背景:2型糖尿病(T2D)增加了许多类型癌症的风险。蛋白酶体相关蛋白降解的失调导致肿瘤发生,而胰高血糖素样肽1受体(GLP-1R)激动剂Exendin-4,具有抗癌作用。
方法:我们探索了蛋白酶体α2亚基(PSMA2)和GLP-1R在癌症基因组图谱(TCGA)数据库和人类宫颈癌标本中的共表达,补充使用多种宫颈癌细胞系的体内和体外研究。
结果:在TCGA数据库中的12种癌症类型和T2D患者的宫颈癌标本中,PSMA2表达增加(T2D与非T2D:3.22(95%置信区间:1.38,5.05)vs1.00(0.66,1.34)倍变化,P=0.01)。psma2-shRNA在体外降低细胞增殖,以及体内肿瘤体积和Ki67表达。Exendin-4降低了psma2的表达,体内肿瘤体积和Ki67表达。TCGA数据库中12种癌症类型的GLP-1R表达没有变化。然而,GLP-1R表达(T2D与非T2D:5.49(3.0,8.1)vs1.00(0.5,1.5)倍变化,P<0.001)在T2D相关的宫颈癌标本中与PSMA2表达呈正相关(r=0.68),而在非T2D相关的宫颈癌标本中与PSMA2表达呈正相关。通过沉默glp-1r降低psma2表达的体外实验证实了这种相关性。Exendin-4减弱了NF-κB途径中磷酸p65和-IκB的表达。
结论:PSMA2和GLP-1R在T2D相关宫颈癌标本中的表达升高并呈正相关,提示高血糖可能通过增加PSMA2表达来促进癌症生长,而Exendin-4可以减弱PSMA2表达。
背景:该项目得到了博士后奖学金计划的支持,直接格兰特,香港中文大学糖尿病研究及教育基金。
BACKGROUND: Type 2 diabetes (T2D) increases the risk of many types of cancer. Dysregulation of proteasome-related protein degradation leads to tumorigenesis, while Exendin-4, a glucagon-like peptide 1 receptor (GLP-1R) agonist, possesses anti-cancer effects.
METHODS: We explored the co-expression of proteasome alpha 2 subunit (PSMA2) and GLP-1R in the Cancer Genome Atlas (TCGA) database and human cervical cancer specimens, supplemented by in vivo and in vitro studies using multiple cervical cancer cell lines.
RESULTS: PSMA2 expression was increased in 12 cancer types in TCGA database and cervical cancer specimens from patients with T2D (T2D vs non-T2D: 3.22 (95% confidence interval CI: 1.38, 5.05) vs 1.00 (0.66, 1.34) fold change, P = 0.01). psma2-shRNA decreased cell proliferation in vitro, and tumour volume and Ki67 expression in vivo. Exendin-4 decreased psma2 expression, tumour volume and Ki67 expression in vivo. There was no change in GLP-1R expression in 12 cancer types in TCGA database. However, GLP-1R expression (T2D vs non-T2D: 5.49 (3.0, 8.1) vs 1.00 (0.5, 1.5) fold change, P < 0.001) was increased and positively correlated with PSMA2 expression in T2D-related (r = 0.68) but not in non-T2D-related cervical cancer specimens. This correlation was corroborated by in vitro experiments where silencing glp-1r decreased psma2 expression. Exendin-4 attenuated phospho-p65 and -IκB expression in the NF-κB pathway.
CONCLUSIONS: PSMA2 and GLP-1R expression in T2D-related cervical cancer specimens was increased and positively correlated, suggesting hyperglycaemia might promote cancer growth by increasing PSMA2 expression which could be attenuated by Exendin-4.
BACKGROUND: This project was supported by Postdoctoral Fellowship Scheme, Direct Grant, Diabetes Research and Education Fund from the Chinese University of Hong Kong (CUHK).