ABSTRACT
Tumor extracellular matrix (ECM) is the center component of tumor microenvironment (TME), ECM diversity constitutes the inherent heterogeneity of TME that contributes to tumor growth, dormancy, drug resistance, and metastasis. Discoidin domain receptor 1 is one of the ECM receptors that interact with multiple ECM ligands. It also regulates the occurrence and development of tumors. Accordingly, DDR1 plays an increasingly important role in the prevention, diagnosis, and treatment of cancer. In this review, we primarily summarize the research of ECM and its receptors with components, regulation, cell receptors, and signaling pathways in tumor progression.
ABSTRACT
Discoidin domain receptor 1(DDR1)is a critical member of the receptor tyrosine kinase family.It may be related to tumor invasion and metastasis,and the abnormal activation of DDR1 can lead to the occurrence and development of malignant tumors,inflammation,and fibrosis.DDR1 are involved in cell adhesion,migration,proliferation,secretion of cytokines,and remodeling of extracellular matrix,thus playing a critical role in various pathophysiological processes of the human body.In this review,we demonstrate the research progress of DDR1 in breast cancer and other malignant tumors,in order to provide a new theoretical basis for the prevention and treatment of breast cancer and other tumors.
Subject(s)
Female , Humans , Breast Neoplasms/genetics , Cell Adhesion , Discoidin Domain Receptor 1 , Fibrosis , Receptor Protein-Tyrosine Kinases/geneticsABSTRACT
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.
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Objective To study the effects of discoidin domain receptor 1 (DDR1) mediated phosphorylation of protein Tau on hypoxic-ischemic brain damage (HIBD) in neonatal rats and its possible mechanism.Methods Sixty-four seven-day-old male specific-pathogen-free Wistar rats were randomly divided into four groups with sixteen in each: Sham, HIBD, HIBD with normal saline (HIBD+NS) and HIBD with DDR1 inhibitor (HIBD+DI) groups. A rat model of HIBD was established by subjecting the rats to left common carotid artery ligation, followed by exposing them to hypoxia for two hours. In HIBD+DI group, the inhibitor of DDR1 was immediately injected into lateral cerebroventricles of the rats following modeling. Forty-eight hours after injection, tissues of left cerebral cortex were collected from each rat to evaluate histopathological changes with HE staining. Western-blotting was used to assess the phosphorylation levels of DDR1 and protein Tau. Enzyme-linked immunosorbent assay was performed to detect the concentrations of acetylcholine. Analysis of variance ort test were used for statistical analysis.Results (1) Damages in cerebral cortex: Percentages of abnormal neurons in the rats of HIBD group were higher than those in Sham group [(80.28±4.51)% vs (10.40±2.17)%,t=39.491,P<0.01]. Pyknotic or necrotic neurons in the rats of HIBD+DI group were less than those in HIBD+NS group [(31.91±3.05)% vs (82.01±7.20)%,t=18.123,P<0.01]. (2) Phosphorylation of DDR1 and protein Tau: Levels of phosphorylated DDR1 in the cerebral cortexes of rats in HIBD group were higher than those in Sham group (0.922±0.199 vs 0.095±0.023,t=10.379,P<0.01), and those levels in HIBD+NS group were higher than those in HIBD+DI group (1.200±0.171 vs 0.255±0.111,t=11.901, P<0.01). The phosphorylation of protein Tau was similar to that of DDR1 (0.919±0.228 vs 0.194±0.224 in HIBD and Sham groups,t=7.347; 1.100±0.167 vs 0.291±0.210 in HIBD+NS and HIBD+DI groups,t=9.447;bothP<0.01). (3) Levels of acetylcholine: Levels of acetylcholine in cerebral cortexes of rats in HIBD group were lower than those in Sham group [(3.685±0.472) vs (7.429±0.861) ng/g protein,t=10.781,P<0.01], and that levels in HIBD+DI group were higher than those in HIBD+NS group [(7.058±0.915) vs (2.521±0.723) ng/g protein,t=10.989,P<0.01].Conclusions Activation of DDR1 plays a key role in enhancing the phosphorylation of protein Tau and in reducing the secretion of acetylcholine in cerebral cortexes of rats with HIBD. Inhibitor of DDR1 could protect neonatal rats from HIBD through the decreasing of protein Tau phosphorylation and increasing of acetylcholine release by inhibiting the activation of DDR1.
ABSTRACT
Discoidin domain receptor 1(DDR1)is a kind of receptor tyrosine kinases(RTKs),which is expressed abnormally in many tumors. It is involved in the development,invasion and metastasis process of tumors and may become a potential target of tumor therapy. This article reviewed the expression and significance of DDR1 in tumors of digestive system.
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Objective To explore the expression of discoidin domain receptor 1 (DDR1) in rats with pulmonary fibrosis induced by paraquat (PQ) poisoning, and its relationship with the expression of transforming growth factor-β1 (TGF-β1). Methods 120 Sprague-Dawley (SD) rats were divided into control group and 20, 40, and 80 mg/kg PQ poisoning groups (each n = 30). Pulmonary fibrosis induced by PQ poisoning model was reproduced by one time administration of 20, 40, 80 mg/kg of 20% PQ, and the rats in control group were given 4 mL normal saline. Fifteen rats in control and different doses of PQ groups were sacrificed at 7 days and 21 days after intragastric administration, and lung tissues were collected. Pulmonary fibrosis was observed after hematoxylin-eosin (HE) staining. The immune-histochemical method was used to determine the expressions of DDR1 and TGF-β1. The relationship between the expression of TGF-β1 and DDR1 was analyzed by Pearson correlation analysis. Results The rats in control group were active, and no pathological changes in lung tissue were found. The rats in PQ groups became shortness of breath, bristles, and slow reaction etc. 0.5 hours after intragastric administration. After 7 days, the lung tissue was dark red, hard texture, appearance of yellow soil fiber nodules and obsolete hemorrhage, destruction of alveolar structure. The extent of lung injury increased gradually with the time of poisoning and the increase of PQ dose. It was shown by immune-histochemical staining that the control group had only a small amount of DDR1 and TGF-β1 positive expressions; in PQ groups, there were a large number of DDR1 and TGF-β1 positive expression particles in the alveolar wall, pulmonary interstitial and alveolar cavity. It was displayed by quantitative analysis that compared with the control group, DDR1 and TGF-β1 expressions were significantly increased in 20, 40, 80 mg/kg PQ groups with time- and dose-dependent [DDR1 (integral A value): 0.221±0.014, 0.249±0.021, 0.364±0.016 vs. 0.121±0.036 at 7 days; 0.247±0.025, 0.321±0.015, 0.432±0.027 vs. 0.139±0.021 at 21 days; TGF-β1 (integral A value): 0.230±0.016, 0.265±0.015, 0.339±0.016 vs. 0.129±0.032 at 7 days; 0.248±0.011, 0.295±0.016, 0.399±0.026 vs. 0.119±0.026 at 21 days; all P < 0.05]. It was shown by Pearson correlation analysis that DDR1 expression was positively correlated with TGF-β1 expression with the increase of PQ dose and poisoning time (DDR1 with TGF-β1: r = 0.996, P < 0.000; DDR1 with PQ dose: r = 0.985, P < 0.000; DDR1 with poisoning time: r = 0.989, P < 0.000; TGF-β1 with PQ dose: r = 0.992, P < 0.000; TGF-β1 with poisoning time: r = 0.972, P < 0.000). Conclusions The expression of DDR1 in the lung tissue in PQ poisoning rats showed a time- and dose-dependent change, and it was positively correlated with TGF-β1 expression. DDR1 may be involved in the process of pulmonary fibrosis induced by PQ poisoning.