NAT10 Promotes Cervical Cancer Cell Malignant Behavior via N4-acetylcytidine Modification of DDR1 mRNA / 中国生物化学与分子生物学报

N-acetyltransferase 10 (NAT10) is a key enzyme involved in the acetylation of mRNA, which regulates the expression of target genes and biological functions of various cancers via ac4C (N4-acetylcytidine) acetylation. However, whether NAT10 is involved in regulating the malignant behavior of cervical cancer is rarely reported. This study investigated the effects and specific mechanism of NAT10 on the growth activity, proliferation capacity, migration and invasion capacity of cervical cancer cells. First, we found a highly expression of NAT10 in cervical cancer and was associated with poor patient prognosis by TCGA database analysis. MTT assays and colony formation assays showed that overexpression of NAT10 promoted the growth activity (P<0. 05) and proliferation ability (P<0. 001) of cervical cancer cells; Transwell migration and invasion assays showed that overexpression of NAT10 promoted the migration (P<0. 01) and invasion (P<0. 05) ability of cervical cancer cells; Western blotting showed that overexpression of NAT10 increased the mesothelial cell marker vimentin and resulted in a decrease in the epithelial cell marker E-cadherin. Bioinformatics analysis exhibited that discoidin domain receptor 1 (DDR1) might be a downstream target gene of NAT10. RNA binding protein immunoprecipitation (RIP) assays showed that NAT10 could directly bind to DDR1 mRNA (P<0. 05), Western blotting and RT-qPCR experiments showed that overexpression of NAT10 significantly increased the expression and mRNA levels of DDR1 (P<0. 05). Furthermore, RNA acetylation co-immunoprecipitation experiments showed that overexpression of NAT10 promoted the acetylation level of DDR1 mRNA (P<0. 001), and EGFP reporter assays confirmed that NAT10 recognized the acetylation site of DDR1 mRNA. The results of mRNA half-life experiments showed that NAT10 increased the stability of DDR1 mRNA (P<0. 05). In conclusion, our research confirms that NAT10 promotes the growth activity, and migration and invasion ability of cervical cancer cells and its specific mechanism is to extend the stability of DDR1 by acetylation modification, thereby increasing its expression levels, which might provide new insights into the molecular mechanism of acetylation modification of mRNA on the pathogenesis of cervical cancers.

DNA-PK inhibition by M3814 enhances chemosensitivity in non-small cell lung cancer

A significant proportion of non-small cell lung cancer (NSCLC) patients experience accumulating chemotherapy-related adverse events, motivating the design of chemosensitizating strategies. The main cytotoxic damage induced by chemotherapeutic agents is DNA double-strand breaks (DSB). It is thus conceivable that DNA-dependent protein kinase (DNA-PK) inhibitors which attenuate DNA repair would enhance the anti-tumor effect of chemotherapy. The present study aims to systematically evaluate the efficacy and safety of a novel DNA-PK inhibitor M3814 in synergy with chemotherapies on NSCLC. We identified increased expression of DNA-PK in human NSCLC tissues which was associated with poor prognosis. M3814 potentiated the anti-tumor effect of paclitaxel and etoposide in A549, H460 and H1703 NSCLC cell lines. In the four combinations based on two NSCLC xenograft models and two chemotherapy, we also observed tumor regression at tolerated doses

DDR1-Akt signaling pathway in myocardial fibrosis of rats with hypertension / 西安交通大学学报(医学版)

Objective: To explore the role of collagen I-discoidin domain receptor 1 (DDR1)-protein kinase B (Akt) signaling pathway in the proliferation of myocardial fibroblasts (MFBs) of hypertensive rats. Methods:A hypertensive rat model via abdominal aorta constriction (AAC) was used in this study. We compared body weight, tail artery systolic blood pressure (SBP) and left ventricular mass index (LVMI) among blank, sham, AAC and spontaneously hypertensive rat (SHR) groups. Expression and phosphorylation levels of DDR1 and Akt were detected using immunoprecipitation in combination with Western blot. We analyzed the correlation between DDR1 phosphorylation level and SBP (or LVMI). Cell proliferation, expression and phosphorylation levels of DDR1 and Akt in primary MFBs of SHR rats were detected using BrdU labeling assay and Western blot, respectively. Results: There was no significant difference in body weight among the four groups (P>0.05). In AAC and SHR groups, SBP, LVMI and phosphorylation levels of DDR1 and Akt were significantly increased. Both SBP and LVMI were positively correlated with phosphorylation level of DDR1. In vitro, collagen I accelerated cell proliferation and promoted DDR1 and Akt phosphorylation in MFBs. Conclusion: This research suggests that an activated collagen -DDR1-Akt pathway exists during the myocardial fibrosis process of rats with hypertension. DDR1 inhibitors may have the potential to relieve myocardial fibrosis.

Progress in genetics of NPHP related signaling pathway / 国际儿科学杂志

Nephronophthisis(NPHP),an autosomal recessive cystic kidney disease,is the most frequent genetic cause for end stage renal failure in the first thirty years of life.NPHP can be caused by Mutations in 22 genes(NPHP1-20,NPHPL1,NPHPL2),with abnormal structure or function of primary cilia,involved in Hh,Wnt,Hippo,DDR signaling pathways.Elucidating the pathogenic genes and possible pathogenesis would make a difference in prevention,diagnosis,treatment,prognosis,and genetic counseling of NPHP.This article reviews the pathogenic genetics and related signaling pathways.

Repair effects of close-to-bone needing combined with electroacupuncture on extracellular matrix of cartilage in rabbits with knee osteoarthritis / 中国针灸

<p><b>OBJECTIVE</b>To observe the effects of close-to-bone needing combined with electroacupuncture (EA) on cartilage collagen type Ⅱ/discoidin domain receptor/matrix metalloproteinase 13 (collagen type Ⅱ/DDR2/MMP 13) signaling pathway in rabbits with knee osteoarthritis (KOA), and to explore the possible action mechanism of this method on repair of extracellular matrix of knee cartilage.</p><p><b>METHODS</b>Forty New Zealand white rabbits were randomly assigned into a normal group (10 rabbits) and a model establishing group (30 rabbits). The Hulth-Telhag technique was applied to establish the model of KOA, and X-ray was used for outcome assessment. The rabbits with successful modeling were randomly assigned into a model group, a close-to-bone needing group, a regular acupuncture group, 10 rabbits in each one. The rabbits in the close-to-bone needing group were treated with close-to-bone needing and EA; the rabbits in the regular acupuncture group were treated with regular acupuncture and EA. "Neixiyan" (EX-LE 4), "Dubi" (ST 35), "Yinlingquan" (SP 9), "Zusanli" (ST 36) and "Liangqiu" (ST 34) were selected in the two groups. The intervention was given for 20 min, once a day; the intervention of 5 days made 1 session, 2 days as the interval and totally 4 sessions were given. Rabbits in normal and model group were immobilized without any treatment. After the treatment, western blotting method was applied to evaluate the expression of DDR2 and collagen type Ⅱ; the activity of collagen type Ⅱ, DDR2 and MMP 13 was assessed by immunohistochemistry method; the mRNA expression of DDR2 and MMP 13 was determined by reverse transcription-polymerase chain reaction (RT-PCR).</p><p><b>RESULTS</b>Compared with the normal group, the activity expression of collagen type Ⅱ were significantly reduced in the other groups (all<0.01),while the activity and mRNA expression of DDR2 and MMP 13 were notably increased (all<0.01). Compared with the model group, the activity expression of collagen type Ⅱ in the close-to-bone needing group and regular acupuncture group were increased (all<0.01), while the activity and mRNA expression of DDR2 and MMP 13 were reduced (all<0.01). Compared with the regular acupuncture group, the activity and mRNA expression of MMP 13 and DDR2 in the close-to-bone needing group were reduced (all<0.01), while the activity expression of collagen type Ⅱ were increased (<0.01).</p><p><b>CONCLUSIONS</b>The close-to-bone needing combined with EA and regular EA could both promote the repair of knee cartilage, where closing-to-bone needing combined with EA shows a superior efficacy. The mechanism may be associated with the blocking effect of collagen type Ⅱ/DDR2/MMP13 signaling pathway and the inhibiting effect of degradation in extracellular matrix of cartilage.</p>

Las representaciones sociales del enemigo: la organización de un campo en tensión / Social representations of the enemy: an organization of a field in tension

El presente artículo es resultado de uno de los componentes de la investigación "Representaciones sociales del enemigo, construidas a través de la memoria social entre sujetos desmovilizados de grupos de Autodefensas Unidas de Colombia (AUC)". Este componente se centró en el estudio de la organización de las representaciones sociales del enemigo, construidas entre los participantes; asimismo, se realizó una lectura psicosociológica de los contenidos que conforman el campo, articulando la teoría de las Representaciones Sociales con aportes de otras alternativas teóricas. La interpretación se orientó a partir de los resultados del análisis de clases latentes. Se utilizó como técnica de generación de datos la asociación libre de palabras. La mayor parte de los contenidos se organizan en torno a tres clases, en las que sobresale una inclinación aversiva contra el que se coloque en la posición de enemigo, destacándose los efectos que tiene haber participado en el conflicto armado. Estas imágenes del enemigo se relacionan con emociones y actitudes como las de eliminarlo, temerle u odiarlo. Una de las clases, la de menos incidencia, ofrece la consideración de prácticas conciliatorias.

The present article is the result of one of the components of the research project "Social representations of the enemy in the social memory among the demobilized individuals of the groups of the United Self-Defense Forces of Colombia (AUC)". This component is the study of the organization of the social representations of the enemy, constructed by the participants of the conflict. It is based on the psycho-sociological theories related to the field, the Theory of Social Representations, as well as other theories. The interpretation was based on the results of the latent class analysis. Free associations of words were used as a data generation technique. The contents are organized mostly around three groups. Attitude to the enemy distinctly is formed around the aversive feelings under the influence of the armed conflict. Enemy image is related to emotions and attitudes such as elimination, fear or hatred. Only one group, the one of less impact, suggests consideration of reconciliation.

Activation of DDR2 Involved in Atherosclerosis by Oxidative Stress

BACKGROUND: Reactive Oxygen species have been known to be a key factor to promote atherosclerosis. DDR2(Discoidin Domain Receptor 2) is a cell surface receptor tyrosine kinase which is activated by fiber collagen. Recently, DDR2 was suggested to be involved in activation of smooth muscle cell in blood vessel of atherosclerosis. METHODS: The effect of antioxidant, N-acetyl cysteine and H2O2(Hydrogen peroxide) in the activation of DDR2 by collagen was studied using HEK293 cells expressing DDR2. The direct activation of DDR2 tyrosine kinase domain by tyrosine phosphorylation upon the treatment of H2O2 was analysed after the kinase domain was expressed in sf9 cells. RESULTS: H2O2 enhanced DDR2 auto-phosphorylation and its cellular signaling to induce MMP-1 expression. However N-acetyl cysteine suppressed the DDR2 activation. The reactive oxygen induced tyrosine phosphorylation in DDR2 tyrosine kinase domain to activate its tyrosine kinase activity. CONCLUSIONS: DDR2 activity can be up-regulated by oxidative stress and this provides a mechanism that DDR2 plays a critical role when reactive oxygen species promote atherosclerosis. Therefore inhibition of the activated DDR2 could be a new therapeutic strategy for atherosclerosis.

Expression of DDR1 in esophageal squamous cell carcinoma tissue / 重庆医科大学学报

Objective:To study the expression of discoidin domain receptor1(DDR1) protein in esophageal squamous cell carcinoma(ESCC) tissues. Methods:The expression of DDR1 protein was detected by Western blotting in 40 cases of ESCC tissues,para-cancer tissues,and matched esophageal normal tissues,and their relation to clinical pathologic characteristics of esophageal cancer was analyzed. Results:The expressionof DDR1 in ESCC(1.201?0.348)were significantly higher than those in para-cancer tissues(0.640?0.323)and normal esophageal tissues(0.551?0.413). The positive expression rate and relative content of DDR1 in ESCC were correlated with degrees of differentiation、lymphnode metastasis and invasion depth of carcinoma (P

Senescence or Tumor:The Dual Role of Activated-oncogene Induction / 生物化学与生物物理进展

The activation of oncogenes occured in most tumors,and is believed to play an important role in tumorigenesis. However,the activation of oncogenes could induce cellular senescence in wild type cells,known as oncogene-induced senescence (OIS). Thus,the activation of oncogenes has the dual role in inducing cellular senescence or tumorigenesis. DNA damage checkpoint response (DDR) is the molecular signal transduction pathway that delay or arrest cell cycle progression in response to DNA damage and is an important molecular mechanism that induce cellular senescence. Activation of oncogenes could produce DNA damage signals and initiate DDR,which subsequently induce cellular senescence. However,when DDR pathway is deficient,activation of oncogenes could induce unlimited DNA hyper-replication and cellular hyper-proliferation,which results in accumulation of genome instability,and tumorigenesis ultimately. Therefore,the dual role of activated oncogenes is regulated by the integrity of DDR pathway. The key role of DDR in regulating activated oncogenes indicates that maintain or restore the integrity of DDR pathway might provide a new strategy in cancer prevention and therapy.

Diagnostic Value of DDR in Synovial Sarcoma (Analysis of 19 Cases) / 医疗卫生装备

Objective To explore the diagnostic value of DDR in synovial sarcoma and compare with the traditional X-ray photography. Methods The DDR manifestation of synovial sarcoma patients which confirmed by operation in our hospital was contrasted with the traditional X-ray photography. Results The DDR performance of synovial sarcoma in soft tissue tumors,small bone destruction around the joints and soft tissue swelling,calcification of tumors are superior to traditional X-ray photography. Conclusion The DDR has better X-ray image quality than traditional X-ray,which can provide more diagnostic information and higher diagnostic value in this disease.

Comparative Analysis of DDR and Screen-film Radiography / 医疗卫生装备

Objective To explore the exposure condition of DDR, screen -film radiography and the radiation dose to patients, and evaluate value of the DDR system. Methods Five thousand images of DDR and screen-film radiography were selected and then analyzed by three junior radiologists and two senior radiologists. Results 1.The quality of the images was classified into grades A ,B ,C: grade A in 92.8 % , grade B in 7.2 % , grade C in 0% ,waste in 0 % for DDR group and grade A in 40.8% , grade B in 41.7 %,grade C in 15.5 % ,waste in 2% for screen-film radiography group. 2. The required voltage of DDR system raises 3-24kV than screen-film radiography and radiation exposure was increased about 25 % . Conclusions The imaging quality of DDR was obviously higher than the screen -film radiography, but the disadvantage of DDR system was the higher exposure condition required, which increase X-ray radiation dose for patients.

The Expression of Death Domain Receptor-3, Caspase-10, Insulin-Like Growth Factor Binding Protein-3 in the Placentas of Preeclampsia / 대한주산의학회잡지

OBJECTIVE: To determine that preeclampsia is associated with differential expression of death domain receptor-3(DDR-3), caspase-10, and insulin-like growth factor binding protein-3(IGFBP-3). METHODS: Placenta were collected from 10 preeclampsias and from 15 normal pregnancies and the samples were immediately frozen and stored at -70degrees C. Total mRNA was extracted from placental tissue and then analysis of the expressions of DDR-3, caspase-10, and IGFBP-3 were performed by quantitative RT-PCR. RESULTS: Quantitative RT-PCR analysis demonstrated significantly increased DDR-3 and caspase-10 expression levels and significantly decreased IGFBP-3 expression level in the placenta of preeclampsia compared with normal pregnancy. CONCLUSION: Placental apoptosis is associated with DDR-3, caspase-10, and IGFBP-3. These results may be one of possible mechanisms in the placental apoptosis of preeclampsia.