脂联素与2型糖尿病乳腺癌发生的相关性及其机制研究

Association of adiponectin and breast cancer with type 2 diabetes mellitus and its mechanism

目的探讨脂联素与2型糖尿病(T2DM)患者乳腺癌发生的相关性及其可能机制。方法选取2016年1至6月于安徽医科大学第一附属医院甲状腺与乳腺外科住院的乳腺癌患者50例作为研究对象。按照是否合并T2DM将纳入患者分为合并T2DM的乳腺癌组(20例)以及单纯乳腺癌组(30例)。检测空腹血糖和胰岛素、血脂、总脂联素、高分子量脂联素水平,计算稳态模型评估胰岛素抵抗指数(HOMA-IR)。收集所有患者癌组织及癌旁乳腺组织,分为合并T2DM的乳腺癌癌组织组(DBCC组),合并T2DM的乳腺癌癌旁正常乳腺组织组(DBCN组),单纯乳腺癌癌组织组(BCC组)和单纯乳腺癌癌旁正常乳腺组织组(BCN组)。采用Western blot和实时定量逆转录聚合酶链反应检测上述四组中脂联素、晚期糖基化终产物受体(RAGE)、细胞周期蛋白D1(Cyclin D1)、核因子-κB(NF-κB)蛋白及mRNA表达水平。两组间差异的比较采用独立样本t检验,四组间组织学指标的比较采用单因素方差分析及两两比较的LSD-t检验。结果与单纯乳腺癌组患者相比,合并T2DM的乳腺癌组患者血清脂联素[分别为(5.35±1.22)和(7.29±1.90)mg/L]及高分子量脂联素水平[分别为(3.33±0.87)和(4.41±1.15)mg/L]降低,差异具有统计学意义(P<0.05)。血清脂联素及高分子量脂联素水平与HOMA-IR(r=-0.916、-0.950)和肿瘤大小(r=-0.896、-0.909)呈负相关(均P<0.01)。DBCC组RAGE蛋白表达量、NF-κB和Cyclin D1蛋白及mRNA表达量均高于BCC组及DBCN组(P<0.05),脂联素蛋白和mRNA表达量低于DBCN、BCC和BCN组(P<0.05)。相关分析显示,血清脂联素水平及乳腺癌组织中脂联素表达量均与RAGE、Cyclin D1、NF-κB表达水平呈负相关(r=-0.817~-0.447,P<0.05)。结论T2DM乳腺癌患者血清脂联素水平降低,癌组织脂联素表达水平下降,RAGE、Cyclin D1和NF-κB表达增高,脂联素可能通过调节RAGE-NF-κB-Cyclin D1信号通路调控T2DM患者乳腺癌的发生发展。

Objective To analyze the possible mechanism of adiponectin in the development of breast cancer patients with type 2 diabetes mellitus(T2DM).Methods A total of 50 breast cancer patients hospitalized in the Department of Thyroid and Breast Surgery of the First Affiliated Hospital of Anhui Medical University from January to June 2016 were selected in this study.According to whether or not combined with T2DM,the patients were divided into the breast cancer with T2DM group(20 cases)and the breast cancer without T2DM group(30 cases).The breast cancer tissue specimen of the diabetic breast cancer patients was classified as DBCC group,the normal breast tissue specimen of the diabetic breast cancer patients was classified as DBCN group,the breast cancer tissue specimen of the non-diabetic breast cancer patients was classified as BCC group,and the normal breast tissue specimen of the non-diabetic breast cancer patients was classified as BCN group.Fasting plasma glucose(FPG),fasting insulin(FINS),serum lipid,total adiponectin,and high molecular weight adiponectin were detected,and homeostasis model assessment of insulin resistance(HOMA-IR)was calculated.The expression of receptor for advanced glycation end products(RAGE),Cyclin D1 and NF-κB in the tissue specimens were detected by Western blot and quantitative reverse transcription polymerase chain reaction(qRT-PCR)in each group.Group differences were compared by independent-samples t test,and the histological indicators among the four groups were analyzed by analysis of variance(ANOVA)and the LSD-t test of pairwise comparison.Results Serum adiponectin[(5.35±1.22)vs(7.29±1.90)mg/L,respectively]and high molecular weight adiponectin[(3.33±0.87)vs(4.41±1.15)mg/L,respectively]in diabetic breast cancer patients were lower than those in non-diabetic breast cancer patients(P<0.05).The correlation analysis showed that serum adiponectin level and high molecular weight adiponectin level were negatively correlated with HOMA-IR(r=-0.916,-0.950,respectively,P<0.05)and tumor size(r=-0.896,-0.909,respectively,P<0.05).The expression of both protein and mRNA of RAGE,NF-κB,Cyclin D1 in DBCC group was higher than that in BCC group and DBCN group(P<0.05).The expression of adiponectin protein and mRNA in DBCC group was lower than that in DBCN group,BCC group and BCN group(P<0.05).Pearson correlation analysis showed that serum adiponectin level was negatively correlated with the expression of RAGE,Cyclin D1 and NF-κB(P<0.05).The expression of adiponectin in breast cancer tissue was negatively correlated with the expression of RAGE,NF-κB and Cyclin D1(P<0.05).Conclusions In the type 2 diabetic breast cancer patients,the serum adiponectin level decreased,the expression of adiponectin in cancer tissues decreased,while the expression of RAGE,Cyclin D1 and NF-κB increased.Adiponectin might play a role in the development of breast cancer patients with T2DM through RAGE-NF-κB-clyin D1 signaling pathway.