目的探讨CMYC、BCL_2与BCL_6蛋白表达与弥漫性大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)患者临床特征及预后的关系。方法采用免疫组织化学染色法检测我院于2012年1月至2014年4月收集的85例DLBCL患者病理组织标本中CMYC、BCL_...目的探讨CMYC、BCL_2与BCL_6蛋白表达与弥漫性大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)患者临床特征及预后的关系。方法采用免疫组织化学染色法检测我院于2012年1月至2014年4月收集的85例DLBCL患者病理组织标本中CMYC、BCL_2、BCL_6、CD10、MUM-1蛋白的表达情况。结果 CMYC、BCL_2、BCL_6蛋白表达阳性率分别为29.4%(25/85)、58.8%(50/85)、69.4%(59/85),其在患者年龄、性别、临床分期、原发部位、血清LDH水平、化疗方案、IPI评分、A/B症状和骨髓侵犯等临床特征之间的表达无显著差异(P>0.05)。单因素生存分析显示,CMYC阴性和BCL_2阴性患者中位OS和中位PFS均显著长于阳性患者(P<0.05),BCL_6阳性和阴性患者中位OS和中位PFS比较差异无统计学意义(P>0.05)。Cox多因素分析显示,CMYC状态可作为DLBCL患者OS和PFS的独立预测指标,差异均具有统计学意义(P<0.05)。结论 CMYC可作为预测DLBCL患者预后的独立有效指标,并可在临床进行应用。展开更多
To improve the efficacy of lenvatinib in combination with programmed death-1(PD-1)blockade therapy for hepatocellular carcinoma(HCC),we screened the suppressive metabolic enzymes that sensitize HCC to lenvatinib and P...To improve the efficacy of lenvatinib in combination with programmed death-1(PD-1)blockade therapy for hepatocellular carcinoma(HCC),we screened the suppressive metabolic enzymes that sensitize HCC to lenvatinib and PD-1 blockade,thus impeding HCC progression.After analysis of the CRISPR‒Cas9 screen,phosphatidylinositol-glycan biosynthesis class L(PIGL)ranked first in the positive selection list.PIGL depletion had no effect on tumor cell growth in vitro but reprogrammed the tumor microenvironment(TME)in vivo to support tumor cell survival.Specifically,nuclear PIGL disrupted the interaction between cMyc/BRD4 on the distant promoter of target genes and thus decreased the expression of CCL2 and CCL20,which are involved in shaping the immunosuppressive TME by recruiting macrophages and regulatory T cells.PIGL phosphorylation at Y81 by FGFR2 abolished the interaction of PIGL with importinα/β1,thus retaining PIGL in the cytosol and facilitating tumor evasion by releasing CCL2 and CCL20.Clinically,elevated nuclear PIGL predicts a better prognosis for HCC patients and presents a positive correlation with CD8+T-cell enrichment in tumors.Clinically,our findings highlight that the nuclear PIGL intensity or the change in PIGL-Y81 phosphorylation should be used as a biomarker to guide lenvatinib with PD-1 blockade therapy.展开更多
Aim:Leelamine(LLM)inhibits the growth of human prostate cancer cells but the underlying mechanism is not fully understood.The present study was undertaken to determine the effect of LLM on cMyc,which is overexpressed ...Aim:Leelamine(LLM)inhibits the growth of human prostate cancer cells but the underlying mechanism is not fully understood.The present study was undertaken to determine the effect of LLM on cMyc,which is overexpressed in a subset of human prostate cancers.Methods:The effect of LLM on cMyc expression and activity was determined by western blotting/confocal microscopy and luciferase reporter assay,respectively.A transgenic mouse model of prostate cancer(Hi-Myc)was used to determine the chemopreventive efficacy of LLM.Results:Exposure of androgen-sensitive(LNCaP)and castration-resistant(22Rv1)human prostate cancer cells to LLM resulted in downregulation of protein and mRNA levels of cMyc.Overexpression of cMyc partially attenuated LLM-mediated inhibition of colony formation,cell viability,and cell migration in 22Rv1 and/or PC-3 cells.LLM treatment decreased protein levels of cMyc targets(e.g.,lactate dehydrogenase),however,overexpression of cMyc did not attenuate these effects.A trend for a decrease in the expression level of cMyc protein was discernible in 22Rv1 xenografts from LLM-treated mice compared with control mice.LLM treatment(10 mg/kg body weight,5 times/week)was well-tolerated by Hi-Myc transgenic mice.The incidence of high-grade prostatic intraepithelial neoplasia,adenocarcinoma in situ,and microinvasion were lower in LLM-treated Hi-Myc mice but the difference was not statistically significant.Conclusion:The present study reveals that LLM inhibits cMyc expression in human prostate cancer cells in vitro but concentrations higher than 10 mg/kg may be required to achieve chemoprevention of prostate cancer.展开更多
文摘目的探讨CMYC、BCL_2与BCL_6蛋白表达与弥漫性大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)患者临床特征及预后的关系。方法采用免疫组织化学染色法检测我院于2012年1月至2014年4月收集的85例DLBCL患者病理组织标本中CMYC、BCL_2、BCL_6、CD10、MUM-1蛋白的表达情况。结果 CMYC、BCL_2、BCL_6蛋白表达阳性率分别为29.4%(25/85)、58.8%(50/85)、69.4%(59/85),其在患者年龄、性别、临床分期、原发部位、血清LDH水平、化疗方案、IPI评分、A/B症状和骨髓侵犯等临床特征之间的表达无显著差异(P>0.05)。单因素生存分析显示,CMYC阴性和BCL_2阴性患者中位OS和中位PFS均显著长于阳性患者(P<0.05),BCL_6阳性和阴性患者中位OS和中位PFS比较差异无统计学意义(P>0.05)。Cox多因素分析显示,CMYC状态可作为DLBCL患者OS和PFS的独立预测指标,差异均具有统计学意义(P<0.05)。结论 CMYC可作为预测DLBCL患者预后的独立有效指标,并可在临床进行应用。
基金supported mainly by the Guangdong Natural Science Foundation of Guangdong Province of China 2021B1515020016in part by NSFC grants No.82000616,82272714,82173149Science and Technology Program of Guangdong Province No.2020B1212060019.
文摘To improve the efficacy of lenvatinib in combination with programmed death-1(PD-1)blockade therapy for hepatocellular carcinoma(HCC),we screened the suppressive metabolic enzymes that sensitize HCC to lenvatinib and PD-1 blockade,thus impeding HCC progression.After analysis of the CRISPR‒Cas9 screen,phosphatidylinositol-glycan biosynthesis class L(PIGL)ranked first in the positive selection list.PIGL depletion had no effect on tumor cell growth in vitro but reprogrammed the tumor microenvironment(TME)in vivo to support tumor cell survival.Specifically,nuclear PIGL disrupted the interaction between cMyc/BRD4 on the distant promoter of target genes and thus decreased the expression of CCL2 and CCL20,which are involved in shaping the immunosuppressive TME by recruiting macrophages and regulatory T cells.PIGL phosphorylation at Y81 by FGFR2 abolished the interaction of PIGL with importinα/β1,thus retaining PIGL in the cytosol and facilitating tumor evasion by releasing CCL2 and CCL20.Clinically,elevated nuclear PIGL predicts a better prognosis for HCC patients and presents a positive correlation with CD8+T-cell enrichment in tumors.Clinically,our findings highlight that the nuclear PIGL intensity or the change in PIGL-Y81 phosphorylation should be used as a biomarker to guide lenvatinib with PD-1 blockade therapy.
基金supported by the National Cancer Institute grant R01 CA225716(to S.V.S.).
文摘Aim:Leelamine(LLM)inhibits the growth of human prostate cancer cells but the underlying mechanism is not fully understood.The present study was undertaken to determine the effect of LLM on cMyc,which is overexpressed in a subset of human prostate cancers.Methods:The effect of LLM on cMyc expression and activity was determined by western blotting/confocal microscopy and luciferase reporter assay,respectively.A transgenic mouse model of prostate cancer(Hi-Myc)was used to determine the chemopreventive efficacy of LLM.Results:Exposure of androgen-sensitive(LNCaP)and castration-resistant(22Rv1)human prostate cancer cells to LLM resulted in downregulation of protein and mRNA levels of cMyc.Overexpression of cMyc partially attenuated LLM-mediated inhibition of colony formation,cell viability,and cell migration in 22Rv1 and/or PC-3 cells.LLM treatment decreased protein levels of cMyc targets(e.g.,lactate dehydrogenase),however,overexpression of cMyc did not attenuate these effects.A trend for a decrease in the expression level of cMyc protein was discernible in 22Rv1 xenografts from LLM-treated mice compared with control mice.LLM treatment(10 mg/kg body weight,5 times/week)was well-tolerated by Hi-Myc transgenic mice.The incidence of high-grade prostatic intraepithelial neoplasia,adenocarcinoma in situ,and microinvasion were lower in LLM-treated Hi-Myc mice but the difference was not statistically significant.Conclusion:The present study reveals that LLM inhibits cMyc expression in human prostate cancer cells in vitro but concentrations higher than 10 mg/kg may be required to achieve chemoprevention of prostate cancer.
