesis-promoting ability of human osteosarcoma cell lines. Methods The expression of Sema6D in clinical tissues and cell lines of human osteosarcoma was detected. After the targeted siRNA transfection, the changes of proliferation, migration and invasion were measured by CCK-8, wound healing and Transwell experiments. HUVECs were co-cultured with tumor conditioned medium to detect their tube formation ability. And the expression of signal pathway proteins was detected by Western blot. Results Sema6D was highly expressed in human osteosarcoma tissues and cell lines(P < 0.05). After silencing Sema6D, the proliferation, migration and invasion of 143B and MG63 cells decreased significantly(P < 0.05), the angiogenesis ability of HUVECs decreased in vitro(P < 0.01), and the expression of PI3K/AKT/mTOR and ERK-related signal pathway proteins decreased(P < 0.05). Conclusion Sema6D is overexpressed in human osteosarcoma tissues and cell lines. Knockdown of Sema6D expression level could inhibit the proliferation, migration, invasion and angiogenesis-promoting ability of human osteosarcoma cells via reducing PI3K/AKT/mTOR and ERK signal pathway.
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Small cell lung cancer (SCLC) is typified by early recurrence and metastasis associated with many genetic changes.The drug ROVA-T composed of the DLL3 antibody Rovalpituzumab and the cytotoxic drug Tesirine achieves the tumor-killing effect by releasing the Tesirine when bound to DLL3.Nfib promotes the SCLC metastasis by altering the structure of the chromosome.The PRAP,EZH2 and Weel inhibitors inhibit the DNA damage repair to improve the antitumor activity of chemotherapeutic drugs.Combination of Ipilimumab and Nivolumab can activate the human immune system to exert antitumor effect.
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<p><b>OBJECTIVE</b>To investigate the expressions of miR-101, protein kinase C-α (PKC-α), and cyclooxygenase-2 (COX-2) in gastric cancer (GC) tissue and their correlations.</p><p><b>METHODS</b>RT-qPCR was used to examine miR-101 expression and Western blotting employed to detect PKC-α and COX-2 expressions in 57 cases of gastric cancer tissues and paired normal gastric mucosal tissues.</p><p><b>RESULTS</b>The gastric cancer tissues showed a significantly lower miR-101 expression (Z=6.102, P<0.05) but significantly higher expressions of COX-2 (Z=14.436, P<0.05) and PKC-α (Z=6.955, P<0.05) than the normal gastric tissues. The expression of COX-2 protein was significantly correlated with the degree of differentiation, invasion depth, lymph node metastasis and TNM stage (P<0.05); PKC-α protein expression was associated with lymph node metastasis and TNM stage (P<0.05). PKC-α expression was positively correlated (r=0.531, P<0.05) and miR-101 expression negatively correlated (r=-0.627, P<0.05) with COX-2 expression in gastric cancer tissues.</p><p><b>CONCLUSIONS</b>miR-101, PKC-α and COX-2 all play a role in the tumorigenesis and progression of gastric cancer. miR-101 and PKC-α might be new potential therapeutic targets for inhibiting COX-2 in gastric cancer.</p>
Subject(s)
Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Cyclooxygenase 2 , Metabolism , Gastric Mucosa , Metabolism , MicroRNAs , Metabolism , Neoplasm Staging , Protein Kinase C-alpha , Metabolism , Stomach Neoplasms , Metabolism , PathologyABSTRACT
Objective: To investigate the association between psychological stress and oxidative damage in TNM stage III patients with poorly differentiated gastric adenocarcinoma (GA). Methods: One hundred and six patients with newly diagnosed poorly differentiated GA were assessed using the Hamilton Depression Rating Scale (HAMD), Zung Self-rating Depression Scale (SDS), Zung Self-rating Anxiety Scale (SAS), Symptom Checklist 90 (SCL-90), activities of daily living (ADL) and other multiple-item questionnaires. Oxidative-stress-related parameters in serum and the expression of DNA repair genes were monitored during a pretreatment period. Results: The patients were divided into depression and nondepression groups (Groups A and B, respectively) based on a HAMD score cutoff of 20. The mean SDS, SAS, SCL-90, ADL and passive coping scores were higher in Group A, whereas social support and quality of life were lower. Serum total antioxidant capacity, catalase, superoxide dismutase concentrations and anti-superoxide anion capacity (A-ASC) were significantly decreased in Group A, whereas serum malondialdehyde (MDA) and 8-hydroxy-deoxyguanosine (8-OHdG) levels were significantly increased. Pearson correlation analysis revealed that depression was positively correlated with MDA, SAS, SCL-90 and ADL, but negatively correlated with A-ASC. Furthermore, real-time PCR revealed that the expression levels of hOGG1 and APEX1 were increased in Group A. Conclusion: Psychological stress might be related to impaired antioxidant system in patients with GA, and it presents the first evidence of the involvement of oxidative DNA damage in the pathogenesis of depression.
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Objective To investigate the association between psychological stress and oxidative damage in TNM stage Ⅲ patients with poorly differentiated gastric adenecarcinoma (GA). Methods One hundred and six patients with newly diagnosed poorly differentiated GA were assessed using the Hamilton Depression Rating Scale (HAMD), Zung Self-rating Depression Scale (SDS), Zung Self-rating Anxiety Scale (SAS), Symptom Checklist 90 (SCL-90), activities of daily living (ADL) and other multiple-item qnestionnaires. Oxidative-stress-related parameters in serum and the expression of DNA repair genes were monitored during a pretreatment period. Results The patients were divided into depression and nondepression groups (Groups A and B, respectively) based on a HAMD score cutoff of 20. The mean SDS, SAS, SCL-90, ADL and passive coping scores were higher in Group A, whereas social support and quality of life were lower. Serum total antioxidant capacity, eatalase, superoxide dismutuse concentrations and anti-superoxide anion capacity (A-ASC) were significantly decreased in Group A, whereas serum malondialdehyde (MDA) and 8-hydroxy-deoxyguanosine (8-OHdG) levels were significantly increased. Pearson correlation analysis revealed that depression was pesitively correlated with MDA, SAS, SCL-90 and ADL, but negatively correlated with A-ASC. Furthermore, real-time PCR revealed that the expression levels of hOGG1 and APEX1 were increased in Group A. Conclusion Psychological stress might be related to impaired antioxidant system in patients with GA, and it presents the first evidence of the involvement of oxidative DNA damage in the pathogenesis of depression.
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Objective To explore the effects of psychosocial f actors including life events and coping style on the onset of upper digestive tr act cancer. Methods A total of 98 patients with upper diges tive tract cancer were chosen as experiment group, while 98 healthy persons were chosen as control group, who matched with experiment group in habits, age, sex and education background. Both the two groups were studied by Life Event Scale a nd Simplified Coping Style Questionnaire. The difference between the contributio n of psychosocial factors in the two groups was analyzed. Results The stimulating amount and frequency of negative life events in experimen t group were much higher than those in control group, while those of its positiv e life events were much lower. The total score of passive coping style in experi ment group was higher than that in control group, while the total score of posit ive coping style was lower. Conclusion Stress may be one of the etiological factors in causing upper digestive tract cancer, and passive co ping style may also be a risk factor for the etiology of upper digestive tract c ancer.
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Objective To explore the contribution of psychoso cial factors including personality and social support to the onset of upper dige stive tract cancer. Methods Ninety-eight patients with up per digestive tract cancer were chosen as disease group, with 98 healthy persons as control group, who matched with disease group in habitation, age, sex and ed ucation level. Both the two groups were studied by Eysenck Personality Questionn aire (EPQ) and social support scale. The differences between the two groups were analyzed. Results The E score of EPQ in disease group was lower than that in control group, but its P and L scores were higher, and the su pport utilization degree in disease group was much lower than that in control gr oup. Positive correlation was found between the E score of EPQ and social suppor t utilization degree in disease group. Conclusion The onset of upper digestive tract cancer is correlated with personality and social suppo rt.
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Objective To examine DNMT1,?-catenin and P-GSK-3? expressions in tissues of colon carcinoma compared with tumor clinicopathological parameters including differentiation and metastasis.Methods SYBR Green real-time PCR and immunoblotting method were used to detect these gene expressions in 62 tissues of colon carcinoma and 21 tissues of normal colon.Results Overexpressions of DNMT1,?-catenin,and P-GSK-3? were found in colon carcinoma tissues.The expression of DNMT1 was found to be higher in poorly differentiated tissues.The results also demonstrated statistical significance in the expression of ?-catenin involving differentiation and metastasis,but no statistical significance in the expression of P-GSK-3?.Conclusion These results show that DNMT1,?-catenin and P-GSK-3? expressions are regulated throughout colon cancer progression.