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Objective:To investigate the expression of USP41 in triple-negative breast cancer (TNBC) and its correlation with malignant phenotype and adriamycin sensitivity.Methods:The expression of USP41 in TNBC resistant cell lines and clinical tissue samples was detected by Western blot and qPCR. Subsequently, the high expression of USP41 molecule was determined, and the role and possible mechanism of USP41 in the malignant phenotype and adriamycin resistance of TNBC were evaluated by cell biological methods such as CCK8, colony formation assay, transwell, Western blot, and CoIP-MS.Results:USP41 expression was significantly higher in triple-negative breast cancer samples than in adjacent non-cancerous tissues. USP41 expression was nearly 40-fold higher in the doxorubicin-resistant cell line MDA-MB-231/DXR, with an IC50 value of 6.86 μM. Interference with USP41 significantly increased the sensitivity of MDA-MB-231/DXR cells to doxorubicin. Interference with USP41 significantly inhibited cell proliferation, colony formation and migration of cells, with a decrease in the number of clones of 30%-80% and a decrease in the number of migrating cells of more than 70%, and the difference was statistically significant. In addition, USP41 knockdown improved the sensitivity of MDA-MB-231 cells to doxorubicin, with an IC50 decrease from 5.49 μM to 2.36 μM and 2.56 μM. CO-IP results showed that USP41 could directly interact with RACK1, and the expression of RACK1 was significantly higher in cancer tissues than in adjacent non-cancerous tissues. Interference with RACK1 inhibited MDA-MB-231 cell proliferation, with IC50 decreasing from 9.87 μM to 4.67 μM and 4.36 μM. Colony formation capacity decreased by more than 30% and the difference was statistically significant. USP41 knockdown decreased cell migration by more than 70% compared to control.Conclusion:High expression of USP41 is associated with malignant surface and adriamycin resistance in TNBC, and RACK1 may be a key molecule in the role of USP41.
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@#Maintaining bone homeostasis relies on the balance between bone remodeling involving bone resorption by osteoclasts and bone formation by osteoblasts under physiological conditions. An increasing number of studies have shown that the ubiquitin-proteasome system plays an important role in bone remodeling. The ubiquitination process is reversible through the action of deubiquitinase (DUB), and ubiquitin-specific proteases (USPs) are the largest of the DUB families. This article summarizes the mechanisms by which USPs regulate bone homeostasis, including USP4 and USP7, by affecting bone formation through signaling pathways such as Wnt/β-catenin and cylindromatosis (CYLD) and regulating bone resorption through signaling pathways such as nuclear factor-kappa B (NF-κB). In addition to affecting bone resorption and bone formation during bone reconstruction, the effect of USPs on bone is also reflected in the osteogenic differentiation of human periodontal membrane stem cells and implant bone binding. Future research should determine whether USPs have a greater regulatory effect on bone reconstruction and the specific mechanism of their regulatory effect to provide more approaches for the treatment of bone diseases.
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Objective:To evaluate the role of tumour necrosis factor-α-induced protein 8-like 2 (TIPE2) in the acute lung injury (ALI) induced by endotoxin in mice.Methods:Forty SPF healthy adult male BALB/c mice, aged 6-8 weeks, weighing 20-25 g, were divided into 4 groups ( n=10 each) using a random number table method: vehicle plasmid group (VP group), vehicle plasmid plus ALI group (VP+ ALI group), TIPE2 adeno-associated virus overexpression group (T group) and TIPE2 adeno-associated virus overexpression plus ALI group (T+ ALI group). The mice in VP and VP+ ALI groups were injected with empty adeno-associated virus, while the mice in T and T+ ALI groups were intratracheally given adeno-associated virus carrying TIPE interference sequence.Three weeks later, the model of endotoxin-induced ALI was established.Lipopolysaccharide (LPS) 5 mg/kg was intratracheally given in VP+ ALI and T+ ALI groups, and the equal volume of phosphate buffered saline (PBS) was given in VP and T groups.Blood samples were obtained from the abdominal aorta at 24 h after injection of LPS for blood gas analysis, oxygenation index (OI) was calculated, and tumor necrosis factor-alpha (TNF-α) in serum were detected by enzyme-linked immunosorbent assay.The animals were then sacrificed, and lung tissues were removed for examination of pathological changes which were scored after haematoxylin and eosin staining, for calculation of the wet/dry weight ratio (W/D ratio) and for determination of myeloperoxidase (MPO) activity and the expression of TIPE2, phosphorylated c-Jun N-terminal kinase (p-JNK) and nuclear factor kappa B(NF-κB) (by Western blot). Results:Compared with VP group, the lung injury score, W/D ratio, MPO activity and concentration of serum TNF-α were significantly increased, PaO 2 and OI were decreased, expression of TIPE2 was down-regulated and expression of p-JNK and NF-κB was up-regulated in VP+ ALI group ( P<0.05). Compared with VP+ ALI group, the lung injury score, W/D ratio, MPO activity and concentration of serum TNF-α were significantly decreased, PaO 2 and OI were increased, expression of TIPE2 was up-regulated and expression of p-JNK and NF-κB was down-regulated in T+ ALI group ( P<0.05). Conclusion:The down-regulation of TIPE2 expression is involved in the process of ALI induced by endotoxin in mice.
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Objective@#To evaluate the effect of penehyelidine hydrochloride (PHCD) on tumor necrosis factor α-induced protein 8-like-2 (TIPE2)-Toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88) signaling pathway in a rat model of traumatic acute lung injury (ALI).@*Methods@#Thirty SPF healthy male Sprague-Dawley rats, aged 8 weeks, weighing 190-210 g, were divided into 3 groups (n=15 each) by a random number table method: sham operation group (group Sham), traumatic ALI group (group ALI) and group PHCD.ALI was induced by blunt chest trauma in ALI and PHCD groups.PHCD 2 mg/kg was intraperitoneally injected immediately after blunt chest trauma in group PHCD.The rats were sacrificed and lung tissues were removed at 8 h after the model was successfully established for examination of the pathological changes and ultrastructure of lung tissues (with a light microscope or an electron microscope) and for determination of the wet to dry weight ratio (W/D ratio) and expression of TLR4 and MyD88 in lung tissues.@*Results@#Compared with group Sham, the W/D ratio was significantly increased, TIPE2 expression was down-regulated, and the expression of TLR4 and MyD88 was up-regulated in ALI and PHCD groups (P<0.05). Compared with group ALI, the W/D ratio was significantly decreased, TIPE2 expression was up-regulated, and the expression of TLR4 and MyD88 was down-regulated (P<0.05), and the pathological changes of lung tissues and ultrastructure were significantly attenuated in group PHCD.@*Conclusion@#The mechanism by which PHCD reduces traumatic AIL is related to activating TIPE2-TLR4-MyD88 signaling pathway in rats.
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Objective To evaluate the effect of penehyelidine hydrochloride(PHCD)on tumor necrosis factor α-induced protein 8-like-2(TIPE2)-Toll-like receptor 4(TLR4)-myeloid differentiation fac-tor 88(MyD88)signaling pathway in a rat model of traumatic acute lung injury(ALI).Methods Thirty SPF healthy male Sprague-Dawley rats,aged 8 weeks,weighing 190-210 g,were divided into 3 groups(n＝15 each)by a random number table method: sham operation group(group Sham),traumatic ALI group(group ALI)and group PHCD.ALI was induced by blunt chest trauma in ALI and PHCD groups.PHCD 2 mg/kg was intraperitoneally injected immediately after blunt chest trauma in group PHCD.The rats were sacrificed and lung tissues were removed at 8 h after the model was successfully established for exami-nation of the pathological changes and ultrastructure of lung tissues(with a light microscope or an electron microscope)and for determination of the wet to dry weight ratio(W/D ratio)and expression of TLR4 and MyD88 in lung tissues.Results Compared with group Sham,the W/D ratio was significantly increased,TIPE2 expression was down-regulated,and the expression of TLR4 and MyD88 was up-regulated in ALI and PHCD groups(P＜0.05).Compared with group ALI,the W/D ratio was significantly decreased,TIPE2 expression was up-regulated,and the expression of TLR4 and MyD88 was down-regulated(P＜0.05),and the pathological changes of lung tissues and ultrastructure were significantly attenuated in group PHCD.Conclusion The mechanism by which PHCD reduces traumatic AIL is related to activating TIPE2-TLR4-MyD88 signaling pathway in rats.
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Ubiquitin-specific protease is a member of the deubiquitinating enzyme family,which can reverse the ubiquitination of proteins and stabilize proteins. It affects radiosensitivity of tumor by regulating DNA damage,cell cycle,nuclear factor-κB signaling pathway,Nrf2-Keap1 signaling pathway and oncogene c-myc. It is expected to become a new target for tumor radiotherapy sensitization.
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Objective@#To investigate the expression and significance of ubiquitin-specific proteases 2-69(USP2-69) in invasive ductal carcinoma of breast.@*Methods@#Twenty-four cases of human breast tissue with invasive ductal carcinoma diagnosed at Huanshan Hospital, Fudan University from 2013 to 2015 were collected, and the expression of USP2-69 mRNA and protein was detected by molecular hybridization, Western blot and immunohistochemistry. USP2-69 was over-expressed in cultured human breast cancer cell line MCF-7 by USP2-69 plasmid transfection. The cellular proliferative activity was investigated in vitro.@*Results@#The USP2-69 mRNA and protein were highly expressed in breast invasive ductal carcinoma, compared to adjacent normal tissues (P<0.01). Ki-67 protein expression was also increased in cases with high USP2-69 protein level. Western blot showed significantly higher USP2-69 protein level in cancer tissue compared to the adjacent normal tissue. In the cultured tumor cells, there was increased S phase fraction, cellular proliferation rate, flat positive clones, cyclin D1 expression and decreased p27 expression in USP2-69-transfected MCF-7 cells.@*Conclusions@#USP2-69 is over-expressed in breast invasive ductal carcinoma, and is closely related to proliferation promoting effects. The data provide an important experimental basis for further study on the molecular mechanism of breast cancer cell proliferation.
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Objective To explore the association of ubiquitin-specific proteases 24 (USP24) gene polymorphisms with susceptibility to sporadic Parkinson's disease (PD) in the Han Guangdong population. Methods From August, 2006 to January, 2014, single nucleotide poly-morphisms (SNPs) of rs12138592 and rs6671533 in the intron region of USP24 were genotyped in 200 patients with sporadic PD and 200 healthy controls using the SNaPshot technique. Results There was significant difference in the allele and genotype frequency of rs12138592 between the patients and the controls (P0.05). Conclusion The SNP of rs12138592 in the intron region of USP24 is associated with the susceptibility to sporadic PD in the Han Guangdong population, and the A allele may contribute a protective roles to PD.
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Ubiquitin-specific proteases (USPs) regulate the deconjugation of ubiquitin tag from substrate proteins. Dysregulation of USPs has been linked to many diseases. Despite extensive efforts by academia and industry,high quality chemical molecules targeting the USPs family of ubiquitin enzymes are still scarce. In this commentary,I propose the criteria of a high quality chemical probe and the strategies to target USPs.