Background:Obese individuals diagnosed with breast cancer often experience a less favorable prognosis;however,the underlying mechanisms linking obesity to breast cancer outcomes remain elusive.This study aimed to iden...Background:Obese individuals diagnosed with breast cancer often experience a less favorable prognosis;however,the underlying mechanisms linking obesity to breast cancer outcomes remain elusive.This study aimed to identify and validate novel prognostic markers associated with breast cancer in patients with obesity.Methods:We conducted a reanalysis of gene expression profiles from normal-weight,overweight,and obese breast cancer patients to identify candidate genes.Subsequently,we validated the protein levels of these candidates using immunohistochemistry.Finally,we investigated the association between candidate genes and breast cancer prognosis at Tongji Hospital,utilizing data from an 8-year follow-up through the Kaplan-Meier method and univariate and multivariate Cox regression models.Results:The fold change of the circadian clock gene period 2(PER2),which exhibited a declining trend with increasing body mass index,was 0.76 in obese patients compared with normal-weight patients.The expression rates of PER2 protein were 44.7%,51.5%,and 61.3%in normal-weight,overweight,and obese patients,respectively.The 8-year recurrence-free survival rates were 75.9%,69.6%,and 64.1%,whereas the 8-year overall survival rates were 86.8%,83.0%,and 76.1%in normal-weight,overweight,and obese patients,respectively(P<0.05).Furthermore,the 8-year recurrence-free survival rates were 66.2%and 76.4%,and the 8-year overall survival rates were 79.9%and 86.3%in the low and high PER2 expression groups,respectively(P<0.05).The unadjusted hazard ratio for PER2 was 1.550(95%confidence interval,1.029–2.335),and the adjusted hazard ratio was 3.003(95%confidence interval,1.838–4.907).Conclusions:Our findings indicate that low PER2 expression serves as an independent risk factor for breast cancer prognosis and may contribute to the unfavorable outcomes observed in obese patients.展开更多
Scope: Circadian disorder and high-fat diet(HFD)can disturb lipid metabolism homeostasis and may promote the development of various metabolic diseases. The relationship between them is of great concern. This study aim...Scope: Circadian disorder and high-fat diet(HFD)can disturb lipid metabolism homeostasis and may promote the development of various metabolic diseases. The relationship between them is of great concern. This study aimed to explore the effects of Per1/Per2 double knockout(DKO)on hepatic lipid metabolism in mice under HFD and HFD with docosahexaenoic acid(DHA)substitution. Methods and results: Both wild type(WT)and DKO male C57BL/6 mice were fed with normal chow diet(CON), HFD, or HFD with DHA substitution(AO)for 15 weeks. At the end of the experiment, mice were sacrificed at zeitgeber time(ZT)0(7:00 am)or ZT12(7:00 pm). Pathological indicators were determined using histological and biochemical methods. Hepatic transcriptome sequencing analysis showed that DKO mice exhibited multiple dysfunctions in diurnal rhythm, drug metabolism, cell cycle, cancer pathways, and lipid metabolism. HFD had greater effects on fatty acid oxidation and cholesterol synthesis and metabolism in Per1-/-Per2-/-mice, which was improved by DHA substitution. Conclusions: Per1/Per2 played an important role in the circadian regulation of hepatic lipid metabolism, and DKO mice were more sensitive to HFD. DHA can improve circadian-related lipid metabolism disruption induced by HFD in mice.展开更多
目的探讨钟基因Per2和钟控基因血管内皮生长因子(VEGF)、Ki67、c-Myc和P53在颊黏膜癌变不同阶段的昼夜节律变化规律以及与癌变发生发展的关系。方法 90只叙利亚金黄地鼠置于12 h光照和12 h黑暗交替环境中饲养,用二甲基苯并蒽(DMBA)涂抹...目的探讨钟基因Per2和钟控基因血管内皮生长因子(VEGF)、Ki67、c-Myc和P53在颊黏膜癌变不同阶段的昼夜节律变化规律以及与癌变发生发展的关系。方法 90只叙利亚金黄地鼠置于12 h光照和12 h黑暗交替环境中饲养,用二甲基苯并蒽(DMBA)涂抹颊黏膜建立金黄地鼠颊癌模型,分别在DMBA涂抹前,涂抹6周和14周后的24 h内的6个不同时间点处死动物,获取正常颊黏膜、癌前病变和癌症3个不同阶段昼夜6个不同时间的组织。经病理学检查确认后,采用实时荧光定量聚合酶链反应检测各时间点Per2、VEGF、Ki67、c-Myc和P53 m RNA的相对表达量,并行余弦分析,以中值、振幅和峰值位相时为指标反映各基因表达的昼夜节律特征。结果 Per2、VEGF、P53和c-Myc m RNA在癌变3个阶段的表达均具有昼夜节律性(P<0.05),而Ki67 m RNA仅在正常黏膜和癌前病变阶段的表达具有昼夜节律性(P<0.05)。Per2和P53 m RNA表达的中值随着癌症的发展而降低(P<0.05),VEGF、c-Myc和Ki67 m RNA表达的中值随着癌症的发展而上升(P<0.05);P53 m RNA的振幅随着癌症的发展而降低(P<0.05),Per2、VEGF、Ki67和c-Myc m RNA的振幅在癌前病变和癌症阶段均高于正常组(P<0.05);在癌前病变阶段,Per2、VEGF和c-Myc m RNA的峰值位相时较正常组提前,而Ki67和P53 m RNA的峰值位相时较正常组滞后。结论随着癌症的发生和发展,钟基因Per2和肿瘤相关钟控基因VEGF、Ki67、c-Myc、P53表达的昼夜节律特征发生明显改变。展开更多
目的探讨Period2(Per2)基因对细胞生长及放射敏感性的影响。方法体外培养C6神经胶质瘤细胞(C6g liom a ce lls),使用脂质体包裹法将Per2表达质粒(pcDNA3.1-Per2)转导入C6细胞内;以免疫组化及流式细胞术检测Per2表达;通过流式细胞术和克...目的探讨Period2(Per2)基因对细胞生长及放射敏感性的影响。方法体外培养C6神经胶质瘤细胞(C6g liom a ce lls),使用脂质体包裹法将Per2表达质粒(pcDNA3.1-Per2)转导入C6细胞内;以免疫组化及流式细胞术检测Per2表达;通过流式细胞术和克隆形成试验检测稳定转染Per2阳性表达的C6细胞在正常情况下和γ射线照射后的凋亡、生长。结果未经γ射线照射的Per2阳性表达的C6细胞较对照组细胞增殖减慢、凋亡率增加,但γ射线照射后的较对照组细胞增殖速度快、凋亡率减少。结论节律基因Per2过表达会增加肿瘤细胞的凋亡,但在射线照射情况下会降低肿瘤细胞对射线的敏感性。展开更多
文摘Background:Obese individuals diagnosed with breast cancer often experience a less favorable prognosis;however,the underlying mechanisms linking obesity to breast cancer outcomes remain elusive.This study aimed to identify and validate novel prognostic markers associated with breast cancer in patients with obesity.Methods:We conducted a reanalysis of gene expression profiles from normal-weight,overweight,and obese breast cancer patients to identify candidate genes.Subsequently,we validated the protein levels of these candidates using immunohistochemistry.Finally,we investigated the association between candidate genes and breast cancer prognosis at Tongji Hospital,utilizing data from an 8-year follow-up through the Kaplan-Meier method and univariate and multivariate Cox regression models.Results:The fold change of the circadian clock gene period 2(PER2),which exhibited a declining trend with increasing body mass index,was 0.76 in obese patients compared with normal-weight patients.The expression rates of PER2 protein were 44.7%,51.5%,and 61.3%in normal-weight,overweight,and obese patients,respectively.The 8-year recurrence-free survival rates were 75.9%,69.6%,and 64.1%,whereas the 8-year overall survival rates were 86.8%,83.0%,and 76.1%in normal-weight,overweight,and obese patients,respectively(P<0.05).Furthermore,the 8-year recurrence-free survival rates were 66.2%and 76.4%,and the 8-year overall survival rates were 79.9%and 86.3%in the low and high PER2 expression groups,respectively(P<0.05).The unadjusted hazard ratio for PER2 was 1.550(95%confidence interval,1.029–2.335),and the adjusted hazard ratio was 3.003(95%confidence interval,1.838–4.907).Conclusions:Our findings indicate that low PER2 expression serves as an independent risk factor for breast cancer prognosis and may contribute to the unfavorable outcomes observed in obese patients.
基金supported by National Natural Science Foundation of China (31271855)the ThirteenFifth Mega-Scientific Project (2017ZX10201301-003-003)+1 种基金Wuhan science and technology project (2018020402011230)the central government guides local science and technology development projects (2019ZYYD)。
文摘Scope: Circadian disorder and high-fat diet(HFD)can disturb lipid metabolism homeostasis and may promote the development of various metabolic diseases. The relationship between them is of great concern. This study aimed to explore the effects of Per1/Per2 double knockout(DKO)on hepatic lipid metabolism in mice under HFD and HFD with docosahexaenoic acid(DHA)substitution. Methods and results: Both wild type(WT)and DKO male C57BL/6 mice were fed with normal chow diet(CON), HFD, or HFD with DHA substitution(AO)for 15 weeks. At the end of the experiment, mice were sacrificed at zeitgeber time(ZT)0(7:00 am)or ZT12(7:00 pm). Pathological indicators were determined using histological and biochemical methods. Hepatic transcriptome sequencing analysis showed that DKO mice exhibited multiple dysfunctions in diurnal rhythm, drug metabolism, cell cycle, cancer pathways, and lipid metabolism. HFD had greater effects on fatty acid oxidation and cholesterol synthesis and metabolism in Per1-/-Per2-/-mice, which was improved by DHA substitution. Conclusions: Per1/Per2 played an important role in the circadian regulation of hepatic lipid metabolism, and DKO mice were more sensitive to HFD. DHA can improve circadian-related lipid metabolism disruption induced by HFD in mice.
文摘目的探讨钟基因Per2和钟控基因血管内皮生长因子(VEGF)、Ki67、c-Myc和P53在颊黏膜癌变不同阶段的昼夜节律变化规律以及与癌变发生发展的关系。方法 90只叙利亚金黄地鼠置于12 h光照和12 h黑暗交替环境中饲养,用二甲基苯并蒽(DMBA)涂抹颊黏膜建立金黄地鼠颊癌模型,分别在DMBA涂抹前,涂抹6周和14周后的24 h内的6个不同时间点处死动物,获取正常颊黏膜、癌前病变和癌症3个不同阶段昼夜6个不同时间的组织。经病理学检查确认后,采用实时荧光定量聚合酶链反应检测各时间点Per2、VEGF、Ki67、c-Myc和P53 m RNA的相对表达量,并行余弦分析,以中值、振幅和峰值位相时为指标反映各基因表达的昼夜节律特征。结果 Per2、VEGF、P53和c-Myc m RNA在癌变3个阶段的表达均具有昼夜节律性(P<0.05),而Ki67 m RNA仅在正常黏膜和癌前病变阶段的表达具有昼夜节律性(P<0.05)。Per2和P53 m RNA表达的中值随着癌症的发展而降低(P<0.05),VEGF、c-Myc和Ki67 m RNA表达的中值随着癌症的发展而上升(P<0.05);P53 m RNA的振幅随着癌症的发展而降低(P<0.05),Per2、VEGF、Ki67和c-Myc m RNA的振幅在癌前病变和癌症阶段均高于正常组(P<0.05);在癌前病变阶段,Per2、VEGF和c-Myc m RNA的峰值位相时较正常组提前,而Ki67和P53 m RNA的峰值位相时较正常组滞后。结论随着癌症的发生和发展,钟基因Per2和肿瘤相关钟控基因VEGF、Ki67、c-Myc、P53表达的昼夜节律特征发生明显改变。
文摘目的探讨Period2(Per2)基因对细胞生长及放射敏感性的影响。方法体外培养C6神经胶质瘤细胞(C6g liom a ce lls),使用脂质体包裹法将Per2表达质粒(pcDNA3.1-Per2)转导入C6细胞内;以免疫组化及流式细胞术检测Per2表达;通过流式细胞术和克隆形成试验检测稳定转染Per2阳性表达的C6细胞在正常情况下和γ射线照射后的凋亡、生长。结果未经γ射线照射的Per2阳性表达的C6细胞较对照组细胞增殖减慢、凋亡率增加,但γ射线照射后的较对照组细胞增殖速度快、凋亡率减少。结论节律基因Per2过表达会增加肿瘤细胞的凋亡,但在射线照射情况下会降低肿瘤细胞对射线的敏感性。
