Downregulation of cytokeratin 18 increases NMIIA expression and promotes breast cancer metastasis / 中国药理学通报

Aim To investigate the role of aberrant cytokeratin 18(CK18) expression in breast cancer metastasis, anrl to elucidate the mechanism by identif¬ying its target.Methods The expression of CK.18 in human breast cancer tissues and cells was determined using immunohistochemical staining and Western blot, respectively.CK18 expression in human breast cancer MCF-7 cells was effectively down-regulated by shRNA, and its effect on breast cancer metastasis was further determined by scratch wound healing assay.The co-lo- cation of CK18 and non-muscle II A ( NMIIA) in MCF-7 cells was examined using double immunofluo¬rescence staining.The effect of CK18 down-regulation on the levels of NMIIA and c-Abl-ERK signaling was quantified by Western blot.Results Lower CK18 lev¬els was found in metastatic than that in primary breast cancer tissues and in highly invasive MDA-MB-231 than that in MCF-7 cells.CK.18 down-regulation pro¬moted the wound repair ability of MCF-7 cells 72h after scratch.CK18 and NMIIA were shown to co-locate in cytoplasm of MCF-7 cells.Moreover, down-regulation of CK18 increased NMIIA expression and activated the c-Abl-ERK signaling pathway in MCF-7 cells.Con¬clusions Down-regulation of CK18 could promote me¬tastasis of breast cancer, which is related to increased NMIIA expression and the activation of c-Abl-ERK sig¬naling pathway.

Effect of nilotinib on silicon dioxide-induced proliferation and collagen synthesis in HFL-1 cells / 中国职业医学

OBJECTIVE: To observe the effects of nilotinib on silicon dioxide(SiO_2)-induced cell proliferation and collagen synthesis in human fetal lung fibroblast-1(HFL-1) cells and to explore the related mechanism. METHODS: ⅰ) HFL-1 cells were induced with different doses of SiO_2 suspension(0, 5,10, 25, 50 and 100 mg/L) for 24.0 hours. The expression of transforming growth factor-β1(TGF-β1), C-Abl, and platelet-derived growth factor receptor(PDGFR) was detected by Western blot, and the dose of SiO_2 in subsequent experiments was screened. ⅱ) HFL-1 cells were randomly divided into 6 groups: 1) the control group: no treatment; 2) the solvent control group: cells were treated with 0.10% dimethyl sulfoxide; 3) the SiO_2 stimulation group: cells were induced with SiO_2 suspension at a dose of 50 mg/L for 24.0 hours; 4)-6) the nilotinib groups: cells were induced with SiO_2 suspension at a dose of 50 mg/L for 24.0 hours and treated with nilotinib at the concentration of 5, 10, or 15 mmol/L for 24.0 hours. Cell proliferation was detected by MTS assay. The TGF-β1 protein secreted by cells was measured using enzyme linked immunosorbent assay. The expression of TGF-β1, C-Abl, platelet derived growth factor(PDGF), PDGFR and collagen typeⅠproteins was measured by Western blot. RESULTS: ⅰ) The dose of the SiO_2 in the experiments was set to 50 mg/L. ⅱ) The cell proliferation rate of HFL-1 cells in the SiO_2 stimulation group and the 3 nilotinib groups was higher than that in control group and solvent control group(P<0.05). The proliferation rates of HFL-1 cells in 10 and 15 mmol/L nilotinib groups were lower than that in SiO_2 stimulation group(P<0.05). The level of TGF-β1 and the protein relative expression levels of TGF-β1, collagen typeⅠ, C-Abl, PDGFR and PDGF in HFL-1 cells of SiO_2 stimulation group were higher than those in control group and solvent control group(P<0.05). The above indexes of HFL-1 cells in 15 mmol/L nilotinib group were lower than that in SiO_2 stimulation group(P<0.05); the above indexes of HFL-1 cells in 5 mmol/L nilotinib group were not significantly different from those in SiO_2 stimulation group(P>0.05). The level of TGF-β1 and the relative expression level of C-Abl protein in HFL-1 cells of 10 mmol/L nilotinib group were lower than those in SiO_2 stimulation group(P<0.05). CONCLUSION: Nilotinib can inhibit the proliferation of HFL-1 cells and reduce the expression of collagen typeⅠprotein induced by SiO_2. This process may be achieved by inhibiting tyrosine kinase-mediated signaling pathway.

Interferon-γ regulates cell malignant growth via the c-Abl/HDAC2 signaling pathway in mammary epithelial cells / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Interferon-γ (IFN-γ) has been used to control cancers in clinical treatment. However, an increasing number of reports have suggested that in some cases effectiveness declines after a long treatment period, the reason being unclear. We have reported previously that long-term IFN-γ treatment induces malignant transformation of healthy lactating bovine mammary epithelial cells (BMECs) in vitro. In this study, we investigated the mechanisms underlying the malignant proliferation of BMECs under IFN-γ treatment. The primary BMECs used in this study were stimulated by IFN-γ (10 ng/mL) for a long term to promote malignancy. We observed that IFN-γ could promote malignant cell proliferation, increase the expression of cyclin D1/cyclin-dependent kinase 4 (CDK4), decrease the expression of p21, and upregulate the expression of cellular-abelsongene (c-Abl) and histone deacetylase 2 (HDAC2). The HDAC2 inhibitor, valproate (VPA) and the c-Abl inhibitor, imatinib, lowered the expression level of cyclin D1/CDK4, and increased the expression level of p21, leading to an inhibitory effect on IFN-γ-induced malignant cell growth. When c-Abl was downregulated, the HDAC2 level was also decreased by promoted proteasome degradation. These data suggest that IFN-γ promotes the growth of malignant BMECs through the c-Abl/HDAC2 signaling pathway. Our findings suggest that long-term application of IFN-γ may be closely associated with the promotion of cell growth and even the carcinogenesis of breast cancer.

Interferon-γ regulates cell malignant growth via the c-Abl/HDAC2 signaling pathway in mammary epithelial cells / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Interferon-γ (IFN-γ) has been used to control cancers in clinical treatment. However, an increasing number of reports have suggested that in some cases effectiveness declines after a long treatment period, the reason being unclear. We have reported previously that long-term IFN-γ treatment induces malignant transformation of healthy lactating bovine mammary epithelial cells (BMECs) in vitro. In this study, we investigated the mechanisms underlying the malignant proliferation of BMECs under IFN-γ treatment. The primary BMECs used in this study were stimulated by IFN-γ (10 ng/mL) for a long term to promote malignancy. We observed that IFN-γ could promote malignant cell proliferation, increase the expression of cyclin D1/cyclin-dependent kinase 4 (CDK4), decrease the expression of p21, and upregulate the expression of cellular-abelsongene (c-Abl) and histone deacetylase 2 (HDAC2). The HDAC2 inhibitor, valproate (VPA) and the c-Abl inhibitor, imatinib, lowered the expression level of cyclin D1/CDK4, and increased the expression level of p21, leading to an inhibitory effect on IFN-γ-induced malignant cell growth. When c-Abl was downregulated, the HDAC2 level was also decreased by promoted proteasome degradation. These data suggest that IFN-γ promotes the growth of malignant BMECs through the c-Abl/HDAC2 signaling pathway. Our findings suggest that long-term application of IFN-γ may be closely associated with the promotion of cell growth and even the carcinogenesis of breast cancer.

Application of c-Abl inhibitors in the treatment of Parkinson′s disease / 医学研究生学报

Parkinson's disease (PD) is a common neurodegenerative disorder associated with aging.Recent studies in animal models of PD and analyses of brain specimen from PD patients revealed an increase in the level and activity of the non-receptor tyrosine kinase Abelson (c-Abl) in dopaminergic neurons with phosphorylation of protein substrates,such as a-synuclein and the E3 ubiquitin ligase, Parkin.Most significantly inhibition of c-Abl kinase activity by small molecular compounds used in the clinic to treat human leukemia has shown promising neuroprotective effects in cell and animal models of PD.This has raised hope that similar beneficial outcome may also be observed in the treatment of PD patients by using c-Abl inhibitors.Here we highlight the background for the current optimism, reviewing c-Abl and its relationship to pathophysiological pathways prevailing in PD, as well as discussing issues related to the pharmacology and safety of current c-Abl inhibitors.Clearly more rigorously controlled and well-designed trials are needed before the c-Abl inhibitors can be used in the neuroclinic to possibly benefit an increasing number of PD patients.

Research progress of the relationship between c-Abl and solid tumors / 肿瘤研究与临床

Non-receptor tyrosine kinase c-Abl has been implicated in the regulation of the cell cycle,adhesion, apoptosis and DNA damage responses.Its excessive activation is related with the development of chronic myeloid leukemia, and the relationship between c-Abl and leukemia is in depth and detailed research.In contrast to leukemia, the research between c-Abl and solid tumors is just at the early stage.This paper briefly reviews research progress of the c-Abl in solid tumors.

Angiotensin Ⅱ induces podocyte c-Abl expression change / 中华肾脏病杂志

ObjectiveTo evaluate the effects of angiotensin Ⅱ (Ang Ⅱ )infusion on renal c-Abl expression in vivo,and on podocyte c-Abl expression change in cultured mouse podocytes.Methods Twenty four male Sprague-Dawley rats (Group C,D,E and F) were assigned to receive Ang Ⅱ(400 ng· kg-1 min-1) by osmotic minipump and of which 12 rats (Group D and F) were assigned to receive telmisartan (3 mg·kg-1·d-1),six rats received normal saline(Group B),and six rats were used as normal control(Group A).Animals were sacrificed at day 14 (Group C and D),day 28 (Group E and F) respectively.Conditionally immortalized mouse podocytes were used in vitro.Podocytes were studied 2 weeks after thermoswitching from 33℃ to 37℃.Cells were fetal bovine serum(FBS) starved for at least 12 hours prior to stimulation.The cultured podocytes were treated withAngⅡdosesranging from10 -9 mol/L to10 -6 mol/L andfor differenthours.Expression of renal and podocytes c-Abl was examined by immunofluorescence staining,real-time PCR and Western blotting.Results(1) Distribution of c-Abl expression was mainly in the cytoplasm and nuclear of the podocytes in vivo and in vitro. (2) Expressions of c-Abl mRNA and protein wereincreasedinAng Ⅱ-infusedratpodocytesandAng Ⅱ-inducedculturedmouse podocytes(P＜0.05),and the effects of Ang Ⅱ were dose-dependent and time-dependent in vitro.Conclusion There are c-Abl mRNA and protein expression in podocytes,and c-Abl may play a critical role in the pathogenesis of Ang Ⅱ -induced podocyte injury.

The Expression and Clinical Significance of C-kit、C-abl and PDGFR? in Ovarian Carcinoma / 医学研究杂志

Objective This study was to examine the expression of tyrosine kinase receptor(TKRs)C-kit,C-abl and PDGFR?,in ovary carcinoma.Methods The expression of C-kit,C-abl and PDGFR? in tumor tissue of 60 specimens of ovary carcinoma and normal fissue of 20 specimens of overy was examined by immunohistochemistry SP method.Results Immunoreactivity was detected in 79% of the tumor to at least one TKR.The total positive expression rate of C-kit,C-abl and PDGFR? in ovary carcinoma was 58.3%,70%,73.3%,respectively.The positive expression rate of C-kit and PDGFR? is significantly higher in tumor tissues than in normal tissues(P