HDL of Patients with Type 2 Diabetes Mellitus Elevates the Capability of Promoting Breast Cancer Metastasis
HDL of Patients with Type 2 Diabetes Mellitus Elevates the Capability of Promoting Breast Cancer Metastasis
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2型糖尿病患者HDL提高促进乳腺癌转移的能力
DOI：
10.1158/1078-0432.ccr-11-0817
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发表时间：
2012-03-01
影响因子：
11.5
通讯作者：
Zheng, Lemin
中科院分区：
文献类型：
--
作者：
Pan, Bing;Ren, Hui;Zheng, Lemin
目的：流行病学研究表明 2 型糖尿病与乳腺癌之间存在复杂的关联。高密度脂蛋白（HDL）与乳腺癌的风险和死亡率呈负相关。我们的研究旨在确定正常和糖尿病 HDL 对乳腺癌细胞转移的不同影响。实验设计：用 N-HDL、D-HDL、G-HDL 和 Ox-HDL 处理 MDA-MB-231 和 MCF7 细胞。使用尾静脉注射模型检查细胞转移效力，并在体外测定细胞对人脐静脉内皮细胞（HUVEC）和细胞外基质（ECM）的粘附能力。评估整合素表达和蛋白激酶C（PKC）活性，并应用PKC抑制剂。结果：D-HDL 显着促进细胞肺转移（注射 1 × 105 细胞的 MDA-MB-231 增加 103.6%，P < 0.001；注射 4 × 105 细胞的 MCF7 增加 157.1%，P < 0.05）和肝转移（注射 4 × 105 细胞的 MCF7 增加 18.1 倍，P < 0.001）与 N-HDL 相比，TC-HUVEC 粘附（MDA-MB-231 增加 21.9%，P < 0.001；MCF7 增加 23.6%，P < 0.05）和 TC-ECM 附着（MDA-MB-231 和 MCF7 分别增加 59.9% 和 47.9%，P < 0.01）。 D-HDL 刺激细胞表面更高的整合素（β1、β2、β3 和 αν）表达并诱导更高的 PKC 活性。 D-HDL、G-HDL 和 Ox-HDL 诱导的 TC-HUVEC 和 TC-ECM 粘附增加可被星形孢菌素抑制。结论：我们的研究表明，糖尿病患者HDL的糖化和氧化可能导致乳腺癌细胞与HUVECs和ECM的粘附异常，从而促进乳腺癌的转移进展。这将在很大程度上引起糖尿病合并乳腺癌患者基于 HDL 的治疗的关注。临床癌症研究； 18(5)； 1246–56。 ©2012 AACR。
Purpose: Epidemiologic studies suggested complicated associations between type 2 diabetes mellitus and breast cancer. High-density lipoprotein (HDL) is inversely associated with the risk and mortality of breast cancer. Our study is to determine the different effects of normal and diabetic HDL on breast cancer cell metastasis. Experimental Design: MDA-MB-231 and MCF7 cells were treated with N-HDL, D-HDL, G-HDL, and Ox-HDL. Cell metastasis potency was examined using a tail-vein injection model, and cell adhesion abilities to human umbilical vein endothelial cells (HUVEC) and extracellular matrix (ECM) were determined in vitro. Integrin expression and protein kinase C (PKC) activity were evaluated, and PKC inhibitor was applied. Results: D-HDL dramatically promoted cell pulmonary metastasis (103.6% increase at P < 0.001 for MDA-MB-231 with 1 × 105 cell injection; 157.1% increase at P < 0.05 for MCF7 with 4 × 105 cell injection) and hepatic metastasis (18.1-fold increase at P < 0.001 for MCF7 with 4 × 105 cell injection), and stimulated higher TC-HUVECs adhesion (21.9% increase at P < 0.001 for MDA-MB-231; 23.6% increase at P < 0.05 for MCF7) and TC-ECM attachment (59.9% and 47.9% increase, respectively, for MDA-MB-231 and MCF7, both at P < 0.01) compared with N-HDL. D-HDL stimulated higher integrin (β1, β2, β3, and αν) expression on cell surface and induced higher PKC activity. Increased TC-HUVECs and TC-ECM adhesion induced by D-HDL, G-HDL, and Ox-HDL could be inhibited by staurosporine. Conclusions: Our study showed that glycation and oxidation of HDL in diabetic patients could lead to abnormal actions on breast cancer cell adhesion to HUVECs and ECM, thereby promoting metastasis progression of breast cancer. This will largely draw the attention of HDL-based treatments in the diabetes patients with breast cancer. Clin Cancer Res; 18(5); 1246–56. ©2012 AACR.