BACKGROUND Previous cellular studies have demonstrated that elevated expression of Cx43 promotes the degradation of cyclin E1 and inhibits cell proliferation through ubiquitination.Conversely,reduced expression result...BACKGROUND Previous cellular studies have demonstrated that elevated expression of Cx43 promotes the degradation of cyclin E1 and inhibits cell proliferation through ubiquitination.Conversely,reduced expression results in a loss of this capacity to facilitate cyclin E degradation.The ubiquitination and degradation of cyclin E1 may be associated with phosphorylation at specific sites on the protein,with Cx43 potentially enhancing this process by facilitating the phosphorylation of these critical residues.AIM To investigate the correlation between expression of Cx43,SKP1/Cullin1/F-box(SCF)FBXW7,p-cyclin E1(ser73,thr77,thr395)and clinicopathological indexes in colon cancer.METHODS Expression levels of Cx43,SCF^(FBXW7),p-cyclin E1(ser73,thr77,thr395)in 38 clinical colon cancer samples were detected by immunohistochemistry and were analyzed by statistical methods to discuss their correlations.RESULTS Positive rate of Cx43,SCF^(FBXW7),p-cyclin E1(Ser73),p-cyclin E1(Thr77)and p-cyclin E1(Thr395)in detected samples were 76.32%,76.32%,65.79%,5.26%and 55.26%respectively.Positive expressions of these proteins were not related to the tissue type,degree of tissue differentiation or lymph node metastasis.Cx43 and SCF^(FBXW7)(r=0.749),p-cyclin E1(Ser73)(r=0.667)and p-cyclin E1(Thr395)(r=0.457),SCF^(FBXW7) and p-cyclin E1(Ser73)(r=0.703)and p-cyclin E1(Thr395)(0.415)were correlated in colon cancer(P<0.05),and expressions of the above proteins were positively correlated in colon cancer.CONCLUSION Cx43 may facilitate the phosphorylation of cyclin E1 at the Ser73 and Thr195 sites through its interaction with SCF^(FBXW7),thereby influencing the ubiquitination and degradation of cyclin E1.展开更多
Background:The prognostic significance of the chemokine receptor CCR7 in diffuse large B-cell lymphoma(DLBCL)has been reported previously.However,the detailed mechanisms of CCR7 in DLBCL,particularly regarding its int...Background:The prognostic significance of the chemokine receptor CCR7 in diffuse large B-cell lymphoma(DLBCL)has been reported previously.However,the detailed mechanisms of CCR7 in DLBCL,particularly regarding its interaction with lenalidomide treatment,are not fully understood.Methods:Our study utilized bioinformatics approaches to identify hub genes in SU-DHL-2 cell lines treated with lenalidomide compared to control groups.Immunohistochemical data and clinical information from 122 patients with DLBCL were analyzed to assess the correlation of CCR7 and p-ERK1/2 expression with the prognosis of DLBCL.Furthermore,in vitro and in vivo experiments were conducted to clarify the role of CCR7 in the response of DLBCL to lenalidomide treatment.Results:Our bioinformatics analysis pinpointed CCR7 as a hub gene in the context of lenalidomide treatment in DLBCL.Notably,31.14%and 36.0%(44/122)of DLBCL cases showed positive expression for CCR7 and ERK1/2 respectively,establishing them as independent prognostic factors for adverse outcomes in DLBCL via multivariate Cox regression analysis.Additionally,our studies demonstrated that the external application of the protein CCL21 promoted proliferation,migration,invasion,and activation of the ERK1/2 pathway in SU-DHL-2 and OCI-LY3 cell lines with high levels of CCR7 expression.This effect was mitigated by CCR7 silencing through siRNA,application of ERK inhibitors,or lenalidomide treatment.In vivo experiments reinforced the efficacy of lenalidomide,significantly reducing tumor growth rate,tumor mass,serum total LDH levels,and expression of CCR7 and p-ERK1/2 in a SUDHL-2 xenograft model in nude mice(p<0.05).Conclusion:Our study clarifies the potential role of the CCL21/CCR7/ERK1/2 axis in the therapeutic effects of lenalidomide in DLBCL treatment.展开更多
Tumor suppressor p53-mediated cell cycle arrest and DNA damage repair may exert cytoprotective effects against cancer therapies,including WEE1 inhibition.Considering that p53 activation can also lead to multiple types...Tumor suppressor p53-mediated cell cycle arrest and DNA damage repair may exert cytoprotective effects against cancer therapies,including WEE1 inhibition.Considering that p53 activation can also lead to multiple types of cell death,the role of this tumor suppressor in WEE1 inhibitor-based therapies remains disputed.In this study,we reported that nucleolar stress-mediated p53 activation enhanced the WEE1 inhibitor AZD1775-induced ferroptosis to suppress lung cancer growth.Our findings showed that AZD1775 promoted ferroptosis by blocking cystine uptake,an action similar to that of Erastin.Meanwhile,inhibition of WEE1 by the WEE1 inhibitors or siRNAs induced compensatory upregulation of SLC7A11,which conferred resistance to ferroptosis.Mechanistically,AZD1775 prevented the enrichment of H3K9me3,a histone marker of transcriptional repression,on the SLC7A11 promoter by repressing the expression of the histone methyltransferase SETDB1,thereby enhancing NRF2-mediated SLC7A11 transcription.This finding was also validated using the H3K9me3 inhibitor BRD4770.Remarkably,we found that the nucleolar stress-inducing agent Actinomycin D(Act.D)inhibited SLC7A11 expression by activating p53,thus augmenting AZD1775-induced ferroptosis.Moreover,the combination of AZD1775 and Act.D synergistically suppressed wild-type p53-harboring lung cancer cell growth both in vitro and in vivo.Altogether,our study demonstrates that AZD1775 promotes ferroptosis by targeting cystine uptake but also mediates the adaptive activation of SLC7A11 through the WEE1-SETDB1 cascade and NRF2-induced transcription,and inhibition of SLC7A11 by Act.D boosts the anti-tumor efficacy of AZD1775 by enhancing ferroptosis in cancers with wild-type p53.展开更多
BACKGROUND Dystrophic epidermolysis bullosa is characterized by fragile ulcerations of the skin caused by mutations in specific genes.However,genetic typing of this con-dition is rare.CASE SUMMARY An 11-year-old femal...BACKGROUND Dystrophic epidermolysis bullosa is characterized by fragile ulcerations of the skin caused by mutations in specific genes.However,genetic typing of this con-dition is rare.CASE SUMMARY An 11-year-old female suffered from recurrent fever,visible ulcerations of the entire skin,and severe malnutrition.Genetic testing revealed a frameshift mu-tation in the coding region 4047 of the 35th intron region of COL7A1,and she was diagnosed as malnutrition-type epidermolysis bullosa.Drug therapy(immu-noglobulin,fresh frozen plasma),topical therapy(silver ion dressing),fever redu-ction,cough relief,and promotion of gastrointestinal peristalsis are mainly used for respiratory and gastrointestinal complications.The patient’s condition impro-ved after treatment.CONCLUSION Dystrophic epidermolysis bullosa caused by a new framework shift mutation in COL7A1 should be taken seriously.展开更多
基金Supported by Innovative Practice Platform for Undergraduate Students,School of Public Health Xiamen University,No.2021001.
文摘BACKGROUND Previous cellular studies have demonstrated that elevated expression of Cx43 promotes the degradation of cyclin E1 and inhibits cell proliferation through ubiquitination.Conversely,reduced expression results in a loss of this capacity to facilitate cyclin E degradation.The ubiquitination and degradation of cyclin E1 may be associated with phosphorylation at specific sites on the protein,with Cx43 potentially enhancing this process by facilitating the phosphorylation of these critical residues.AIM To investigate the correlation between expression of Cx43,SKP1/Cullin1/F-box(SCF)FBXW7,p-cyclin E1(ser73,thr77,thr395)and clinicopathological indexes in colon cancer.METHODS Expression levels of Cx43,SCF^(FBXW7),p-cyclin E1(ser73,thr77,thr395)in 38 clinical colon cancer samples were detected by immunohistochemistry and were analyzed by statistical methods to discuss their correlations.RESULTS Positive rate of Cx43,SCF^(FBXW7),p-cyclin E1(Ser73),p-cyclin E1(Thr77)and p-cyclin E1(Thr395)in detected samples were 76.32%,76.32%,65.79%,5.26%and 55.26%respectively.Positive expressions of these proteins were not related to the tissue type,degree of tissue differentiation or lymph node metastasis.Cx43 and SCF^(FBXW7)(r=0.749),p-cyclin E1(Ser73)(r=0.667)and p-cyclin E1(Thr395)(r=0.457),SCF^(FBXW7) and p-cyclin E1(Ser73)(r=0.703)and p-cyclin E1(Thr395)(0.415)were correlated in colon cancer(P<0.05),and expressions of the above proteins were positively correlated in colon cancer.CONCLUSION Cx43 may facilitate the phosphorylation of cyclin E1 at the Ser73 and Thr195 sites through its interaction with SCF^(FBXW7),thereby influencing the ubiquitination and degradation of cyclin E1.
基金supported by the Key Research and Development Program of Science and Technology Department of Guizhou Province(No.20204Y147).
文摘Background:The prognostic significance of the chemokine receptor CCR7 in diffuse large B-cell lymphoma(DLBCL)has been reported previously.However,the detailed mechanisms of CCR7 in DLBCL,particularly regarding its interaction with lenalidomide treatment,are not fully understood.Methods:Our study utilized bioinformatics approaches to identify hub genes in SU-DHL-2 cell lines treated with lenalidomide compared to control groups.Immunohistochemical data and clinical information from 122 patients with DLBCL were analyzed to assess the correlation of CCR7 and p-ERK1/2 expression with the prognosis of DLBCL.Furthermore,in vitro and in vivo experiments were conducted to clarify the role of CCR7 in the response of DLBCL to lenalidomide treatment.Results:Our bioinformatics analysis pinpointed CCR7 as a hub gene in the context of lenalidomide treatment in DLBCL.Notably,31.14%and 36.0%(44/122)of DLBCL cases showed positive expression for CCR7 and ERK1/2 respectively,establishing them as independent prognostic factors for adverse outcomes in DLBCL via multivariate Cox regression analysis.Additionally,our studies demonstrated that the external application of the protein CCL21 promoted proliferation,migration,invasion,and activation of the ERK1/2 pathway in SU-DHL-2 and OCI-LY3 cell lines with high levels of CCR7 expression.This effect was mitigated by CCR7 silencing through siRNA,application of ERK inhibitors,or lenalidomide treatment.In vivo experiments reinforced the efficacy of lenalidomide,significantly reducing tumor growth rate,tumor mass,serum total LDH levels,and expression of CCR7 and p-ERK1/2 in a SUDHL-2 xenograft model in nude mice(p<0.05).Conclusion:Our study clarifies the potential role of the CCL21/CCR7/ERK1/2 axis in the therapeutic effects of lenalidomide in DLBCL treatment.
基金supported by the National Natural Science Foundation of China(82173022,82072879,82273098)the Innovative Research Team of High-level Local University in Shanghai.
文摘Tumor suppressor p53-mediated cell cycle arrest and DNA damage repair may exert cytoprotective effects against cancer therapies,including WEE1 inhibition.Considering that p53 activation can also lead to multiple types of cell death,the role of this tumor suppressor in WEE1 inhibitor-based therapies remains disputed.In this study,we reported that nucleolar stress-mediated p53 activation enhanced the WEE1 inhibitor AZD1775-induced ferroptosis to suppress lung cancer growth.Our findings showed that AZD1775 promoted ferroptosis by blocking cystine uptake,an action similar to that of Erastin.Meanwhile,inhibition of WEE1 by the WEE1 inhibitors or siRNAs induced compensatory upregulation of SLC7A11,which conferred resistance to ferroptosis.Mechanistically,AZD1775 prevented the enrichment of H3K9me3,a histone marker of transcriptional repression,on the SLC7A11 promoter by repressing the expression of the histone methyltransferase SETDB1,thereby enhancing NRF2-mediated SLC7A11 transcription.This finding was also validated using the H3K9me3 inhibitor BRD4770.Remarkably,we found that the nucleolar stress-inducing agent Actinomycin D(Act.D)inhibited SLC7A11 expression by activating p53,thus augmenting AZD1775-induced ferroptosis.Moreover,the combination of AZD1775 and Act.D synergistically suppressed wild-type p53-harboring lung cancer cell growth both in vitro and in vivo.Altogether,our study demonstrates that AZD1775 promotes ferroptosis by targeting cystine uptake but also mediates the adaptive activation of SLC7A11 through the WEE1-SETDB1 cascade and NRF2-induced transcription,and inhibition of SLC7A11 by Act.D boosts the anti-tumor efficacy of AZD1775 by enhancing ferroptosis in cancers with wild-type p53.
文摘BACKGROUND Dystrophic epidermolysis bullosa is characterized by fragile ulcerations of the skin caused by mutations in specific genes.However,genetic typing of this con-dition is rare.CASE SUMMARY An 11-year-old female suffered from recurrent fever,visible ulcerations of the entire skin,and severe malnutrition.Genetic testing revealed a frameshift mu-tation in the coding region 4047 of the 35th intron region of COL7A1,and she was diagnosed as malnutrition-type epidermolysis bullosa.Drug therapy(immu-noglobulin,fresh frozen plasma),topical therapy(silver ion dressing),fever redu-ction,cough relief,and promotion of gastrointestinal peristalsis are mainly used for respiratory and gastrointestinal complications.The patient’s condition impro-ved after treatment.CONCLUSION Dystrophic epidermolysis bullosa caused by a new framework shift mutation in COL7A1 should be taken seriously.
