目的探究人乳腺癌裸鼠移植动物模型体内孕激素受体膜组分1(PGRMC1)在黄体酮与炔诺酮(NET)刺激下对乳腺癌异种移植瘤增殖影响的差异性。方法构建PGRMC1稳定表达的人乳腺癌细胞系(MCF7),36只雌性BALB/c-nu裸鼠按随机数字表法分为MCF7/HA-P...目的探究人乳腺癌裸鼠移植动物模型体内孕激素受体膜组分1(PGRMC1)在黄体酮与炔诺酮(NET)刺激下对乳腺癌异种移植瘤增殖影响的差异性。方法构建PGRMC1稳定表达的人乳腺癌细胞系(MCF7),36只雌性BALB/c-nu裸鼠按随机数字表法分为MCF7/HA-PGRMC1组(n=18)和MCF7/HA-Vector组(n=18)。各鼠于颈部皮下包埋雌二醇(E_(2))缓释片。24 h后两组裸鼠左、右侧面皮下分别注射MCF7/HA-PGRMC1和MCF7/HA-Vector细胞悬液150μL,注射细胞数为1×107个。肿瘤生长至100 mm 3左右,将两组裸鼠进行组内分组,分别皮下联合包埋安慰剂、黄体酮缓释片、NET缓释片,即E_(2)+安慰剂亚组(n=6)、E_(2)+黄体酮亚组(n=6)、E_(2)+NET亚组(n=6)。记录肿瘤体积变化,绘制肿瘤生长曲线。45 d后完整摘除肿瘤组织免疫组化染色检测PGRMC1和Ki67表达情况。结果MCF7/HA-PGRMC1株系构建成功,在MCF7/HA-PGRMC1组中,与E_(2)+安慰剂亚组相比,E_(2)+黄体酮亚组肿瘤增长差异无统计学意义(P>0.05),而E_(2)+NET亚组肿瘤明显生长(P<0.05)。在MCF7/HA-Vector组中,与E_(2)+安慰剂亚组相比,E_(2)+NET亚组、E_(2)+黄体酮亚组的肿瘤增长差异均无统计学意义(P>0.05)。在MCF7/HA-PGRMC1组中,E_(2)+NET亚组Ki67呈强阳性表达,PGRMC1与Ki67表达呈正相关(r=0.892,P=0.014)。结论该实验在裸鼠体内证实PGRMC1过表达可特异性介导NET联合E_(2)的促乳腺癌增殖效应,而联合黄体酮并没有促进额外增殖。这一发现为临床激素治疗中孕激素类型的选择提供了关键的动物实验依据。展开更多
Cancer is one of the leading causes of death in America, and there is an urgent need for new therapeutic approaches. The progesterone receptor membrane component 1 (PGRMC1) is a cytochrome b5 related protein that bind...Cancer is one of the leading causes of death in America, and there is an urgent need for new therapeutic approaches. The progesterone receptor membrane component 1 (PGRMC1) is a cytochrome b5 related protein that binds heme and is associated with signaling, apoptotic suppression and autophagy. PGRMC1 is essential for tumor formation, invasion and metastasis, and is upregulated in breast, colon, lung and thyroid tumors. In the present study, we have analyzed PGRMC1 levels in over 600 tumor sections, including a larger cohort of lung tumors than in previous studies, and report the first clinical analysis of PGRMC1 levels in human oral cavity and ovarian tumors compared to corresponding nonmalignant tissues. PGRMC1 was highly expressed in lung and ovarian cancers and correlated with patient survival. PGRMC1 has been previously associated with drug resistance, a characteristic of cancer stem cells. The stem cell theory proposes that a subset of cancerous stem cells contribute to drug resistance and tumor maintenance, and PGRMC1 was detected in lung-tumor derived stem cells. Drug treatment with a PGRMC1 inhibitor, AG-205, triggered stem cell death whereas treatment with erlotinib and the ERK inhibitor, PD98059, did not, suggesting a specific role for PGRMC1 in cancer stem cell viability. Together, our data demonstrate PGRMC1 as a potential tumor biomarker across a variety of tumors, as well as a therapeutic target for cancer stem cells.展开更多
文摘目的探究人乳腺癌裸鼠移植动物模型体内孕激素受体膜组分1(PGRMC1)在黄体酮与炔诺酮(NET)刺激下对乳腺癌异种移植瘤增殖影响的差异性。方法构建PGRMC1稳定表达的人乳腺癌细胞系(MCF7),36只雌性BALB/c-nu裸鼠按随机数字表法分为MCF7/HA-PGRMC1组(n=18)和MCF7/HA-Vector组(n=18)。各鼠于颈部皮下包埋雌二醇(E_(2))缓释片。24 h后两组裸鼠左、右侧面皮下分别注射MCF7/HA-PGRMC1和MCF7/HA-Vector细胞悬液150μL,注射细胞数为1×107个。肿瘤生长至100 mm 3左右,将两组裸鼠进行组内分组,分别皮下联合包埋安慰剂、黄体酮缓释片、NET缓释片,即E_(2)+安慰剂亚组(n=6)、E_(2)+黄体酮亚组(n=6)、E_(2)+NET亚组(n=6)。记录肿瘤体积变化,绘制肿瘤生长曲线。45 d后完整摘除肿瘤组织免疫组化染色检测PGRMC1和Ki67表达情况。结果MCF7/HA-PGRMC1株系构建成功,在MCF7/HA-PGRMC1组中,与E_(2)+安慰剂亚组相比,E_(2)+黄体酮亚组肿瘤增长差异无统计学意义(P>0.05),而E_(2)+NET亚组肿瘤明显生长(P<0.05)。在MCF7/HA-Vector组中,与E_(2)+安慰剂亚组相比,E_(2)+NET亚组、E_(2)+黄体酮亚组的肿瘤增长差异均无统计学意义(P>0.05)。在MCF7/HA-PGRMC1组中,E_(2)+NET亚组Ki67呈强阳性表达,PGRMC1与Ki67表达呈正相关(r=0.892,P=0.014)。结论该实验在裸鼠体内证实PGRMC1过表达可特异性介导NET联合E_(2)的促乳腺癌增殖效应,而联合黄体酮并没有促进额外增殖。这一发现为临床激素治疗中孕激素类型的选择提供了关键的动物实验依据。
文摘Cancer is one of the leading causes of death in America, and there is an urgent need for new therapeutic approaches. The progesterone receptor membrane component 1 (PGRMC1) is a cytochrome b5 related protein that binds heme and is associated with signaling, apoptotic suppression and autophagy. PGRMC1 is essential for tumor formation, invasion and metastasis, and is upregulated in breast, colon, lung and thyroid tumors. In the present study, we have analyzed PGRMC1 levels in over 600 tumor sections, including a larger cohort of lung tumors than in previous studies, and report the first clinical analysis of PGRMC1 levels in human oral cavity and ovarian tumors compared to corresponding nonmalignant tissues. PGRMC1 was highly expressed in lung and ovarian cancers and correlated with patient survival. PGRMC1 has been previously associated with drug resistance, a characteristic of cancer stem cells. The stem cell theory proposes that a subset of cancerous stem cells contribute to drug resistance and tumor maintenance, and PGRMC1 was detected in lung-tumor derived stem cells. Drug treatment with a PGRMC1 inhibitor, AG-205, triggered stem cell death whereas treatment with erlotinib and the ERK inhibitor, PD98059, did not, suggesting a specific role for PGRMC1 in cancer stem cell viability. Together, our data demonstrate PGRMC1 as a potential tumor biomarker across a variety of tumors, as well as a therapeutic target for cancer stem cells.
