目的探讨乳腺癌转移抑制基因(breast cancer metastasis suppressor 1,BRMS1)在声门上型喉鳞状细胞癌组织中的表达及其临床意义。方法免疫组化法检测60例原发性声门上型喉癌组织(肿瘤组)和其相邻的癌旁正常喉黏膜(对照组)石蜡标本组织...目的探讨乳腺癌转移抑制基因(breast cancer metastasis suppressor 1,BRMS1)在声门上型喉鳞状细胞癌组织中的表达及其临床意义。方法免疫组化法检测60例原发性声门上型喉癌组织(肿瘤组)和其相邻的癌旁正常喉黏膜(对照组)石蜡标本组织细胞中BRMS1蛋白的表达。结果对照组均有较强的BRMS1蛋白的表达,肿瘤组阳性表达率为35.0%(21/60),且均为低表达,两者之间差异有统计学意义(P<0.05)。BRMS1蛋白在病理高分化标本中阳性表达率为43.6%(17/39),在中、低分化标本阳性表达率19.0%(4/21),两者之间差异有统计学意义(P<0.05);在临床Ⅱ期标本阳性表达率为72.7%(8/11),临床Ⅲ+Ⅳ期标本阳性表达率26.5%(13/49),两者之间差异有统计学意义(P<0.05);颈部淋巴结N0组标本阳性表达率72.7%(16/22),颈部淋巴结N+组阳性率13.7%(5/38),两者之间差异有统计学意义(P<0.05)。BRMS1蛋白阳性组患者与BRMS1蛋白阴性组患者的术后生存率无统计学差异(P>0.05)。结论BRMS1蛋白在声门上型喉癌中低表达或不表达,且其表达可能与声门上型喉癌的临床分期、病理分化以及颈部淋巴结转移有关。展开更多
Background Triple negative breast cancer(TNBC),the most aggressive subtype of breast cancer,is characterized by a high incidence of brain metastasis(BrM)and a poor prognosis.As the most lethal form of breast cancer,Br...Background Triple negative breast cancer(TNBC),the most aggressive subtype of breast cancer,is characterized by a high incidence of brain metastasis(BrM)and a poor prognosis.As the most lethal form of breast cancer,BrM remains a major clinical challenge due to its rising incidence and lack of effective treatment strategies.Recent evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastasis(BCBrM),but the underlying mechanisms are far from being fully elucidated.Methods Through analysis of BCBrM transcriptome data from mice and patients,and immunohistochemical validation on patient tissues,we identified and verified the specific down-regulation of retinoic acid receptor responder 2(RARRES2),a multifunctional adipokine and chemokine,in BrM of TNBC.We investigated the effect of aberrant RARRES2 expression of BrM in both in vitro and in vivo studies.Key signaling pathway components were evaluated using multi-omics approaches.Lipidomics were performed to elucidate the regulation of lipid metabolic reprogramming of RARRES2.Results We found that downregulation of RARRES2 is specifically associated with BCBrM,and that RARRES2 deficiency promoted BCBrM through lipid metabolic reprogramming.Mechanistically,reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue(PTEN)-mammalian target of rapamycin(mTOR)-sterol regulatory element-binding protein 1(SREBP1)signaling pathway to facilitate the survival of breast cancer cells in the unique brain microenvironment.Conclusions Our work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of BrM.RARRES2-dependent metabolic functions may serve as potential biomarkers or therapeutic targets for BCBrM.展开更多
目的探讨乳腺癌转移抑制因子1(BRMS1)在肺癌中的表达及对肺癌细胞侵袭转移能力的影响。方法 Western blot及RT-PCR法检测肺癌及癌旁组织中BRMS1的表达,并将真核表达质粒p CMV-mycBRMS1及空白质粒转染到肺癌细胞A549。Transwell法检测细...目的探讨乳腺癌转移抑制因子1(BRMS1)在肺癌中的表达及对肺癌细胞侵袭转移能力的影响。方法 Western blot及RT-PCR法检测肺癌及癌旁组织中BRMS1的表达,并将真核表达质粒p CMV-mycBRMS1及空白质粒转染到肺癌细胞A549。Transwell法检测细胞迁移和侵袭能力;Western blot检测核因子-κB(NF-κB)磷酸化水平及下游蛋白基质金属蛋白酶(MMP2),MMP9,骨桥蛋白(Osteopontin),E-钙粘蛋白(Ecadherin)的表达量。结果肺癌组织中BRMS1的蛋白及mRNA表达量都显著低于癌旁组织。与空白质粒组比较,真核表达质粒组中细胞迁移及侵袭能力降低,比值分别为[(0.98±0.10)及(0.17±0.03)],[(1.29±0.14)及(0.22±0.04)];NF-κB p65磷酸化水平降低,MMP2,MMP9,Osteopontin表达量下降,E-cadherin表达量上升(P<0.01)。结论 BRMS1在肺癌组织中低表达,其过表达能显著抑制肺癌细胞A549侵袭转移,推测恢复肺癌组织BRMS1表达可能是转移性肺癌治疗方式之一。展开更多
文摘目的探讨乳腺癌转移抑制基因(breast cancer metastasis suppressor 1,BRMS1)在声门上型喉鳞状细胞癌组织中的表达及其临床意义。方法免疫组化法检测60例原发性声门上型喉癌组织(肿瘤组)和其相邻的癌旁正常喉黏膜(对照组)石蜡标本组织细胞中BRMS1蛋白的表达。结果对照组均有较强的BRMS1蛋白的表达,肿瘤组阳性表达率为35.0%(21/60),且均为低表达,两者之间差异有统计学意义(P<0.05)。BRMS1蛋白在病理高分化标本中阳性表达率为43.6%(17/39),在中、低分化标本阳性表达率19.0%(4/21),两者之间差异有统计学意义(P<0.05);在临床Ⅱ期标本阳性表达率为72.7%(8/11),临床Ⅲ+Ⅳ期标本阳性表达率26.5%(13/49),两者之间差异有统计学意义(P<0.05);颈部淋巴结N0组标本阳性表达率72.7%(16/22),颈部淋巴结N+组阳性率13.7%(5/38),两者之间差异有统计学意义(P<0.05)。BRMS1蛋白阳性组患者与BRMS1蛋白阴性组患者的术后生存率无统计学差异(P>0.05)。结论BRMS1蛋白在声门上型喉癌中低表达或不表达,且其表达可能与声门上型喉癌的临床分期、病理分化以及颈部淋巴结转移有关。
基金supported by the National Natural Science Foundation of China(82203185,82230058,82172875 and 82073094)the National Key Research and Development Program of China(2021YFF1201300 and 2022YFE0103600)+3 种基金the CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-014,2021-I2M-1-022,and 2022-I2M-2-001)the Open Issue of State Key Laboratory of Molecular Oncology(SKL-KF-2021-16)the Independent Issue of State Key Laboratory of Molecular Oncology(SKL-2021-16)the Beijing Hope Marathon Special Fund of Chinese Cancer Foundation(LC2020B14).
文摘Background Triple negative breast cancer(TNBC),the most aggressive subtype of breast cancer,is characterized by a high incidence of brain metastasis(BrM)and a poor prognosis.As the most lethal form of breast cancer,BrM remains a major clinical challenge due to its rising incidence and lack of effective treatment strategies.Recent evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastasis(BCBrM),but the underlying mechanisms are far from being fully elucidated.Methods Through analysis of BCBrM transcriptome data from mice and patients,and immunohistochemical validation on patient tissues,we identified and verified the specific down-regulation of retinoic acid receptor responder 2(RARRES2),a multifunctional adipokine and chemokine,in BrM of TNBC.We investigated the effect of aberrant RARRES2 expression of BrM in both in vitro and in vivo studies.Key signaling pathway components were evaluated using multi-omics approaches.Lipidomics were performed to elucidate the regulation of lipid metabolic reprogramming of RARRES2.Results We found that downregulation of RARRES2 is specifically associated with BCBrM,and that RARRES2 deficiency promoted BCBrM through lipid metabolic reprogramming.Mechanistically,reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue(PTEN)-mammalian target of rapamycin(mTOR)-sterol regulatory element-binding protein 1(SREBP1)signaling pathway to facilitate the survival of breast cancer cells in the unique brain microenvironment.Conclusions Our work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of BrM.RARRES2-dependent metabolic functions may serve as potential biomarkers or therapeutic targets for BCBrM.
